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MRI matches standard biopsy at detecting significant prostate cancers
Men who dread the prospect of multicore prostate biopsies can take heart in the news that multiparametric MRI with or without targeted biopsy was noninferior to transrectal ultrasound at detecting clinically significant cancers, results of a multicenter randomized trial indicate.
The rate of clinically significant cancers detected in men with clinical suspicion of prostate cancer who were randomly assigned to undergo MRI was 38%, compared with 26% (P = .005) for men assigned to standard transrectal ultrasound guided biopsy with 10 or 12 biopsy cores, reported Veeru Kasivisvanathan, MRCS, of University College London, and colleagues in the PRECISION trial (Prostate Evaluation for Clinically Important Disease: Sampling Using Image-guidance or Not?).
Significantly fewer men assigned to MRI-targeted biopsy were diagnosed with clinically insignificant cancers, suggesting that MRI could help to reduce the number of invasive biopsies and the associated pain, discomfort, and infection risks, the investigators stated in the New England Journal of Medicine.
“MRI, with or without targeted biopsy, led to fewer men undergoing biopsy, more clinically significant cancers being identified, less overdetection of clinically insignificant cancer, and fewer biopsy cores being obtained than did standard transrectal ultrasonography-guided biopsy,” they wrote.
Multiparametric MRI combines several different imaging modalities, including standard T1- and T2-weighted scans with dynamic contrast–enhanced and/or diffusion-weighted imaging to provide a wealth of information to aid in diagnosis. The technique has been shown in single-center studies to be similar or superior to ultrasound guided biopsy at detecting clinically significant cancers and minimizing detection of cancers that turn out to be clinically insignificant, the investigators said.
To add to the body of evidence, investigators from 25 centers in 11 countries randomized a total of 500 men with clinical suspicion of prostate cancer and no history of prostate biopsy to undergo either MRI plus targeted biopsy (not 10- or 12-core biopsy) if the scans indicated suspicion of malignancy, or standard transrectal ultrasound-guided biopsy with 10 or 12 core samples.
The investigators defined clinically significant cancer as the presence of a single biopsy core indicating disease of Gleason score 3 plus 4 (Gleason sum of 7), or greater.
Of the 252 men assigned to MRI, 71 (28%) had results that did not suggest prostate cancer, and these men did not undergo biopsy.
As noted before, MRI was noninferior to standard ultrasound-guided biopsy. In the MRI group, 95 men (38%) were determined to have clinically significant tumors, compared with 64 of 248 men (26%) in the standard biopsy group.
Getting down into the statistical weeds, the lower boundary of the 95% confidence interval for the difference was greater than −5%, showing that MRI with or without targeted biopsy was noninferior to standard transrectal ultrasonography-guided biopsy for the detection of clinically significant cancers. In fact, the 95% confidence interval for the 12-point difference between the two techniques (95% confidence interval, 4-20) showed that MRI was superior to standard biopsy, the authors stated.
There were no health-related quality of life differences at either 24 hours or 30 days after the procedure, and immediate postintervention discomfort and pain were also similar between the groups. However, patient-reported complications were lower in patients assigned to MRI, including blood in urine (30% vs. 63% for standard biopsy), blood in semen (32% vs. 60%), procedural-site pain (13% vs. 23%), rectal bleeding (14% vs. 22%), and erectile dysfunction (11% vs. 16%).
“We found that a diagnostic pathway including risk assessment with MRI before biopsy and MRI-targeted biopsy in the presence of a lesion suggestive of cancer was superior to the diagnostic pathway of standard transrectal ultrasonography-guided biopsy,” Dr. Kasivisvanathan and his associates concluded.
The study was supported by awards to Dr. Kasivisvanathan from the U.K. National Institute for Health Research and by the European Association of Urology Research Foundation. He reported no other significant conflicts of interest to disclose.
SOURCE: Kasivisvanathan V et al. N Engl J Med. 2018 Mar 19. doi: 10.1056/NEJMoa1801993.
Men who dread the prospect of multicore prostate biopsies can take heart in the news that multiparametric MRI with or without targeted biopsy was noninferior to transrectal ultrasound at detecting clinically significant cancers, results of a multicenter randomized trial indicate.
The rate of clinically significant cancers detected in men with clinical suspicion of prostate cancer who were randomly assigned to undergo MRI was 38%, compared with 26% (P = .005) for men assigned to standard transrectal ultrasound guided biopsy with 10 or 12 biopsy cores, reported Veeru Kasivisvanathan, MRCS, of University College London, and colleagues in the PRECISION trial (Prostate Evaluation for Clinically Important Disease: Sampling Using Image-guidance or Not?).
Significantly fewer men assigned to MRI-targeted biopsy were diagnosed with clinically insignificant cancers, suggesting that MRI could help to reduce the number of invasive biopsies and the associated pain, discomfort, and infection risks, the investigators stated in the New England Journal of Medicine.
“MRI, with or without targeted biopsy, led to fewer men undergoing biopsy, more clinically significant cancers being identified, less overdetection of clinically insignificant cancer, and fewer biopsy cores being obtained than did standard transrectal ultrasonography-guided biopsy,” they wrote.
Multiparametric MRI combines several different imaging modalities, including standard T1- and T2-weighted scans with dynamic contrast–enhanced and/or diffusion-weighted imaging to provide a wealth of information to aid in diagnosis. The technique has been shown in single-center studies to be similar or superior to ultrasound guided biopsy at detecting clinically significant cancers and minimizing detection of cancers that turn out to be clinically insignificant, the investigators said.
To add to the body of evidence, investigators from 25 centers in 11 countries randomized a total of 500 men with clinical suspicion of prostate cancer and no history of prostate biopsy to undergo either MRI plus targeted biopsy (not 10- or 12-core biopsy) if the scans indicated suspicion of malignancy, or standard transrectal ultrasound-guided biopsy with 10 or 12 core samples.
The investigators defined clinically significant cancer as the presence of a single biopsy core indicating disease of Gleason score 3 plus 4 (Gleason sum of 7), or greater.
Of the 252 men assigned to MRI, 71 (28%) had results that did not suggest prostate cancer, and these men did not undergo biopsy.
As noted before, MRI was noninferior to standard ultrasound-guided biopsy. In the MRI group, 95 men (38%) were determined to have clinically significant tumors, compared with 64 of 248 men (26%) in the standard biopsy group.
Getting down into the statistical weeds, the lower boundary of the 95% confidence interval for the difference was greater than −5%, showing that MRI with or without targeted biopsy was noninferior to standard transrectal ultrasonography-guided biopsy for the detection of clinically significant cancers. In fact, the 95% confidence interval for the 12-point difference between the two techniques (95% confidence interval, 4-20) showed that MRI was superior to standard biopsy, the authors stated.
There were no health-related quality of life differences at either 24 hours or 30 days after the procedure, and immediate postintervention discomfort and pain were also similar between the groups. However, patient-reported complications were lower in patients assigned to MRI, including blood in urine (30% vs. 63% for standard biopsy), blood in semen (32% vs. 60%), procedural-site pain (13% vs. 23%), rectal bleeding (14% vs. 22%), and erectile dysfunction (11% vs. 16%).
“We found that a diagnostic pathway including risk assessment with MRI before biopsy and MRI-targeted biopsy in the presence of a lesion suggestive of cancer was superior to the diagnostic pathway of standard transrectal ultrasonography-guided biopsy,” Dr. Kasivisvanathan and his associates concluded.
The study was supported by awards to Dr. Kasivisvanathan from the U.K. National Institute for Health Research and by the European Association of Urology Research Foundation. He reported no other significant conflicts of interest to disclose.
SOURCE: Kasivisvanathan V et al. N Engl J Med. 2018 Mar 19. doi: 10.1056/NEJMoa1801993.
Men who dread the prospect of multicore prostate biopsies can take heart in the news that multiparametric MRI with or without targeted biopsy was noninferior to transrectal ultrasound at detecting clinically significant cancers, results of a multicenter randomized trial indicate.
The rate of clinically significant cancers detected in men with clinical suspicion of prostate cancer who were randomly assigned to undergo MRI was 38%, compared with 26% (P = .005) for men assigned to standard transrectal ultrasound guided biopsy with 10 or 12 biopsy cores, reported Veeru Kasivisvanathan, MRCS, of University College London, and colleagues in the PRECISION trial (Prostate Evaluation for Clinically Important Disease: Sampling Using Image-guidance or Not?).
Significantly fewer men assigned to MRI-targeted biopsy were diagnosed with clinically insignificant cancers, suggesting that MRI could help to reduce the number of invasive biopsies and the associated pain, discomfort, and infection risks, the investigators stated in the New England Journal of Medicine.
“MRI, with or without targeted biopsy, led to fewer men undergoing biopsy, more clinically significant cancers being identified, less overdetection of clinically insignificant cancer, and fewer biopsy cores being obtained than did standard transrectal ultrasonography-guided biopsy,” they wrote.
Multiparametric MRI combines several different imaging modalities, including standard T1- and T2-weighted scans with dynamic contrast–enhanced and/or diffusion-weighted imaging to provide a wealth of information to aid in diagnosis. The technique has been shown in single-center studies to be similar or superior to ultrasound guided biopsy at detecting clinically significant cancers and minimizing detection of cancers that turn out to be clinically insignificant, the investigators said.
To add to the body of evidence, investigators from 25 centers in 11 countries randomized a total of 500 men with clinical suspicion of prostate cancer and no history of prostate biopsy to undergo either MRI plus targeted biopsy (not 10- or 12-core biopsy) if the scans indicated suspicion of malignancy, or standard transrectal ultrasound-guided biopsy with 10 or 12 core samples.
The investigators defined clinically significant cancer as the presence of a single biopsy core indicating disease of Gleason score 3 plus 4 (Gleason sum of 7), or greater.
Of the 252 men assigned to MRI, 71 (28%) had results that did not suggest prostate cancer, and these men did not undergo biopsy.
As noted before, MRI was noninferior to standard ultrasound-guided biopsy. In the MRI group, 95 men (38%) were determined to have clinically significant tumors, compared with 64 of 248 men (26%) in the standard biopsy group.
Getting down into the statistical weeds, the lower boundary of the 95% confidence interval for the difference was greater than −5%, showing that MRI with or without targeted biopsy was noninferior to standard transrectal ultrasonography-guided biopsy for the detection of clinically significant cancers. In fact, the 95% confidence interval for the 12-point difference between the two techniques (95% confidence interval, 4-20) showed that MRI was superior to standard biopsy, the authors stated.
There were no health-related quality of life differences at either 24 hours or 30 days after the procedure, and immediate postintervention discomfort and pain were also similar between the groups. However, patient-reported complications were lower in patients assigned to MRI, including blood in urine (30% vs. 63% for standard biopsy), blood in semen (32% vs. 60%), procedural-site pain (13% vs. 23%), rectal bleeding (14% vs. 22%), and erectile dysfunction (11% vs. 16%).
“We found that a diagnostic pathway including risk assessment with MRI before biopsy and MRI-targeted biopsy in the presence of a lesion suggestive of cancer was superior to the diagnostic pathway of standard transrectal ultrasonography-guided biopsy,” Dr. Kasivisvanathan and his associates concluded.
The study was supported by awards to Dr. Kasivisvanathan from the U.K. National Institute for Health Research and by the European Association of Urology Research Foundation. He reported no other significant conflicts of interest to disclose.
SOURCE: Kasivisvanathan V et al. N Engl J Med. 2018 Mar 19. doi: 10.1056/NEJMoa1801993.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Clinically significant cancers were detected in 38% of men on MRI vs. 26% on standard biopsy (P = .005).
Study details: A randomized noninferiority trial in 500 men with clinical suspicion of prostate cancer.
Disclosures: The study was supported by awards to Dr. Kasivisvanathan from the U.K. National Institute for Health Research and by the European Association of Urology Research Foundation. He reported no other significant conflicts of interest to disclose.
Source: Kasivisvanathan V et al. N Engl J Med. 2018 Mar 19. doi: 10.1056/NEJMoa1801993.
Protons linked to lower urinary AEs, higher costs than with IMRT for prostate cancer
Among men younger than 65 with prostate cancer, proton beam radiotherapy (PBT) was associated with significantly lower rates of urinary toxicities than was intensity-modulated radiotherapy (IMRT), but this safety advantage came at the cost of nearly $60,000 extra per patient, results of an insurance claims study show.
The rate of a composite of urinary toxicities at 2 years among 693 men treated with PBT was 33%, compared with 42% for 3,465 men matched by propensity score who were treated with IMRT. Respective rates of erectile dysfunction were 21% vs. 28%. The mean cost for PBT, however, was nearly double that for IMRT, reported Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
Although PBT was better at sparing patients from urinary toxicities, it was associated with increased bowel toxicities, and a second comparison of IMRT with stereotactic body radiotherapy (SBRT) showed that SBRT, while slightly cheaper than IMRT, was associated with modest increases in some urinary toxicities, the researchers reported in a study published online in the Journal of Clinical Oncology.
“These key findings, coupled with the real-world private insurance cost reported herein, will be useful for patients selecting the most appropriate treatment and for researchers designing cost-effectiveness models to guide treatment decisions in prostate cancer,” they wrote.
The investigators combed through the MarketScan Commercial Claims and Encounters database to identify men who underwent radiation therapy for prostate cancer between 2008 and 2015. They used propensity-score matching, a technique designed to even out potential confounding factors, to compare those treated with IMRT with others treated with PBT or SBRT.
As noted, PBT was associated with significantly lower urinary toxicities and erectile dysfunction compared with IMRT (P less than .001 for each comparison), but with a higher rate of bowel toxicities at 2 years (20% vs. 15%, P = .02).
The mean cost per patient in 2015 dollars for PBT was $115,501, compared with $59,012 for IMRT.
In a comparison of outcomes and costs for 310 patients who underwent SBRT matched with 3,100 who underwent IMRT, the investigators found no significant differences in composite urinary, erectile dysfunction, or bowel toxicities. However, the risk of urinary fistula, while low, was significantly higher with SBRT compared with IMRT, with rates of 1% vs. 0.1%, respectively (P = .009).
The mean cost of SBRT in this analysis was $49,504, compared with $57,244 for IMRT (P less than .001).
The investigators acknowledged that by using claims data they were unable to plug information about potential confounding factors such as Gleason score, prostate-specific antigen level, clinical stage, or radiation field and dose into their propensity-score models. They also noted that follow-up was relatively short because of the vicissitudes of the U.S. insurance market, which causes many patients to change insurers frequently.
The study was supported by grants from the National Cancer Institute and by Varian Medical Systems. Dr. Smith, lead author Hubert Y. Pan, MD, and others disclosed research support, consulting, and/or travel support from Varian.
SOURCE: Smith BD et al. J Clin Oncol. 2018 Mar 21. doi: 10.1200/JCO.2017.75.5371.
Among men younger than 65 with prostate cancer, proton beam radiotherapy (PBT) was associated with significantly lower rates of urinary toxicities than was intensity-modulated radiotherapy (IMRT), but this safety advantage came at the cost of nearly $60,000 extra per patient, results of an insurance claims study show.
The rate of a composite of urinary toxicities at 2 years among 693 men treated with PBT was 33%, compared with 42% for 3,465 men matched by propensity score who were treated with IMRT. Respective rates of erectile dysfunction were 21% vs. 28%. The mean cost for PBT, however, was nearly double that for IMRT, reported Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
Although PBT was better at sparing patients from urinary toxicities, it was associated with increased bowel toxicities, and a second comparison of IMRT with stereotactic body radiotherapy (SBRT) showed that SBRT, while slightly cheaper than IMRT, was associated with modest increases in some urinary toxicities, the researchers reported in a study published online in the Journal of Clinical Oncology.
“These key findings, coupled with the real-world private insurance cost reported herein, will be useful for patients selecting the most appropriate treatment and for researchers designing cost-effectiveness models to guide treatment decisions in prostate cancer,” they wrote.
The investigators combed through the MarketScan Commercial Claims and Encounters database to identify men who underwent radiation therapy for prostate cancer between 2008 and 2015. They used propensity-score matching, a technique designed to even out potential confounding factors, to compare those treated with IMRT with others treated with PBT or SBRT.
As noted, PBT was associated with significantly lower urinary toxicities and erectile dysfunction compared with IMRT (P less than .001 for each comparison), but with a higher rate of bowel toxicities at 2 years (20% vs. 15%, P = .02).
The mean cost per patient in 2015 dollars for PBT was $115,501, compared with $59,012 for IMRT.
In a comparison of outcomes and costs for 310 patients who underwent SBRT matched with 3,100 who underwent IMRT, the investigators found no significant differences in composite urinary, erectile dysfunction, or bowel toxicities. However, the risk of urinary fistula, while low, was significantly higher with SBRT compared with IMRT, with rates of 1% vs. 0.1%, respectively (P = .009).
The mean cost of SBRT in this analysis was $49,504, compared with $57,244 for IMRT (P less than .001).
The investigators acknowledged that by using claims data they were unable to plug information about potential confounding factors such as Gleason score, prostate-specific antigen level, clinical stage, or radiation field and dose into their propensity-score models. They also noted that follow-up was relatively short because of the vicissitudes of the U.S. insurance market, which causes many patients to change insurers frequently.
The study was supported by grants from the National Cancer Institute and by Varian Medical Systems. Dr. Smith, lead author Hubert Y. Pan, MD, and others disclosed research support, consulting, and/or travel support from Varian.
SOURCE: Smith BD et al. J Clin Oncol. 2018 Mar 21. doi: 10.1200/JCO.2017.75.5371.
Among men younger than 65 with prostate cancer, proton beam radiotherapy (PBT) was associated with significantly lower rates of urinary toxicities than was intensity-modulated radiotherapy (IMRT), but this safety advantage came at the cost of nearly $60,000 extra per patient, results of an insurance claims study show.
The rate of a composite of urinary toxicities at 2 years among 693 men treated with PBT was 33%, compared with 42% for 3,465 men matched by propensity score who were treated with IMRT. Respective rates of erectile dysfunction were 21% vs. 28%. The mean cost for PBT, however, was nearly double that for IMRT, reported Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
Although PBT was better at sparing patients from urinary toxicities, it was associated with increased bowel toxicities, and a second comparison of IMRT with stereotactic body radiotherapy (SBRT) showed that SBRT, while slightly cheaper than IMRT, was associated with modest increases in some urinary toxicities, the researchers reported in a study published online in the Journal of Clinical Oncology.
“These key findings, coupled with the real-world private insurance cost reported herein, will be useful for patients selecting the most appropriate treatment and for researchers designing cost-effectiveness models to guide treatment decisions in prostate cancer,” they wrote.
The investigators combed through the MarketScan Commercial Claims and Encounters database to identify men who underwent radiation therapy for prostate cancer between 2008 and 2015. They used propensity-score matching, a technique designed to even out potential confounding factors, to compare those treated with IMRT with others treated with PBT or SBRT.
As noted, PBT was associated with significantly lower urinary toxicities and erectile dysfunction compared with IMRT (P less than .001 for each comparison), but with a higher rate of bowel toxicities at 2 years (20% vs. 15%, P = .02).
The mean cost per patient in 2015 dollars for PBT was $115,501, compared with $59,012 for IMRT.
In a comparison of outcomes and costs for 310 patients who underwent SBRT matched with 3,100 who underwent IMRT, the investigators found no significant differences in composite urinary, erectile dysfunction, or bowel toxicities. However, the risk of urinary fistula, while low, was significantly higher with SBRT compared with IMRT, with rates of 1% vs. 0.1%, respectively (P = .009).
The mean cost of SBRT in this analysis was $49,504, compared with $57,244 for IMRT (P less than .001).
The investigators acknowledged that by using claims data they were unable to plug information about potential confounding factors such as Gleason score, prostate-specific antigen level, clinical stage, or radiation field and dose into their propensity-score models. They also noted that follow-up was relatively short because of the vicissitudes of the U.S. insurance market, which causes many patients to change insurers frequently.
The study was supported by grants from the National Cancer Institute and by Varian Medical Systems. Dr. Smith, lead author Hubert Y. Pan, MD, and others disclosed research support, consulting, and/or travel support from Varian.
SOURCE: Smith BD et al. J Clin Oncol. 2018 Mar 21. doi: 10.1200/JCO.2017.75.5371.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Proton beam therapy is nearly twice as costly as intensity-modulated radiation for prostate cancer.
Major finding: Proton therapy was associated with a 9% lower incidence of urinary toxicities, but at a significantly greater cost than IMRT.
Study details: Retrospective claims data study of 693 men treated with protons compared with 3,465 propensity-matched men treated with IMRT, and 310 men treated with SBRT vs. 3,100 matched men treated with IMRT.
Disclosures: The study was supported by grants from the National Cancer Institute and by Varian Medical Systems. Dr. Smith, lead author Hubert Y. Pan, MD, and others disclosed research support, consulting, and/or travel support from Varian.
Source: Smith BD et al. J Clin Oncol. 2018 Mar 21. doi: 10.1200/JCO.2017.75.5371.
Dose-escalated radiation therapy brings mixed results in prostate cancer
Dose-escalated radiation therapy reduced the need for subsequent therapy in patients with intermediate-risk prostate cancer but did not improve overall survival, according to results of a large, randomized clinical trial.
The absence of a survival benefit compared with standard radiation therapy was seen despite a reduction in rates of both biochemical failure and distant metastases, Jeff M. Michalski, MD, and his associates reported in JAMA Oncology.
Negative overall survival results may be attributable to the growing availability of systemic salvage therapies that have prolonged the natural history of this disease, said Dr. Michalski, MD, of the department of radiation oncology at Washington University in St. Louis.
“Patients experiencing a biochemical or clinical failure may go on to receive several life-prolonging systemic agents, which may negate any clinical advantage from a more effective primary local therapy,” Dr. Michalski and associates wrote.
Results of the study support that hypothesis. Patients who received the standard dose radiotherapy were significantly more likely to go on to salvage therapy, compared with patients in the dose-escalation arm.
Dr. Michalski and his associated reported on the randomized NRG Oncology/RTOG 0126 clinical trial, which included 1,532 patients with intermediate-risk cancer enrolled between March 2002 and August 2008 at one of 104 North American sites.
In the trial, patients with intermediate-risk prostate cancer were randomized to receive three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions, the study said.
With a median follow-up of 8.4 years for 1,499 patients, there was no difference in overall survival between arms, study results show. The 8-year rates of overall survival were 76% for dose-escalated radiotherapy and 75% for standard radiotherapy (hazard ratio, 1.00; 95% confidence interval, 0.83-1.20; P = .98).
Otherwise, patients in the dose-escalated radiotherapy arm had significantly lower rates of distant metastases (4% vs. 6%; P = 0.05), and lower rates of biochemical failure rates at both 5 and 8 years, investigators said.
Patients in the high-dose arm less often went on to salvage therapy; however, investigators noted that they also had more toxic effects. compared with patients in the standard radiotherapy arm.
“,” Dr. Michalski and his associates wrote.
Dr. Michalski reported no conflicts of interest. The co-authors reported several conflicts of interest, including ties to ViewRay, Augmenix, Sanofi, AstraZeneca, AbbVie, and other companies.
op@frontlinemedcom.com
SOURCE: Michalsky Jeff M et al. JAMA Oncol. 2018 Mar 15. doi: 10.1001/jamaoncol.2018.0039.
Dose-escalated radiation therapy reduced the need for subsequent therapy in patients with intermediate-risk prostate cancer but did not improve overall survival, according to results of a large, randomized clinical trial.
The absence of a survival benefit compared with standard radiation therapy was seen despite a reduction in rates of both biochemical failure and distant metastases, Jeff M. Michalski, MD, and his associates reported in JAMA Oncology.
Negative overall survival results may be attributable to the growing availability of systemic salvage therapies that have prolonged the natural history of this disease, said Dr. Michalski, MD, of the department of radiation oncology at Washington University in St. Louis.
“Patients experiencing a biochemical or clinical failure may go on to receive several life-prolonging systemic agents, which may negate any clinical advantage from a more effective primary local therapy,” Dr. Michalski and associates wrote.
Results of the study support that hypothesis. Patients who received the standard dose radiotherapy were significantly more likely to go on to salvage therapy, compared with patients in the dose-escalation arm.
Dr. Michalski and his associated reported on the randomized NRG Oncology/RTOG 0126 clinical trial, which included 1,532 patients with intermediate-risk cancer enrolled between March 2002 and August 2008 at one of 104 North American sites.
In the trial, patients with intermediate-risk prostate cancer were randomized to receive three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions, the study said.
With a median follow-up of 8.4 years for 1,499 patients, there was no difference in overall survival between arms, study results show. The 8-year rates of overall survival were 76% for dose-escalated radiotherapy and 75% for standard radiotherapy (hazard ratio, 1.00; 95% confidence interval, 0.83-1.20; P = .98).
Otherwise, patients in the dose-escalated radiotherapy arm had significantly lower rates of distant metastases (4% vs. 6%; P = 0.05), and lower rates of biochemical failure rates at both 5 and 8 years, investigators said.
Patients in the high-dose arm less often went on to salvage therapy; however, investigators noted that they also had more toxic effects. compared with patients in the standard radiotherapy arm.
“,” Dr. Michalski and his associates wrote.
Dr. Michalski reported no conflicts of interest. The co-authors reported several conflicts of interest, including ties to ViewRay, Augmenix, Sanofi, AstraZeneca, AbbVie, and other companies.
op@frontlinemedcom.com
SOURCE: Michalsky Jeff M et al. JAMA Oncol. 2018 Mar 15. doi: 10.1001/jamaoncol.2018.0039.
Dose-escalated radiation therapy reduced the need for subsequent therapy in patients with intermediate-risk prostate cancer but did not improve overall survival, according to results of a large, randomized clinical trial.
The absence of a survival benefit compared with standard radiation therapy was seen despite a reduction in rates of both biochemical failure and distant metastases, Jeff M. Michalski, MD, and his associates reported in JAMA Oncology.
Negative overall survival results may be attributable to the growing availability of systemic salvage therapies that have prolonged the natural history of this disease, said Dr. Michalski, MD, of the department of radiation oncology at Washington University in St. Louis.
“Patients experiencing a biochemical or clinical failure may go on to receive several life-prolonging systemic agents, which may negate any clinical advantage from a more effective primary local therapy,” Dr. Michalski and associates wrote.
Results of the study support that hypothesis. Patients who received the standard dose radiotherapy were significantly more likely to go on to salvage therapy, compared with patients in the dose-escalation arm.
Dr. Michalski and his associated reported on the randomized NRG Oncology/RTOG 0126 clinical trial, which included 1,532 patients with intermediate-risk cancer enrolled between March 2002 and August 2008 at one of 104 North American sites.
In the trial, patients with intermediate-risk prostate cancer were randomized to receive three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions, the study said.
With a median follow-up of 8.4 years for 1,499 patients, there was no difference in overall survival between arms, study results show. The 8-year rates of overall survival were 76% for dose-escalated radiotherapy and 75% for standard radiotherapy (hazard ratio, 1.00; 95% confidence interval, 0.83-1.20; P = .98).
Otherwise, patients in the dose-escalated radiotherapy arm had significantly lower rates of distant metastases (4% vs. 6%; P = 0.05), and lower rates of biochemical failure rates at both 5 and 8 years, investigators said.
Patients in the high-dose arm less often went on to salvage therapy; however, investigators noted that they also had more toxic effects. compared with patients in the standard radiotherapy arm.
“,” Dr. Michalski and his associates wrote.
Dr. Michalski reported no conflicts of interest. The co-authors reported several conflicts of interest, including ties to ViewRay, Augmenix, Sanofi, AstraZeneca, AbbVie, and other companies.
op@frontlinemedcom.com
SOURCE: Michalsky Jeff M et al. JAMA Oncol. 2018 Mar 15. doi: 10.1001/jamaoncol.2018.0039.
FROM JAMA ONCOLOGY
Key clinical point: Despite reducing the need for subsequent therapy, dose-escalated radiation therapy for intermediate-risk prostate cancer did not improve overall survival.
Major finding: Eight-year overall survival rates were 76% for dose-escalated radiation therapy, compared with 75% for standard radiation therapy (P = 0.98).
Study details: The randomized NRG Oncology/RTOG 0126 clinical trial including 1,532 patients enrolled between March 2002 and August 2008 at one of 104 North American sites.
Disclosures: Dr. Michalsky reported no conflicts of interest. The study authors disclosed conflicts tied to several companies, including ViewRay, Augmenix, Sanofi, AstraZeneca, and AbbVie.
Source: Michalsky Jeff M et al. JAMA Oncol. 2018 Mar 15. doi: 10.1001/jamaoncol.2018.0039.
Emerging data help inform immunotherapy for urothelial cancer
SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.
An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.
Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.
Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“It is clear that PD-1 and PD-L1 targeted immunotherapy now has a role in most patients with advanced urothelial cancer,” Robert J. Jones, MBChB, PhD, professor of clinical cancer research, University of Glasgow, Beatson West of Scotland Cancer Centre, commented in an invited discussion. “It is also true that cytotoxic chemotherapy maintains a role for many, and that both modalities are often ineffective and may be toxic.”
KEYNOTE-045 trial update
Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).
Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.
Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).
Median overall survival was 10.3 months and 7.3 months, respectively. Corresponding 1-year survival rates were 44.4% and 29.8%, and corresponding 2-year survival rates, 27.0% and 14.3%.
At 24 months, 60.6% of patients in the chemotherapy arm had received an immunotherapy agent, including some who had received pembrolizumab as part of crossover, Dr. Bellmunt noted.
Overall survival benefit was generally similar across subgroups, including patients with PD-L1–positive tumors (defined as a combined positive score of 10% or higher) (HR, 0.56; P = .00153) and patients with PD-L1–negative tumors (HR, 0.75; P = .00859).
The lack of a progression-free survival benefit of pembrolizumab over chemotherapy in the initial analysis (HR, 0.98; P = .420) persisted in the updated analysis (HR, 0.96; P = .317).
The overall response rate now was 21.1% with pembrolizumab and 11.0% with chemotherapy. In the former group, the rate of complete response had increased from 7.0% to 9.3% with the longer follow-up. Median time to response was identical, at 2.1 months, but duration of response was longer with pembrolizumab (not reached vs. 4.4 months).
“We haven’t seen any signals of cumulative toxicity with subsequent follow-up,” Dr. Bellmunt reported. Similar to findings of the initial analysis, the most common grade 3-5 treatment-related adverse events were pruritus, fatigue, and diarrhea with pembrolizumab, and neutropenia, anemia, and fatigue with chemotherapy. As expected, the pembrolizumab group had higher rates of hypothyroidism, pneumonitis, hyperthyroidism, and colitis.
“The overall survival benefit and superior safety of pembrolizumab versus chemotherapy in this second-line patient population is maintained after 2 years of follow-up. At 24 months, 27% of patients are alive, and this is similar to what we are seeing with other immune-sensitive diseases like melanoma,” he concluded. “Results in patients with PD-L1–positive or –negative tumors were consistent with the intent-to-treat population. We have seen some hints with this biomarker, but they are not very striking.”
IMvigor 211 trial biomarker analyses
The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.
At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).
Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.
“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.
Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.
However, a different pattern was seen with tumor mutational burden (TMB), a FoundationOne panel. Patients with TMB-high tumors had a substantial gain in overall survival from atezolizumab versus chemotherapy (HR, 0.68; 95% CI, 0.51-0.90), whereas those with TMB-low tumors did not (HR, 1.00; 95% CI, 0.75-1.32).
“TMB appears to be a predictive but not a prognostic biomarker,” Dr. Powles said. “It’s not perfect. Complete and partial responses and long overall survival were seen in both arms. Nevertheless, it seems like a step in the right direction.”
Finally, with insight on the nature and relationships of the various biomarkers, the investigators assessed the combination of TMB with PD-L1, finding that atezolizumab had a marked overall survival benefit in patients with TMB-high and PD-L1–positive tumors (17.8 vs. 10.6 months; HR, 0.50; 95% CI, 0.29-0.86).
“I think by using combinations of biomarkers, first-generation and second-generation, we may actually be able to better select patients for treatment in the future,” Dr. Powles concluded.
New data, new insights
“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”
The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”
Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.
Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.
“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.
Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”
Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.
“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”
“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”
SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.
SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.
An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.
Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.
Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“It is clear that PD-1 and PD-L1 targeted immunotherapy now has a role in most patients with advanced urothelial cancer,” Robert J. Jones, MBChB, PhD, professor of clinical cancer research, University of Glasgow, Beatson West of Scotland Cancer Centre, commented in an invited discussion. “It is also true that cytotoxic chemotherapy maintains a role for many, and that both modalities are often ineffective and may be toxic.”
KEYNOTE-045 trial update
Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).
Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.
Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).
Median overall survival was 10.3 months and 7.3 months, respectively. Corresponding 1-year survival rates were 44.4% and 29.8%, and corresponding 2-year survival rates, 27.0% and 14.3%.
At 24 months, 60.6% of patients in the chemotherapy arm had received an immunotherapy agent, including some who had received pembrolizumab as part of crossover, Dr. Bellmunt noted.
Overall survival benefit was generally similar across subgroups, including patients with PD-L1–positive tumors (defined as a combined positive score of 10% or higher) (HR, 0.56; P = .00153) and patients with PD-L1–negative tumors (HR, 0.75; P = .00859).
The lack of a progression-free survival benefit of pembrolizumab over chemotherapy in the initial analysis (HR, 0.98; P = .420) persisted in the updated analysis (HR, 0.96; P = .317).
The overall response rate now was 21.1% with pembrolizumab and 11.0% with chemotherapy. In the former group, the rate of complete response had increased from 7.0% to 9.3% with the longer follow-up. Median time to response was identical, at 2.1 months, but duration of response was longer with pembrolizumab (not reached vs. 4.4 months).
“We haven’t seen any signals of cumulative toxicity with subsequent follow-up,” Dr. Bellmunt reported. Similar to findings of the initial analysis, the most common grade 3-5 treatment-related adverse events were pruritus, fatigue, and diarrhea with pembrolizumab, and neutropenia, anemia, and fatigue with chemotherapy. As expected, the pembrolizumab group had higher rates of hypothyroidism, pneumonitis, hyperthyroidism, and colitis.
“The overall survival benefit and superior safety of pembrolizumab versus chemotherapy in this second-line patient population is maintained after 2 years of follow-up. At 24 months, 27% of patients are alive, and this is similar to what we are seeing with other immune-sensitive diseases like melanoma,” he concluded. “Results in patients with PD-L1–positive or –negative tumors were consistent with the intent-to-treat population. We have seen some hints with this biomarker, but they are not very striking.”
IMvigor 211 trial biomarker analyses
The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.
At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).
Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.
“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.
Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.
However, a different pattern was seen with tumor mutational burden (TMB), a FoundationOne panel. Patients with TMB-high tumors had a substantial gain in overall survival from atezolizumab versus chemotherapy (HR, 0.68; 95% CI, 0.51-0.90), whereas those with TMB-low tumors did not (HR, 1.00; 95% CI, 0.75-1.32).
“TMB appears to be a predictive but not a prognostic biomarker,” Dr. Powles said. “It’s not perfect. Complete and partial responses and long overall survival were seen in both arms. Nevertheless, it seems like a step in the right direction.”
Finally, with insight on the nature and relationships of the various biomarkers, the investigators assessed the combination of TMB with PD-L1, finding that atezolizumab had a marked overall survival benefit in patients with TMB-high and PD-L1–positive tumors (17.8 vs. 10.6 months; HR, 0.50; 95% CI, 0.29-0.86).
“I think by using combinations of biomarkers, first-generation and second-generation, we may actually be able to better select patients for treatment in the future,” Dr. Powles concluded.
New data, new insights
“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”
The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”
Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.
Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.
“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.
Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”
Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.
“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”
“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”
SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.
SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.
An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.
Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.
Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“It is clear that PD-1 and PD-L1 targeted immunotherapy now has a role in most patients with advanced urothelial cancer,” Robert J. Jones, MBChB, PhD, professor of clinical cancer research, University of Glasgow, Beatson West of Scotland Cancer Centre, commented in an invited discussion. “It is also true that cytotoxic chemotherapy maintains a role for many, and that both modalities are often ineffective and may be toxic.”
KEYNOTE-045 trial update
Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).
Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.
Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).
Median overall survival was 10.3 months and 7.3 months, respectively. Corresponding 1-year survival rates were 44.4% and 29.8%, and corresponding 2-year survival rates, 27.0% and 14.3%.
At 24 months, 60.6% of patients in the chemotherapy arm had received an immunotherapy agent, including some who had received pembrolizumab as part of crossover, Dr. Bellmunt noted.
Overall survival benefit was generally similar across subgroups, including patients with PD-L1–positive tumors (defined as a combined positive score of 10% or higher) (HR, 0.56; P = .00153) and patients with PD-L1–negative tumors (HR, 0.75; P = .00859).
The lack of a progression-free survival benefit of pembrolizumab over chemotherapy in the initial analysis (HR, 0.98; P = .420) persisted in the updated analysis (HR, 0.96; P = .317).
The overall response rate now was 21.1% with pembrolizumab and 11.0% with chemotherapy. In the former group, the rate of complete response had increased from 7.0% to 9.3% with the longer follow-up. Median time to response was identical, at 2.1 months, but duration of response was longer with pembrolizumab (not reached vs. 4.4 months).
“We haven’t seen any signals of cumulative toxicity with subsequent follow-up,” Dr. Bellmunt reported. Similar to findings of the initial analysis, the most common grade 3-5 treatment-related adverse events were pruritus, fatigue, and diarrhea with pembrolizumab, and neutropenia, anemia, and fatigue with chemotherapy. As expected, the pembrolizumab group had higher rates of hypothyroidism, pneumonitis, hyperthyroidism, and colitis.
“The overall survival benefit and superior safety of pembrolizumab versus chemotherapy in this second-line patient population is maintained after 2 years of follow-up. At 24 months, 27% of patients are alive, and this is similar to what we are seeing with other immune-sensitive diseases like melanoma,” he concluded. “Results in patients with PD-L1–positive or –negative tumors were consistent with the intent-to-treat population. We have seen some hints with this biomarker, but they are not very striking.”
IMvigor 211 trial biomarker analyses
The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.
At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).
Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.
“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.
Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.
However, a different pattern was seen with tumor mutational burden (TMB), a FoundationOne panel. Patients with TMB-high tumors had a substantial gain in overall survival from atezolizumab versus chemotherapy (HR, 0.68; 95% CI, 0.51-0.90), whereas those with TMB-low tumors did not (HR, 1.00; 95% CI, 0.75-1.32).
“TMB appears to be a predictive but not a prognostic biomarker,” Dr. Powles said. “It’s not perfect. Complete and partial responses and long overall survival were seen in both arms. Nevertheless, it seems like a step in the right direction.”
Finally, with insight on the nature and relationships of the various biomarkers, the investigators assessed the combination of TMB with PD-L1, finding that atezolizumab had a marked overall survival benefit in patients with TMB-high and PD-L1–positive tumors (17.8 vs. 10.6 months; HR, 0.50; 95% CI, 0.29-0.86).
“I think by using combinations of biomarkers, first-generation and second-generation, we may actually be able to better select patients for treatment in the future,” Dr. Powles concluded.
New data, new insights
“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”
The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”
Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.
Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.
“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.
Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”
Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.
“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”
“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”
SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Pembrolizumab yielded a higher 2-year rate of survival vs. chemotherapy (27.0% vs. 14.3%). Atezolizumab had a marked survival benefit vs. chemotherapy in patients with TMB-high, PD-L1–positive tumors (17.8 vs. 10.6 months; HR, 0.50).
Data source: Two-year follow-up of a phase 3 randomized trial among 542 patients with recurrent, advanced urothelial cancer (KEYNOTE-045 trial). Biomarker analyses of a phase 3 randomized trial among 931 patients with platinum-treated locally advanced or metastatic urothelial cancer (IMvigor 211 trial).
Disclosures: Dr. Bellmunt disclosed that he has a consulting or advisory role with Astellas Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Genentech, Merck, Novartis, Pfizer, and Pierre Fabre; that his institution receives research funding from Millennium and Sanofi; and that he receives travel, accommodations, and/or expenses from MSD Oncology and Pfizer. KEYNOTE-045 was funded by Merck & Co. Dr. Powles disclosed that he receives honoraria from Bristol-Myers Squibb, Merck, and Roche/Genentech; has a consulting or advisory role with AstraZeneca; Bristol-Myers Squibb, Roche/Genentech, Merck, and Novartis; receives research funding from AstraZeneca/MedImmune and Roche/Genentech; and has another relationship with Bristol-Myers Squibb and Ipsen. IMvigor 211 was sponsored by Hoffmann-La Roche.
Sources: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.
DNA repair gene mutations predict response to anti–PD-1/PD-L1 in urothelial cancer
Alterations in DNA damage response and repair genes may be useful biomarkers for response to immune checkpoint inhibitors in patients with urothelial carcinoma, investigators contend.
Among 60 patients with urothelial carcinoma in prospective trials of antibodies directed against the immune checkpoint inhibitor programmed cell death protein-1 and its ligand (PD-1/PD-L1), 28 (47%) had a damage response and repair (DDR) gene of any kind, and 15 (25%) had DDR mutations that are thought to be deleterious. Patients with any DDR mutations were more likely to have a clinical response to anti–PD-1/PD-L1 therapy, especially patients with likely deleterious mutations, reported Jonathan E. Rosenberg, MD and colleagues from Memorial Sloan Kettering Cancer Center, New York.
“This study shows that patients with DDR gene alterations are more likely to experience objective responses, longer PFS, and improved OS than patients with wild-type DDR genes. Whether the association is predictive or prognostic should be investigated further in larger data sets from randomized studies that have led to the FDA [Food and Drug Administration] approval of several anti–PD-1/PD-L1 agents,” they wrote.
Previous studies have shown that in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy, alterations in DDR genes are associated with elevations in mutational load, increases in tumor-infiltrating lymphocytes, and improved survival, the investigators noted.
To see whether DDR gene alterations were also associated with better outcomes with PD-1/PD-L1 inhibitors, the investigators examined tumor genomes and survival data from patients with metastatic urothelial carcinoma who were enrolled in prospective clinical trials of anti–PD-1/PD-L1 monotherapy. The agents used in the trials were atezolizumab(Tecentriq) and nivolumab(Opdivo).
The investigators correlated the presence of DDR gene alterations with best objective responses according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1.
They found that the presence of any DDR gene alteration was associated with higher response rates, compared with wild-type DDR (67.9% vs. 18.8%; P less than .001).
Additionally, patients whose tumors contained known or likely deleterious DDR mutations were significantly more likely to respond than were patients with either mutations of uncertain significance or wild-type DDR (overall response rate 80%, 54%, and 19%, respectively; P less than .001).
Patients with deleterious DDR alterations had significantly better PFS than patients without detectable alterations (hazard ratio, 0.20; P less than .001); DDR mutations of unknown significance trended toward better PFS (HR, 0.44), but was not statistically significant.
Median OS was not reached for patients with deleterious DDR gene mutations, with 71.5% alive at 12 months, compared with a median of 23 months for patients with alterations of unknown significance, and 9.3 months for patients with wild-type DDR.
In multivariable analysis, independent predictors for worse OS included hemoglobin levels below 10 g/dL and visceral metastases. In contrast, any versus no detectable DDR gene alterations was associated with better OS (HR, 0.27; P = .001).
The investigators are planning a prospective evaluation of the potential association between DDR alterations and outcomes in a phase 2 study of atezolizumab with or without bevacizumab(Avastin) in patients with metastatic urothelial carcinoma.
“Additional investigation is warranted to evaluate the mechanisms that link DDR alterations beyond MMR [DNA mismatch repair], [mutational] and neoantigen load, and immunotherapy response. If validated in other studies, DDR alterations may represent a useful predictive biomarker of response to anti–PD-1/PD-L1 in urothelial carcinoma,” they concluded.
The study was funded by Roche, Genentech, Bristol-Myers Squibb, and a National Cancer Institute Cancer Center support grant. Dr. Rosenberg disclosed stock or other ownership with Merck and Illumina, and consulting/advisory roles and travel support from Roche, Genentech, Bayer, and others. Multiple coauthors reported similar relationships.
SOURCE: Rosenberg JE et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.7740.
Alterations in DNA damage response and repair genes may be useful biomarkers for response to immune checkpoint inhibitors in patients with urothelial carcinoma, investigators contend.
Among 60 patients with urothelial carcinoma in prospective trials of antibodies directed against the immune checkpoint inhibitor programmed cell death protein-1 and its ligand (PD-1/PD-L1), 28 (47%) had a damage response and repair (DDR) gene of any kind, and 15 (25%) had DDR mutations that are thought to be deleterious. Patients with any DDR mutations were more likely to have a clinical response to anti–PD-1/PD-L1 therapy, especially patients with likely deleterious mutations, reported Jonathan E. Rosenberg, MD and colleagues from Memorial Sloan Kettering Cancer Center, New York.
“This study shows that patients with DDR gene alterations are more likely to experience objective responses, longer PFS, and improved OS than patients with wild-type DDR genes. Whether the association is predictive or prognostic should be investigated further in larger data sets from randomized studies that have led to the FDA [Food and Drug Administration] approval of several anti–PD-1/PD-L1 agents,” they wrote.
Previous studies have shown that in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy, alterations in DDR genes are associated with elevations in mutational load, increases in tumor-infiltrating lymphocytes, and improved survival, the investigators noted.
To see whether DDR gene alterations were also associated with better outcomes with PD-1/PD-L1 inhibitors, the investigators examined tumor genomes and survival data from patients with metastatic urothelial carcinoma who were enrolled in prospective clinical trials of anti–PD-1/PD-L1 monotherapy. The agents used in the trials were atezolizumab(Tecentriq) and nivolumab(Opdivo).
The investigators correlated the presence of DDR gene alterations with best objective responses according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1.
They found that the presence of any DDR gene alteration was associated with higher response rates, compared with wild-type DDR (67.9% vs. 18.8%; P less than .001).
Additionally, patients whose tumors contained known or likely deleterious DDR mutations were significantly more likely to respond than were patients with either mutations of uncertain significance or wild-type DDR (overall response rate 80%, 54%, and 19%, respectively; P less than .001).
Patients with deleterious DDR alterations had significantly better PFS than patients without detectable alterations (hazard ratio, 0.20; P less than .001); DDR mutations of unknown significance trended toward better PFS (HR, 0.44), but was not statistically significant.
Median OS was not reached for patients with deleterious DDR gene mutations, with 71.5% alive at 12 months, compared with a median of 23 months for patients with alterations of unknown significance, and 9.3 months for patients with wild-type DDR.
In multivariable analysis, independent predictors for worse OS included hemoglobin levels below 10 g/dL and visceral metastases. In contrast, any versus no detectable DDR gene alterations was associated with better OS (HR, 0.27; P = .001).
The investigators are planning a prospective evaluation of the potential association between DDR alterations and outcomes in a phase 2 study of atezolizumab with or without bevacizumab(Avastin) in patients with metastatic urothelial carcinoma.
“Additional investigation is warranted to evaluate the mechanisms that link DDR alterations beyond MMR [DNA mismatch repair], [mutational] and neoantigen load, and immunotherapy response. If validated in other studies, DDR alterations may represent a useful predictive biomarker of response to anti–PD-1/PD-L1 in urothelial carcinoma,” they concluded.
The study was funded by Roche, Genentech, Bristol-Myers Squibb, and a National Cancer Institute Cancer Center support grant. Dr. Rosenberg disclosed stock or other ownership with Merck and Illumina, and consulting/advisory roles and travel support from Roche, Genentech, Bayer, and others. Multiple coauthors reported similar relationships.
SOURCE: Rosenberg JE et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.7740.
Alterations in DNA damage response and repair genes may be useful biomarkers for response to immune checkpoint inhibitors in patients with urothelial carcinoma, investigators contend.
Among 60 patients with urothelial carcinoma in prospective trials of antibodies directed against the immune checkpoint inhibitor programmed cell death protein-1 and its ligand (PD-1/PD-L1), 28 (47%) had a damage response and repair (DDR) gene of any kind, and 15 (25%) had DDR mutations that are thought to be deleterious. Patients with any DDR mutations were more likely to have a clinical response to anti–PD-1/PD-L1 therapy, especially patients with likely deleterious mutations, reported Jonathan E. Rosenberg, MD and colleagues from Memorial Sloan Kettering Cancer Center, New York.
“This study shows that patients with DDR gene alterations are more likely to experience objective responses, longer PFS, and improved OS than patients with wild-type DDR genes. Whether the association is predictive or prognostic should be investigated further in larger data sets from randomized studies that have led to the FDA [Food and Drug Administration] approval of several anti–PD-1/PD-L1 agents,” they wrote.
Previous studies have shown that in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy, alterations in DDR genes are associated with elevations in mutational load, increases in tumor-infiltrating lymphocytes, and improved survival, the investigators noted.
To see whether DDR gene alterations were also associated with better outcomes with PD-1/PD-L1 inhibitors, the investigators examined tumor genomes and survival data from patients with metastatic urothelial carcinoma who were enrolled in prospective clinical trials of anti–PD-1/PD-L1 monotherapy. The agents used in the trials were atezolizumab(Tecentriq) and nivolumab(Opdivo).
The investigators correlated the presence of DDR gene alterations with best objective responses according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1.
They found that the presence of any DDR gene alteration was associated with higher response rates, compared with wild-type DDR (67.9% vs. 18.8%; P less than .001).
Additionally, patients whose tumors contained known or likely deleterious DDR mutations were significantly more likely to respond than were patients with either mutations of uncertain significance or wild-type DDR (overall response rate 80%, 54%, and 19%, respectively; P less than .001).
Patients with deleterious DDR alterations had significantly better PFS than patients without detectable alterations (hazard ratio, 0.20; P less than .001); DDR mutations of unknown significance trended toward better PFS (HR, 0.44), but was not statistically significant.
Median OS was not reached for patients with deleterious DDR gene mutations, with 71.5% alive at 12 months, compared with a median of 23 months for patients with alterations of unknown significance, and 9.3 months for patients with wild-type DDR.
In multivariable analysis, independent predictors for worse OS included hemoglobin levels below 10 g/dL and visceral metastases. In contrast, any versus no detectable DDR gene alterations was associated with better OS (HR, 0.27; P = .001).
The investigators are planning a prospective evaluation of the potential association between DDR alterations and outcomes in a phase 2 study of atezolizumab with or without bevacizumab(Avastin) in patients with metastatic urothelial carcinoma.
“Additional investigation is warranted to evaluate the mechanisms that link DDR alterations beyond MMR [DNA mismatch repair], [mutational] and neoantigen load, and immunotherapy response. If validated in other studies, DDR alterations may represent a useful predictive biomarker of response to anti–PD-1/PD-L1 in urothelial carcinoma,” they concluded.
The study was funded by Roche, Genentech, Bristol-Myers Squibb, and a National Cancer Institute Cancer Center support grant. Dr. Rosenberg disclosed stock or other ownership with Merck and Illumina, and consulting/advisory roles and travel support from Roche, Genentech, Bayer, and others. Multiple coauthors reported similar relationships.
SOURCE: Rosenberg JE et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.7740.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: DNA damage response and repair gene alterations may be biomarkers for response to immune checkpoint inhibitors in patients with metastatic urothelial carcinoma.
Major finding: Any DDR gene alteration was associated with higher response rates, compared with wild-type DDR (67.9% vs. 18.8%; P less than .001).
Data source: Retrospective study of 60 patients with metastatic urothelial carcinoma enrolled in phase 3 trials of PD-1/PD-L1 inhibitors.
Disclosures: The study was funded by Roche, Genentech, Bristol-Myers Squibb, and a National Cancer Institute Cancer Center support grant. Dr. Rosenberg disclosed stock or other ownership with Merck and Illumina, and consulting/advisory roles and travel support from Roche, Genentech, Bayer, and others. Multiple coauthors reported similar relationships.
Source: Rosenberg JE et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.7740.
Excellent prognosis for cystic RCC evaluated with radiologic threshold of greater than 50%
When a standardized radiologic threshold of greater than 50% is used, patients with unifocal cystic renal cell carcinoma (cRCC) have an excellent prognosis with active surveillance and following surgical resection, findings from a new study show.
At a median follow-up of 5.4 years (IQR 2.8-7.8), none of the 138 patients in the cohort experienced a tumor recurrence or metastasis from cRCC, and 7 (5.1%) died from non–renal-related causes. When comparing patients who initially underwent surgery to those who were initially managed with active surveillance, the researchers found that there was no significant difference in overall survival (P = .07). There were no deaths due to kidney cancer in the entire cohort.
The terminology of cRCC has historically been used to describe an indolent version of RCC that consists primarily of cysts, and the threshold of cystic involvement has traditionally been greater than 75% cystic on pathologic examination.
However, this classification does not contribute to the preoperative decision-making process, the study authors noted in Journal of Urology.
“Cross-sectional imaging provides the benefit of assessing tumor morphology without surgical manipulation, allowing for an accurate assessment of the solid and cystic components and classification of cRCC ,” write Ari Hakimi, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.
Studies evaluating radiologic criteria for cRCC diagnosis have suggested that cystic changes in 5%-45% of the total mass observed on imaging are associated with favorable survival. Thus, the authors sought to improve the preoperative assessment of cystic renal masses by evaluating cRCC as an enhancing renal lesion that is greater than 50% cystic on cross-sectional imaging. The goal of the current study was then to compare the long-term outcomes of patients with cRCC who underwent surgery and active surveillance using this hypothesized threshold.
The cohort included 138 patients who underwent surgery at Memorial Sloan Kettering Cancer Center for a renal mass from January 2000 to December 2015, and of this group, 102 (73.9%) had renal cell carcinoma and 36 (26.1%) had benign masses. Most of the tumors were Fuhrman grade 1-2 (77.5%), ≤pT2 stage (83.4%) and clear cell histology (65.9%), while the majority of cRCC lesions were Bosniak 3 and 4 (93.5%) and had a solid component of less than 25% (83.3%). On multivariate analysis, men (P = .007) were more likely to have malignant lesions and Bosniak 3 lesions were more likely to be malignant (P = .01).
In the subgroup of 38 active surveillance patients, 27 (71.1%) remained on active surveillance while 11 (28.9%) subsequently had surgery, of which all underwent partial nephrectomy. The median overall growth rate for lesions was 1.0 mm/year (IQR 0-2.8) over 25.3 months (IQR 16.3-44.8), and no evidence of recurrence or metastasis was reported in any of these patients at a median follow-up of 4.3 years (IQR 2.1-5.7) from first imaging diagnosis or 6.9 years (IQR 4.9-8.5) after surgery.
“We believe that our radiologic definition allows for more inclusive criteria of cRCC and would encourage kidney sparing approaches or implementation of AS protocols when feasible,” the authors concluded.
SOURCE: Hakimi A et al. J Urol. 2018 Feb 26 doi: 10.1016/j.juro.2018.02.3087
When a standardized radiologic threshold of greater than 50% is used, patients with unifocal cystic renal cell carcinoma (cRCC) have an excellent prognosis with active surveillance and following surgical resection, findings from a new study show.
At a median follow-up of 5.4 years (IQR 2.8-7.8), none of the 138 patients in the cohort experienced a tumor recurrence or metastasis from cRCC, and 7 (5.1%) died from non–renal-related causes. When comparing patients who initially underwent surgery to those who were initially managed with active surveillance, the researchers found that there was no significant difference in overall survival (P = .07). There were no deaths due to kidney cancer in the entire cohort.
The terminology of cRCC has historically been used to describe an indolent version of RCC that consists primarily of cysts, and the threshold of cystic involvement has traditionally been greater than 75% cystic on pathologic examination.
However, this classification does not contribute to the preoperative decision-making process, the study authors noted in Journal of Urology.
“Cross-sectional imaging provides the benefit of assessing tumor morphology without surgical manipulation, allowing for an accurate assessment of the solid and cystic components and classification of cRCC ,” write Ari Hakimi, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.
Studies evaluating radiologic criteria for cRCC diagnosis have suggested that cystic changes in 5%-45% of the total mass observed on imaging are associated with favorable survival. Thus, the authors sought to improve the preoperative assessment of cystic renal masses by evaluating cRCC as an enhancing renal lesion that is greater than 50% cystic on cross-sectional imaging. The goal of the current study was then to compare the long-term outcomes of patients with cRCC who underwent surgery and active surveillance using this hypothesized threshold.
The cohort included 138 patients who underwent surgery at Memorial Sloan Kettering Cancer Center for a renal mass from January 2000 to December 2015, and of this group, 102 (73.9%) had renal cell carcinoma and 36 (26.1%) had benign masses. Most of the tumors were Fuhrman grade 1-2 (77.5%), ≤pT2 stage (83.4%) and clear cell histology (65.9%), while the majority of cRCC lesions were Bosniak 3 and 4 (93.5%) and had a solid component of less than 25% (83.3%). On multivariate analysis, men (P = .007) were more likely to have malignant lesions and Bosniak 3 lesions were more likely to be malignant (P = .01).
In the subgroup of 38 active surveillance patients, 27 (71.1%) remained on active surveillance while 11 (28.9%) subsequently had surgery, of which all underwent partial nephrectomy. The median overall growth rate for lesions was 1.0 mm/year (IQR 0-2.8) over 25.3 months (IQR 16.3-44.8), and no evidence of recurrence or metastasis was reported in any of these patients at a median follow-up of 4.3 years (IQR 2.1-5.7) from first imaging diagnosis or 6.9 years (IQR 4.9-8.5) after surgery.
“We believe that our radiologic definition allows for more inclusive criteria of cRCC and would encourage kidney sparing approaches or implementation of AS protocols when feasible,” the authors concluded.
SOURCE: Hakimi A et al. J Urol. 2018 Feb 26 doi: 10.1016/j.juro.2018.02.3087
When a standardized radiologic threshold of greater than 50% is used, patients with unifocal cystic renal cell carcinoma (cRCC) have an excellent prognosis with active surveillance and following surgical resection, findings from a new study show.
At a median follow-up of 5.4 years (IQR 2.8-7.8), none of the 138 patients in the cohort experienced a tumor recurrence or metastasis from cRCC, and 7 (5.1%) died from non–renal-related causes. When comparing patients who initially underwent surgery to those who were initially managed with active surveillance, the researchers found that there was no significant difference in overall survival (P = .07). There were no deaths due to kidney cancer in the entire cohort.
The terminology of cRCC has historically been used to describe an indolent version of RCC that consists primarily of cysts, and the threshold of cystic involvement has traditionally been greater than 75% cystic on pathologic examination.
However, this classification does not contribute to the preoperative decision-making process, the study authors noted in Journal of Urology.
“Cross-sectional imaging provides the benefit of assessing tumor morphology without surgical manipulation, allowing for an accurate assessment of the solid and cystic components and classification of cRCC ,” write Ari Hakimi, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.
Studies evaluating radiologic criteria for cRCC diagnosis have suggested that cystic changes in 5%-45% of the total mass observed on imaging are associated with favorable survival. Thus, the authors sought to improve the preoperative assessment of cystic renal masses by evaluating cRCC as an enhancing renal lesion that is greater than 50% cystic on cross-sectional imaging. The goal of the current study was then to compare the long-term outcomes of patients with cRCC who underwent surgery and active surveillance using this hypothesized threshold.
The cohort included 138 patients who underwent surgery at Memorial Sloan Kettering Cancer Center for a renal mass from January 2000 to December 2015, and of this group, 102 (73.9%) had renal cell carcinoma and 36 (26.1%) had benign masses. Most of the tumors were Fuhrman grade 1-2 (77.5%), ≤pT2 stage (83.4%) and clear cell histology (65.9%), while the majority of cRCC lesions were Bosniak 3 and 4 (93.5%) and had a solid component of less than 25% (83.3%). On multivariate analysis, men (P = .007) were more likely to have malignant lesions and Bosniak 3 lesions were more likely to be malignant (P = .01).
In the subgroup of 38 active surveillance patients, 27 (71.1%) remained on active surveillance while 11 (28.9%) subsequently had surgery, of which all underwent partial nephrectomy. The median overall growth rate for lesions was 1.0 mm/year (IQR 0-2.8) over 25.3 months (IQR 16.3-44.8), and no evidence of recurrence or metastasis was reported in any of these patients at a median follow-up of 4.3 years (IQR 2.1-5.7) from first imaging diagnosis or 6.9 years (IQR 4.9-8.5) after surgery.
“We believe that our radiologic definition allows for more inclusive criteria of cRCC and would encourage kidney sparing approaches or implementation of AS protocols when feasible,” the authors concluded.
SOURCE: Hakimi A et al. J Urol. 2018 Feb 26 doi: 10.1016/j.juro.2018.02.3087
FROM THE JOURNAL OF UROLOGY
Key clinical point: Patients with unifocal cystic renal cell carcinoma have an excellent prognosis for both active surveillance and following surgery when evaluated with a standardized radiologic threshold of greater than 50% cystic.
Major finding: There was no evidence of tumor recurrence or metastasis from cRCC at a median follow-up of 5.4 years, and seven patients died of other causes.
Study details: Retrospective single-center study that looked at outcomes and clinicopathologic and oncologic features of 138 cases of cystic renal cell carcinoma.
Disclosures: The study was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers and an NIH/NCI Cancer Center Support Grant. There were no author disclosures listed.
Source: Hakimi A et al. J Urol. 2018 Feb 26 doi: 10.1016/j.juro.2018.02.3087.
FDA authorizes first direct-to-consumer BRCA1/2 test
The Food and Drug Administration has authorized the first direct-to-consumer (DTC) test to report on three specific BRCA1/BRCA2 breast cancer gene mutations.
Personal Genome Service Genetic Health Risk (GHR) Report for BRCA1/BRCA2 (Selected Variants) does not identify the most common BRCA1/2 mutations but rather the three most common in people of Ashkenazi (Eastern European) Jewish descent, the FDA said in a press statement.
The test, marketed by 23andMe, analyzes DNA from a self-collected saliva sample.
The three mutations identified by the test are present in about 2% of Ashkenazi Jewish women, but rarely in other ethnic populations. Any individual who takes the test may have other mutations in BRCA1 or BRCA2 genes, or other cancer-related gene mutations that are not detected by this test.
“This test provides information to certain individuals who may be at increased breast, ovarian, or prostate cancer risk and who might not otherwise get genetic screening and is a step forward in the availability of DTC genetic tests. But it has a lot of caveats,” Donald St. Pierre, acting director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, said in the press statement. “While the detection of a BRCA mutation on this test does indicate an increased risk, only a small percentage of Americans carry one of these three mutations and most BRCA mutations that increase an individual’s risk are not detected by this test. The test should not be used as a substitute for seeing your doctor for cancer screenings or counseling on genetic and lifestyle factors that can increase or decrease cancer risk.”
The authorization was based on data provided by the company to indicate the test correctly identifies the three genetic variants in saliva samples and is reproducible. In addition, the company submitted data to demonstrate that the instructions are comprehensible and easy to follow.
The FDA cautions that consumers and health care professionals “should not use the test results to determine any treatments, including antihormone therapies and prophylactic removal of the breasts or ovaries.” Decisions should be made only after confirmatory testing and genetic counseling, they said.
The Food and Drug Administration has authorized the first direct-to-consumer (DTC) test to report on three specific BRCA1/BRCA2 breast cancer gene mutations.
Personal Genome Service Genetic Health Risk (GHR) Report for BRCA1/BRCA2 (Selected Variants) does not identify the most common BRCA1/2 mutations but rather the three most common in people of Ashkenazi (Eastern European) Jewish descent, the FDA said in a press statement.
The test, marketed by 23andMe, analyzes DNA from a self-collected saliva sample.
The three mutations identified by the test are present in about 2% of Ashkenazi Jewish women, but rarely in other ethnic populations. Any individual who takes the test may have other mutations in BRCA1 or BRCA2 genes, or other cancer-related gene mutations that are not detected by this test.
“This test provides information to certain individuals who may be at increased breast, ovarian, or prostate cancer risk and who might not otherwise get genetic screening and is a step forward in the availability of DTC genetic tests. But it has a lot of caveats,” Donald St. Pierre, acting director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, said in the press statement. “While the detection of a BRCA mutation on this test does indicate an increased risk, only a small percentage of Americans carry one of these three mutations and most BRCA mutations that increase an individual’s risk are not detected by this test. The test should not be used as a substitute for seeing your doctor for cancer screenings or counseling on genetic and lifestyle factors that can increase or decrease cancer risk.”
The authorization was based on data provided by the company to indicate the test correctly identifies the three genetic variants in saliva samples and is reproducible. In addition, the company submitted data to demonstrate that the instructions are comprehensible and easy to follow.
The FDA cautions that consumers and health care professionals “should not use the test results to determine any treatments, including antihormone therapies and prophylactic removal of the breasts or ovaries.” Decisions should be made only after confirmatory testing and genetic counseling, they said.
The Food and Drug Administration has authorized the first direct-to-consumer (DTC) test to report on three specific BRCA1/BRCA2 breast cancer gene mutations.
Personal Genome Service Genetic Health Risk (GHR) Report for BRCA1/BRCA2 (Selected Variants) does not identify the most common BRCA1/2 mutations but rather the three most common in people of Ashkenazi (Eastern European) Jewish descent, the FDA said in a press statement.
The test, marketed by 23andMe, analyzes DNA from a self-collected saliva sample.
The three mutations identified by the test are present in about 2% of Ashkenazi Jewish women, but rarely in other ethnic populations. Any individual who takes the test may have other mutations in BRCA1 or BRCA2 genes, or other cancer-related gene mutations that are not detected by this test.
“This test provides information to certain individuals who may be at increased breast, ovarian, or prostate cancer risk and who might not otherwise get genetic screening and is a step forward in the availability of DTC genetic tests. But it has a lot of caveats,” Donald St. Pierre, acting director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, said in the press statement. “While the detection of a BRCA mutation on this test does indicate an increased risk, only a small percentage of Americans carry one of these three mutations and most BRCA mutations that increase an individual’s risk are not detected by this test. The test should not be used as a substitute for seeing your doctor for cancer screenings or counseling on genetic and lifestyle factors that can increase or decrease cancer risk.”
The authorization was based on data provided by the company to indicate the test correctly identifies the three genetic variants in saliva samples and is reproducible. In addition, the company submitted data to demonstrate that the instructions are comprehensible and easy to follow.
The FDA cautions that consumers and health care professionals “should not use the test results to determine any treatments, including antihormone therapies and prophylactic removal of the breasts or ovaries.” Decisions should be made only after confirmatory testing and genetic counseling, they said.
Avelumab safety compares with other checkpoint inhibitors
The immune checkpoint inhibitor avelumab (Bavencio), targeted against programmed cell death protein 1 and its ligand (PD1/PD-L1), appears to be well tolerated with a manageable safety profile, pooled data from two clinical trials suggest.
Of the 1,738 patients enrolled in the phase 1 JAVELIN solid tumor trial and the phase 2 JAVELIN Merkel 200 trial, 1,164 (67%) had a treatment-related adverse event (TRAE), and 177 (10.2%) had grade 3 or greater TRAEs. Grade 3 or greater immune-related adverse events (irAEs) occurred in just 2.2% of patients, reported Karen Kelly, MD, from the University of California, Davis, and her colleagues.
“Although conclusions drawn from cross-study comparisons should be made with caution, and to the best of our knowledge the number of pan-tumor clinical studies of [immune checkpoint inhibitor] monotherapy is limited, this analysis of a large population of patients across a broad scope of tumor types suggests that avelumab was associated with an incidence of irAEs that is consistent with that of other ICIs,” they wrote in Cancer.
Adverse events common with other immune checkpoint inhibitors include low-grade fatigue, pruritus, and rash, as well as serious irAEs, including high-grade pneumonitis and autoimmune-like side effects, the authors noted.
To characterize the adverse event profile of avelumab, they reviewed safety data on 1,650 patients enrolled in the solid tumor trial and 88 enrolled in the Merkel cell carcinoma trial, which included all patients in the trial who had received at least one dose of avelumab monotherapy by the cutoff date.
At the time of the analysis, 287 patients (16.5%) were continuing treatment, and 1,451 had discontinued therapy, largely because of disease progression.
Nearly all patients – 1,697 (97.6%) – had at least one adverse event of any grade or cause.
Four patients died from what investigators determined were TRAEs, including autoimmune hepatitis with peritoneal metastases and ascites in a patient with gastric cancer, liver metastases and acute liver failure in a patient with metastatic breast cancer, respiratory distress in a patient with breast cancer and multiple comorbidities, and treatment-related pneumonitis with ongoing Clostridium difficile colitis and diverticulitis not related to study treatment in a patient with urothelial carcinoma.
An additional 59 patients (3.4%) died from adverse events not deemed to be treatment-related, and 104 patient (6%) died from unknown or undocumented causes.
Any grade of irAE occurred in 247 patients (14.2%) and were grade 3 or greater in 39 (2.2%). Management of irAEs included systemic corticosteroids and nonsteroidal immunosuppressants.
In all, 439 patients (25.3%) had infusion-related reactions, which were treated generally with systemic corticosteroid. The protocol of the solid tumor trial was amended later to include diphenhydramine and acetaminophen before the first avelumab infusion as prophylaxis.
The study was sponsored by Merck and part of an alliance between Merck and Pfizer. Dr. Kelly reported no conflicts of interest. Multiple coauthors reported research funding, consulting fees, honoraria, or other consideration from various companies, and several coauthors are Merck employees.
SOURCE: Kelly K et al. Cancer. 2018 Feb 22. doi: 10.1002/cncr.31293.
The immune checkpoint inhibitor avelumab (Bavencio), targeted against programmed cell death protein 1 and its ligand (PD1/PD-L1), appears to be well tolerated with a manageable safety profile, pooled data from two clinical trials suggest.
Of the 1,738 patients enrolled in the phase 1 JAVELIN solid tumor trial and the phase 2 JAVELIN Merkel 200 trial, 1,164 (67%) had a treatment-related adverse event (TRAE), and 177 (10.2%) had grade 3 or greater TRAEs. Grade 3 or greater immune-related adverse events (irAEs) occurred in just 2.2% of patients, reported Karen Kelly, MD, from the University of California, Davis, and her colleagues.
“Although conclusions drawn from cross-study comparisons should be made with caution, and to the best of our knowledge the number of pan-tumor clinical studies of [immune checkpoint inhibitor] monotherapy is limited, this analysis of a large population of patients across a broad scope of tumor types suggests that avelumab was associated with an incidence of irAEs that is consistent with that of other ICIs,” they wrote in Cancer.
Adverse events common with other immune checkpoint inhibitors include low-grade fatigue, pruritus, and rash, as well as serious irAEs, including high-grade pneumonitis and autoimmune-like side effects, the authors noted.
To characterize the adverse event profile of avelumab, they reviewed safety data on 1,650 patients enrolled in the solid tumor trial and 88 enrolled in the Merkel cell carcinoma trial, which included all patients in the trial who had received at least one dose of avelumab monotherapy by the cutoff date.
At the time of the analysis, 287 patients (16.5%) were continuing treatment, and 1,451 had discontinued therapy, largely because of disease progression.
Nearly all patients – 1,697 (97.6%) – had at least one adverse event of any grade or cause.
Four patients died from what investigators determined were TRAEs, including autoimmune hepatitis with peritoneal metastases and ascites in a patient with gastric cancer, liver metastases and acute liver failure in a patient with metastatic breast cancer, respiratory distress in a patient with breast cancer and multiple comorbidities, and treatment-related pneumonitis with ongoing Clostridium difficile colitis and diverticulitis not related to study treatment in a patient with urothelial carcinoma.
An additional 59 patients (3.4%) died from adverse events not deemed to be treatment-related, and 104 patient (6%) died from unknown or undocumented causes.
Any grade of irAE occurred in 247 patients (14.2%) and were grade 3 or greater in 39 (2.2%). Management of irAEs included systemic corticosteroids and nonsteroidal immunosuppressants.
In all, 439 patients (25.3%) had infusion-related reactions, which were treated generally with systemic corticosteroid. The protocol of the solid tumor trial was amended later to include diphenhydramine and acetaminophen before the first avelumab infusion as prophylaxis.
The study was sponsored by Merck and part of an alliance between Merck and Pfizer. Dr. Kelly reported no conflicts of interest. Multiple coauthors reported research funding, consulting fees, honoraria, or other consideration from various companies, and several coauthors are Merck employees.
SOURCE: Kelly K et al. Cancer. 2018 Feb 22. doi: 10.1002/cncr.31293.
The immune checkpoint inhibitor avelumab (Bavencio), targeted against programmed cell death protein 1 and its ligand (PD1/PD-L1), appears to be well tolerated with a manageable safety profile, pooled data from two clinical trials suggest.
Of the 1,738 patients enrolled in the phase 1 JAVELIN solid tumor trial and the phase 2 JAVELIN Merkel 200 trial, 1,164 (67%) had a treatment-related adverse event (TRAE), and 177 (10.2%) had grade 3 or greater TRAEs. Grade 3 or greater immune-related adverse events (irAEs) occurred in just 2.2% of patients, reported Karen Kelly, MD, from the University of California, Davis, and her colleagues.
“Although conclusions drawn from cross-study comparisons should be made with caution, and to the best of our knowledge the number of pan-tumor clinical studies of [immune checkpoint inhibitor] monotherapy is limited, this analysis of a large population of patients across a broad scope of tumor types suggests that avelumab was associated with an incidence of irAEs that is consistent with that of other ICIs,” they wrote in Cancer.
Adverse events common with other immune checkpoint inhibitors include low-grade fatigue, pruritus, and rash, as well as serious irAEs, including high-grade pneumonitis and autoimmune-like side effects, the authors noted.
To characterize the adverse event profile of avelumab, they reviewed safety data on 1,650 patients enrolled in the solid tumor trial and 88 enrolled in the Merkel cell carcinoma trial, which included all patients in the trial who had received at least one dose of avelumab monotherapy by the cutoff date.
At the time of the analysis, 287 patients (16.5%) were continuing treatment, and 1,451 had discontinued therapy, largely because of disease progression.
Nearly all patients – 1,697 (97.6%) – had at least one adverse event of any grade or cause.
Four patients died from what investigators determined were TRAEs, including autoimmune hepatitis with peritoneal metastases and ascites in a patient with gastric cancer, liver metastases and acute liver failure in a patient with metastatic breast cancer, respiratory distress in a patient with breast cancer and multiple comorbidities, and treatment-related pneumonitis with ongoing Clostridium difficile colitis and diverticulitis not related to study treatment in a patient with urothelial carcinoma.
An additional 59 patients (3.4%) died from adverse events not deemed to be treatment-related, and 104 patient (6%) died from unknown or undocumented causes.
Any grade of irAE occurred in 247 patients (14.2%) and were grade 3 or greater in 39 (2.2%). Management of irAEs included systemic corticosteroids and nonsteroidal immunosuppressants.
In all, 439 patients (25.3%) had infusion-related reactions, which were treated generally with systemic corticosteroid. The protocol of the solid tumor trial was amended later to include diphenhydramine and acetaminophen before the first avelumab infusion as prophylaxis.
The study was sponsored by Merck and part of an alliance between Merck and Pfizer. Dr. Kelly reported no conflicts of interest. Multiple coauthors reported research funding, consulting fees, honoraria, or other consideration from various companies, and several coauthors are Merck employees.
SOURCE: Kelly K et al. Cancer. 2018 Feb 22. doi: 10.1002/cncr.31293.
FROM CANCER
Key clinical point: The immune checkpoint inhibitor avelumab appears to be well tolerated with a manageable safety profile.
Major finding: In all, 67% of patients had a treatment-related adverse event, and 10.2% had ones that were grade 3 or greater.
Study details: Safety analysis of pooled data on 1,738 patients treated with avelumab in a phase 1 and a phase 2 clinical trial.
Disclosures: The study was sponsored by Merck and part of an alliance between Merck and Pfizer. Dr. Kelly reported no conflicts of interest. Multiple coauthors reported research funding, consulting fees, honoraria, or other consideration from various companies, and several coauthors are Merck employees.
Source: Kelly K et al. Cancer. 2018 Feb 22. doi: 10.1002/cncr.31293.
Prostate cancer survival similar with EBRT/brachytherapy or surgery, analysts claim
More fuel for the radiation vs. surgery in prostate cancer debate comes from a study suggesting that patients with high-risk localized prostate cancer treated with external beam radiotherapy (EBRT) plus brachytherapy – with or without androgen deprivation (AD) – have survival rates equivalent to those of patients treated with radical prostatectomy (RP).
However, patients treated with EBRT and androgen deprivation without brachytherapy had significantly worse survival compared with patients treated with surgery, according to Ronald D. Ennis, MD, of Rutgers Cancer Institute of New Jersey, New Brunswick, and his colleagues.
“The data reported herein suggest that RT plus brachytherapy with or without AD and RP are associated with similar survival. This finding reinforces the need for patients to seek opinions from both a urologic oncologic surgeon with expertise in RP and a radiation oncologist with expertise in brachytherapy. The natural human tendency for physicians to prefer their modality necessitates this dual consultation approach, preferably in a single joint consultation visit,” the researchers wrote. The report was published in the Journal of Clinical Oncology.
The investigators attempted to control for variables that could influence the results by drawing on data on a large number of patients – 42,765 – who were treated at a large number of facilities across the United States. In addition, they incorporated data on clinical stage and Gleason score for all patients, prostate-specific antigen measurements, comorbidities, and socioeconomic factors that are either known or thought to influence treatment decisions.
They used inverse probability of treatment weight to adjust for imbalances of covariables among the treatment groups, and then created weighted time-dependent Cox proportional hazard models to estimate the effects of each type of treatment on survival.
Their sample included 24,688 patients who underwent RP, 15,435 who received EBRT with AD, and 2,642 who underwent EBRT and brachytherapy with or without AD.
They found no statistical difference in survival between RP and EBRT plus brachytherapy with/without AD in inverse probability of treatment weighted analysis. The hazard ratio for EBRT/brachytherapy was 1.17, but this was not statistically significant (95% confidence interval, 0.88-1.55).
In contrast. EBRT plus AD was associated with significantly worse survival, with a hazard ration of 1.53 (95% CI, 1.22-1.92).
The authors noted that “this finding reinforces the importance of complications, particularly in the urinary, sexual, and bowel domains, in combination with patient priorities and preferences, in determining an individual patient’s optimal choice. Significant data have been published in recent years regarding patient-reported outcomes that should be shared with all new patients to help guide them to their personal optimal treatment.”
They added that for some patients, quality of life may be a more important factor than survival when choosing a treatment modality.
SOURCE: Ennis et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.9134
Clinicians interpreting this and other retrospective studies using large cancer registry data need to consider:
1) Whether treatment groups are comparable. For most retrospective studies, treatment groups are not comparable. Surgery versus RT is especially difficult to compare. In many studies in various cancers that have compared surgery alone versus surgery plus adjuvant therapy, the latter patients are inherently healthier. The ability or inability of investigators to address these confounding issues is central to assessing the quality of the evidence in a study.
(2) Limitations related to the data elements that are contained in the registry and data accuracy.
(3) Whether the results are believable clinically. If survival is the endpoint in a study, when do the survival curves separate – and is that consistent with the known clinical course of a particular disease? The main advantage of randomized trials is the ability to create comparable patient groups and minimize confounding, which is also the biggest limitation of retrospective studies. In clinical scenarios where multiple randomized trials have consistently confirmed a result (e.g., adding androgen deprivation therapy to RT improves survival for high-risk patients), repeated retrospective analyses asking these same questions that may show either the same or an opposite result are less useful.
Perhaps the biggest challenge in conducting studies using cancer registry data and interpreting their results as researchers and clinicians relates to the personal biases most of us harbor; these biases tempt us to analyze registry data in an attempt to refute clinical trials and to selectively believe studies that provide results supporting our own biases. For each clinician interpreting retrospective results along with or in absence of clinical trial data, recognizing our own biases by following the framework outlined previously to assess the quality and believability of each study can potentially remove the greatest confounder of all.
Ronald C. Chen, MD, MPH, is associate professor of radiation oncology at the University of North Carolina at Chapel Hill. He serves in a consulting or advisory role for Medivation/Astellas, Accuray, and Bayer, and has received research funding from Accuray. His remarks are adapted from an editorial (J Clin Oncol. 2018 Feb 28. doi: 0.1200/JCO.2017.77.5833).
Clinicians interpreting this and other retrospective studies using large cancer registry data need to consider:
1) Whether treatment groups are comparable. For most retrospective studies, treatment groups are not comparable. Surgery versus RT is especially difficult to compare. In many studies in various cancers that have compared surgery alone versus surgery plus adjuvant therapy, the latter patients are inherently healthier. The ability or inability of investigators to address these confounding issues is central to assessing the quality of the evidence in a study.
(2) Limitations related to the data elements that are contained in the registry and data accuracy.
(3) Whether the results are believable clinically. If survival is the endpoint in a study, when do the survival curves separate – and is that consistent with the known clinical course of a particular disease? The main advantage of randomized trials is the ability to create comparable patient groups and minimize confounding, which is also the biggest limitation of retrospective studies. In clinical scenarios where multiple randomized trials have consistently confirmed a result (e.g., adding androgen deprivation therapy to RT improves survival for high-risk patients), repeated retrospective analyses asking these same questions that may show either the same or an opposite result are less useful.
Perhaps the biggest challenge in conducting studies using cancer registry data and interpreting their results as researchers and clinicians relates to the personal biases most of us harbor; these biases tempt us to analyze registry data in an attempt to refute clinical trials and to selectively believe studies that provide results supporting our own biases. For each clinician interpreting retrospective results along with or in absence of clinical trial data, recognizing our own biases by following the framework outlined previously to assess the quality and believability of each study can potentially remove the greatest confounder of all.
Ronald C. Chen, MD, MPH, is associate professor of radiation oncology at the University of North Carolina at Chapel Hill. He serves in a consulting or advisory role for Medivation/Astellas, Accuray, and Bayer, and has received research funding from Accuray. His remarks are adapted from an editorial (J Clin Oncol. 2018 Feb 28. doi: 0.1200/JCO.2017.77.5833).
Clinicians interpreting this and other retrospective studies using large cancer registry data need to consider:
1) Whether treatment groups are comparable. For most retrospective studies, treatment groups are not comparable. Surgery versus RT is especially difficult to compare. In many studies in various cancers that have compared surgery alone versus surgery plus adjuvant therapy, the latter patients are inherently healthier. The ability or inability of investigators to address these confounding issues is central to assessing the quality of the evidence in a study.
(2) Limitations related to the data elements that are contained in the registry and data accuracy.
(3) Whether the results are believable clinically. If survival is the endpoint in a study, when do the survival curves separate – and is that consistent with the known clinical course of a particular disease? The main advantage of randomized trials is the ability to create comparable patient groups and minimize confounding, which is also the biggest limitation of retrospective studies. In clinical scenarios where multiple randomized trials have consistently confirmed a result (e.g., adding androgen deprivation therapy to RT improves survival for high-risk patients), repeated retrospective analyses asking these same questions that may show either the same or an opposite result are less useful.
Perhaps the biggest challenge in conducting studies using cancer registry data and interpreting their results as researchers and clinicians relates to the personal biases most of us harbor; these biases tempt us to analyze registry data in an attempt to refute clinical trials and to selectively believe studies that provide results supporting our own biases. For each clinician interpreting retrospective results along with or in absence of clinical trial data, recognizing our own biases by following the framework outlined previously to assess the quality and believability of each study can potentially remove the greatest confounder of all.
Ronald C. Chen, MD, MPH, is associate professor of radiation oncology at the University of North Carolina at Chapel Hill. He serves in a consulting or advisory role for Medivation/Astellas, Accuray, and Bayer, and has received research funding from Accuray. His remarks are adapted from an editorial (J Clin Oncol. 2018 Feb 28. doi: 0.1200/JCO.2017.77.5833).
More fuel for the radiation vs. surgery in prostate cancer debate comes from a study suggesting that patients with high-risk localized prostate cancer treated with external beam radiotherapy (EBRT) plus brachytherapy – with or without androgen deprivation (AD) – have survival rates equivalent to those of patients treated with radical prostatectomy (RP).
However, patients treated with EBRT and androgen deprivation without brachytherapy had significantly worse survival compared with patients treated with surgery, according to Ronald D. Ennis, MD, of Rutgers Cancer Institute of New Jersey, New Brunswick, and his colleagues.
“The data reported herein suggest that RT plus brachytherapy with or without AD and RP are associated with similar survival. This finding reinforces the need for patients to seek opinions from both a urologic oncologic surgeon with expertise in RP and a radiation oncologist with expertise in brachytherapy. The natural human tendency for physicians to prefer their modality necessitates this dual consultation approach, preferably in a single joint consultation visit,” the researchers wrote. The report was published in the Journal of Clinical Oncology.
The investigators attempted to control for variables that could influence the results by drawing on data on a large number of patients – 42,765 – who were treated at a large number of facilities across the United States. In addition, they incorporated data on clinical stage and Gleason score for all patients, prostate-specific antigen measurements, comorbidities, and socioeconomic factors that are either known or thought to influence treatment decisions.
They used inverse probability of treatment weight to adjust for imbalances of covariables among the treatment groups, and then created weighted time-dependent Cox proportional hazard models to estimate the effects of each type of treatment on survival.
Their sample included 24,688 patients who underwent RP, 15,435 who received EBRT with AD, and 2,642 who underwent EBRT and brachytherapy with or without AD.
They found no statistical difference in survival between RP and EBRT plus brachytherapy with/without AD in inverse probability of treatment weighted analysis. The hazard ratio for EBRT/brachytherapy was 1.17, but this was not statistically significant (95% confidence interval, 0.88-1.55).
In contrast. EBRT plus AD was associated with significantly worse survival, with a hazard ration of 1.53 (95% CI, 1.22-1.92).
The authors noted that “this finding reinforces the importance of complications, particularly in the urinary, sexual, and bowel domains, in combination with patient priorities and preferences, in determining an individual patient’s optimal choice. Significant data have been published in recent years regarding patient-reported outcomes that should be shared with all new patients to help guide them to their personal optimal treatment.”
They added that for some patients, quality of life may be a more important factor than survival when choosing a treatment modality.
SOURCE: Ennis et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.9134
More fuel for the radiation vs. surgery in prostate cancer debate comes from a study suggesting that patients with high-risk localized prostate cancer treated with external beam radiotherapy (EBRT) plus brachytherapy – with or without androgen deprivation (AD) – have survival rates equivalent to those of patients treated with radical prostatectomy (RP).
However, patients treated with EBRT and androgen deprivation without brachytherapy had significantly worse survival compared with patients treated with surgery, according to Ronald D. Ennis, MD, of Rutgers Cancer Institute of New Jersey, New Brunswick, and his colleagues.
“The data reported herein suggest that RT plus brachytherapy with or without AD and RP are associated with similar survival. This finding reinforces the need for patients to seek opinions from both a urologic oncologic surgeon with expertise in RP and a radiation oncologist with expertise in brachytherapy. The natural human tendency for physicians to prefer their modality necessitates this dual consultation approach, preferably in a single joint consultation visit,” the researchers wrote. The report was published in the Journal of Clinical Oncology.
The investigators attempted to control for variables that could influence the results by drawing on data on a large number of patients – 42,765 – who were treated at a large number of facilities across the United States. In addition, they incorporated data on clinical stage and Gleason score for all patients, prostate-specific antigen measurements, comorbidities, and socioeconomic factors that are either known or thought to influence treatment decisions.
They used inverse probability of treatment weight to adjust for imbalances of covariables among the treatment groups, and then created weighted time-dependent Cox proportional hazard models to estimate the effects of each type of treatment on survival.
Their sample included 24,688 patients who underwent RP, 15,435 who received EBRT with AD, and 2,642 who underwent EBRT and brachytherapy with or without AD.
They found no statistical difference in survival between RP and EBRT plus brachytherapy with/without AD in inverse probability of treatment weighted analysis. The hazard ratio for EBRT/brachytherapy was 1.17, but this was not statistically significant (95% confidence interval, 0.88-1.55).
In contrast. EBRT plus AD was associated with significantly worse survival, with a hazard ration of 1.53 (95% CI, 1.22-1.92).
The authors noted that “this finding reinforces the importance of complications, particularly in the urinary, sexual, and bowel domains, in combination with patient priorities and preferences, in determining an individual patient’s optimal choice. Significant data have been published in recent years regarding patient-reported outcomes that should be shared with all new patients to help guide them to their personal optimal treatment.”
They added that for some patients, quality of life may be a more important factor than survival when choosing a treatment modality.
SOURCE: Ennis et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.9134
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: This analysis of cancer registry data suggests that surgery and external beam radiotherapy plus brachytherapy have similar survival outcomes in patients with localized high-risk cancers.
Major finding: The hazard ratio for EBRT/brachytherapy vs. radical prostatectomy was 1.17 and was not statistically significant.
Data source: Retrospective review of data on 42,765 patients with localized high-risk prostate cancer.
Disclosures: No funding source was reported. Coauthor Madhu Mazumdar, PhD, reported National Cancer Institute funding. All other authors had no disclosures.
Source: Ennis et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.9134.
Checkpoint inhibitors forge new treatment paradigm for metastatic bladder cancer
Last spring, the US Food and Drug Administration (FDA) granted accelerated approval to 3 different immune checkpoint inhibitors for the treatment of patients with metastatic urothelial carcinoma in the second-line setting, bringing the total number of approved members of this drug class for this indication to 5.
Avelumab and durvalumab, like atezolizumab, are monoclonal antibodies that target the programmed cell death protein ligand-1 (PD-L1) and prevent it from binding to and activating the programmed cell death protein-1 (PD-1) and CD80 receptors, which transmit inhibitory signals into T cells. In this way, it is hypothesized that their use reactivates the anti-tumor immune response conducted by tumor-infiltrating T cells. Both drugs were approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are refractory to platinum-based chemotherapy, and the approvals provide additional treatment options for this group of patients who typically have poor prognosis.1,2
Avelumab trial findings
The approval of avelumab was based on the urothelial cancer cohorts of the JAVELIN Solid Tumor trial, a phase 1, open-label, dose-escalation study.3 Patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), life expectancy of at least 3 months, and cytologically or histologically confirmed metastatic or locally advanced solid tumors were eligible.
Patients were excluded from the study if they had a history of or active central nervous system metastases, had other malignancies within the previous 5 years, had undergone organ transplant, had conditions requiring immune suppression, had active HIV or hepatitis B or C infection, or had autoimmune diseases other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that does not require immunosuppressive treatment.
Patients were also required to have adequate end organ function (white blood cell count, ≥3 x 109 cells/L; absolute neutrophil count, ≥1.5 x 109 cells/L; lymphocyte count, ≥0.5 x 109 cells/L; platelet count, ≥100 x 109 platelets/L; hemoglobin, ≥9 g/dL; total bilirubin concentration, ≤1.5 x upper limit of normal [ULN] range; aspartate- and alanine- aminotransferase (ALT/AST) concentrations, ≤2.5 x ULN); and estimated creatinine clearance, >50 mL/min.
A total of 242 patients were treated with a 10 mg/kg intravenous dose of avelumab every 2 weeks until disease progression or unacceptable toxicity. Before avelumab infusion, all patients received premedication with an antihistamine and acetaminophen.
The primary endpoint was objective response rate (ORR), which was 13.3% among 226 patients followed for at least 13 weeks, including 4% complete response (CR) rate, and 16.1% among 161 patients followed for at least 6 months, including 5.6% CR rate. The median time to response was 2 months and the median response duration had not been reached at the time of data cut-off. PD-L1 expression was evaluable in 84% of patients and there was no discernable variation in the response rates according to the levels of PD-L1 expression on the tumor.
The most common adverse events (AEs) that occurred in at least 20% of patients included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection (UTI). Serious AEs occurred in 41% of patients and most commonly involved UTI, abdominal pain, musculoskeletal pain, creatinine increase/renal failure, dehydration, hematuria, intestinal obstruction, and pyrexia. Deaths owing to AEs occurred in 6% of patients and were related to pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal AEs.
Durvalumab approval
The agency’s approval of durvalumab rested on the results of an ongoing single-arm phase 1/2 trial (Study 1108).4 Eligibility criteria were the same as for the avelumab study. Patients were ineligible for the trial if they had received any immunotherapy within the previous 4 weeks, any monoclonal antibody within the previous 6 weeks, or had received concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy.
Durvalumab was administered as an intravenous infusion at a dose of 10 mg/kg every 2 weeks, for up to 12 months or until disease progression or unacceptable toxicity. PD-L1 expression was evaluated by immunohistochemistry in tumor tissue obtained before treatment using the Ventana PD-L1 (SP263) assay (Ventana Medical Systems), which was approved by the FDA alongside durvalumab as a companion diagnostic. The first 20 patients were enrolled regardless of their PD-L1 expression, and the subsequent 43 patients were required to have PD-L1 expression of at least 5% of their tumor cells, but that requirement was removed at an interim analysis when objective responses occurred in patients with a PD-L1 expression of lessthan 5%.
In the most up-to-date analysis, published after FDA approval, a total of 191 patients had been treated. The ORR as assessed by blinded independent central review per RECIST-1.1, was 17.8%, including 7 CRs (3.7%). In patients with high PD-L1 expression, the ORR was 27.6%, compared with 5.1% in those with low or no PD-L1 expression. Responses were observed across all subgroups, including patients with a poor prognosis. The ORRs in patients with visceral and liver metastases were 15.3% and 7.3%, respectively. The median time to response was 1.41 months, and the median duration of response had not yet been reached.
The most common AEs experienced by patients treated with durvalumab included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and UTI. Serious treatment-related AEs occurred in 4.7% of patients, and treatment-related AEs leading to death occurred in 2 patients owing to autoimmune hepatitis and pneumonitis.
Toxicities and warnings for both therapies
Avelumab is marketed as Bavencio by EMD Serono, and durvalumab as Imfinzi by AstraZeneca. According to the prescribing information for both drugs, the recommended dose is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks.5,6
Both drugs are associated with serious or potentially life-threatening toxicities for which warnings and precautions are detailed in the prescribing information, predominantly for immune-mediated toxicities such as pneumonitis, hepatitis, colitis, nephritis, and endocrinpathy. Patients should be monitored for signs and symptoms of these toxicities and managed appropriately. Avelumab and durvalumab should both be withheld for grade 2 or higher pneumonitis, hepatitis, colitis, severe or life-threatening adrenal insufficiency, thyroid disorders or hyperglycemia, and moderate or severe nephritis or renal dysfunction.
These drugs should be permanently discontinued in the event of life-threatening or recurrent AEs. Immune-mediated pneumonitis, colitis, and hepatitis and adrenal insufficiency can be managed with corticosteroids; hypothyroidism, with hormone-replacement therapy; and hyperglycemia, with hyperglycemics or insulin.
To manage infusion-related reactions, patients should be premedicated with antihistamines and acetaminophen before the first 4 infusions and closely monitored for symptoms such as pyrexia, chills, flushing, hypotension, and dyspnea. Infusion can be interrupted or slowed for mild to moderate infusion-related reactions, but should be stopped and the drug discontinued for severe or life-threatening reactions.
Durvalumab is also associated with a risk of infection and patients should be monitored for signs and symptoms of infection and treated with anti-infectives. Durvalumab should be withheld for grade 3 infections. Patients being treated with durvalumab or avelumab should also be warned of the potential for embryofetal toxicity and advised to take appropriate precautions.
1. United States Food and Drug Administration. FDA grants accelerated approval to avelumab for urothelial carcinoma. US FDA Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm557162.htm. Last updated May 9, 2017. Accessed September 15, 2017.
2. United States Food and Drug Administration. Durvalumab (Imfinzi). US FDA Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm555930.htm. Last updated May 1, 2017. Accessed September 15, 2017
3. Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, et al. Avelumab for metastatic or locally advanced previously treated solid tumors (JAVELIN Solid Tumos): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18(5):587-598.
4. Powles T, O’Donnell PH, Massard C, Arkenau H-T, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma. Updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(8):e172411.
5. Bavencio (avelumab) injection, for intravenous use. Prescribing information. EMD Serono Inc. https://www.bavencio.com/en_US/document/Prescribing-Information.pdf. Revised October 2017. Accessed September 18th, 2017.
6. Imfinzi (durvalumab) injection, for intravenous use. Prescribing information. AstraZeneca Pharmaceuticals. https://www.azpicentral.com/imfinzi/imfinzi.pdf#page=1. Revised May 2017. Accessed September 18, 2017.
Last spring, the US Food and Drug Administration (FDA) granted accelerated approval to 3 different immune checkpoint inhibitors for the treatment of patients with metastatic urothelial carcinoma in the second-line setting, bringing the total number of approved members of this drug class for this indication to 5.
Avelumab and durvalumab, like atezolizumab, are monoclonal antibodies that target the programmed cell death protein ligand-1 (PD-L1) and prevent it from binding to and activating the programmed cell death protein-1 (PD-1) and CD80 receptors, which transmit inhibitory signals into T cells. In this way, it is hypothesized that their use reactivates the anti-tumor immune response conducted by tumor-infiltrating T cells. Both drugs were approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are refractory to platinum-based chemotherapy, and the approvals provide additional treatment options for this group of patients who typically have poor prognosis.1,2
Avelumab trial findings
The approval of avelumab was based on the urothelial cancer cohorts of the JAVELIN Solid Tumor trial, a phase 1, open-label, dose-escalation study.3 Patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), life expectancy of at least 3 months, and cytologically or histologically confirmed metastatic or locally advanced solid tumors were eligible.
Patients were excluded from the study if they had a history of or active central nervous system metastases, had other malignancies within the previous 5 years, had undergone organ transplant, had conditions requiring immune suppression, had active HIV or hepatitis B or C infection, or had autoimmune diseases other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that does not require immunosuppressive treatment.
Patients were also required to have adequate end organ function (white blood cell count, ≥3 x 109 cells/L; absolute neutrophil count, ≥1.5 x 109 cells/L; lymphocyte count, ≥0.5 x 109 cells/L; platelet count, ≥100 x 109 platelets/L; hemoglobin, ≥9 g/dL; total bilirubin concentration, ≤1.5 x upper limit of normal [ULN] range; aspartate- and alanine- aminotransferase (ALT/AST) concentrations, ≤2.5 x ULN); and estimated creatinine clearance, >50 mL/min.
A total of 242 patients were treated with a 10 mg/kg intravenous dose of avelumab every 2 weeks until disease progression or unacceptable toxicity. Before avelumab infusion, all patients received premedication with an antihistamine and acetaminophen.
The primary endpoint was objective response rate (ORR), which was 13.3% among 226 patients followed for at least 13 weeks, including 4% complete response (CR) rate, and 16.1% among 161 patients followed for at least 6 months, including 5.6% CR rate. The median time to response was 2 months and the median response duration had not been reached at the time of data cut-off. PD-L1 expression was evaluable in 84% of patients and there was no discernable variation in the response rates according to the levels of PD-L1 expression on the tumor.
The most common adverse events (AEs) that occurred in at least 20% of patients included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection (UTI). Serious AEs occurred in 41% of patients and most commonly involved UTI, abdominal pain, musculoskeletal pain, creatinine increase/renal failure, dehydration, hematuria, intestinal obstruction, and pyrexia. Deaths owing to AEs occurred in 6% of patients and were related to pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal AEs.
Durvalumab approval
The agency’s approval of durvalumab rested on the results of an ongoing single-arm phase 1/2 trial (Study 1108).4 Eligibility criteria were the same as for the avelumab study. Patients were ineligible for the trial if they had received any immunotherapy within the previous 4 weeks, any monoclonal antibody within the previous 6 weeks, or had received concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy.
Durvalumab was administered as an intravenous infusion at a dose of 10 mg/kg every 2 weeks, for up to 12 months or until disease progression or unacceptable toxicity. PD-L1 expression was evaluated by immunohistochemistry in tumor tissue obtained before treatment using the Ventana PD-L1 (SP263) assay (Ventana Medical Systems), which was approved by the FDA alongside durvalumab as a companion diagnostic. The first 20 patients were enrolled regardless of their PD-L1 expression, and the subsequent 43 patients were required to have PD-L1 expression of at least 5% of their tumor cells, but that requirement was removed at an interim analysis when objective responses occurred in patients with a PD-L1 expression of lessthan 5%.
In the most up-to-date analysis, published after FDA approval, a total of 191 patients had been treated. The ORR as assessed by blinded independent central review per RECIST-1.1, was 17.8%, including 7 CRs (3.7%). In patients with high PD-L1 expression, the ORR was 27.6%, compared with 5.1% in those with low or no PD-L1 expression. Responses were observed across all subgroups, including patients with a poor prognosis. The ORRs in patients with visceral and liver metastases were 15.3% and 7.3%, respectively. The median time to response was 1.41 months, and the median duration of response had not yet been reached.
The most common AEs experienced by patients treated with durvalumab included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and UTI. Serious treatment-related AEs occurred in 4.7% of patients, and treatment-related AEs leading to death occurred in 2 patients owing to autoimmune hepatitis and pneumonitis.
Toxicities and warnings for both therapies
Avelumab is marketed as Bavencio by EMD Serono, and durvalumab as Imfinzi by AstraZeneca. According to the prescribing information for both drugs, the recommended dose is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks.5,6
Both drugs are associated with serious or potentially life-threatening toxicities for which warnings and precautions are detailed in the prescribing information, predominantly for immune-mediated toxicities such as pneumonitis, hepatitis, colitis, nephritis, and endocrinpathy. Patients should be monitored for signs and symptoms of these toxicities and managed appropriately. Avelumab and durvalumab should both be withheld for grade 2 or higher pneumonitis, hepatitis, colitis, severe or life-threatening adrenal insufficiency, thyroid disorders or hyperglycemia, and moderate or severe nephritis or renal dysfunction.
These drugs should be permanently discontinued in the event of life-threatening or recurrent AEs. Immune-mediated pneumonitis, colitis, and hepatitis and adrenal insufficiency can be managed with corticosteroids; hypothyroidism, with hormone-replacement therapy; and hyperglycemia, with hyperglycemics or insulin.
To manage infusion-related reactions, patients should be premedicated with antihistamines and acetaminophen before the first 4 infusions and closely monitored for symptoms such as pyrexia, chills, flushing, hypotension, and dyspnea. Infusion can be interrupted or slowed for mild to moderate infusion-related reactions, but should be stopped and the drug discontinued for severe or life-threatening reactions.
Durvalumab is also associated with a risk of infection and patients should be monitored for signs and symptoms of infection and treated with anti-infectives. Durvalumab should be withheld for grade 3 infections. Patients being treated with durvalumab or avelumab should also be warned of the potential for embryofetal toxicity and advised to take appropriate precautions.
Last spring, the US Food and Drug Administration (FDA) granted accelerated approval to 3 different immune checkpoint inhibitors for the treatment of patients with metastatic urothelial carcinoma in the second-line setting, bringing the total number of approved members of this drug class for this indication to 5.
Avelumab and durvalumab, like atezolizumab, are monoclonal antibodies that target the programmed cell death protein ligand-1 (PD-L1) and prevent it from binding to and activating the programmed cell death protein-1 (PD-1) and CD80 receptors, which transmit inhibitory signals into T cells. In this way, it is hypothesized that their use reactivates the anti-tumor immune response conducted by tumor-infiltrating T cells. Both drugs were approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are refractory to platinum-based chemotherapy, and the approvals provide additional treatment options for this group of patients who typically have poor prognosis.1,2
Avelumab trial findings
The approval of avelumab was based on the urothelial cancer cohorts of the JAVELIN Solid Tumor trial, a phase 1, open-label, dose-escalation study.3 Patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), life expectancy of at least 3 months, and cytologically or histologically confirmed metastatic or locally advanced solid tumors were eligible.
Patients were excluded from the study if they had a history of or active central nervous system metastases, had other malignancies within the previous 5 years, had undergone organ transplant, had conditions requiring immune suppression, had active HIV or hepatitis B or C infection, or had autoimmune diseases other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that does not require immunosuppressive treatment.
Patients were also required to have adequate end organ function (white blood cell count, ≥3 x 109 cells/L; absolute neutrophil count, ≥1.5 x 109 cells/L; lymphocyte count, ≥0.5 x 109 cells/L; platelet count, ≥100 x 109 platelets/L; hemoglobin, ≥9 g/dL; total bilirubin concentration, ≤1.5 x upper limit of normal [ULN] range; aspartate- and alanine- aminotransferase (ALT/AST) concentrations, ≤2.5 x ULN); and estimated creatinine clearance, >50 mL/min.
A total of 242 patients were treated with a 10 mg/kg intravenous dose of avelumab every 2 weeks until disease progression or unacceptable toxicity. Before avelumab infusion, all patients received premedication with an antihistamine and acetaminophen.
The primary endpoint was objective response rate (ORR), which was 13.3% among 226 patients followed for at least 13 weeks, including 4% complete response (CR) rate, and 16.1% among 161 patients followed for at least 6 months, including 5.6% CR rate. The median time to response was 2 months and the median response duration had not been reached at the time of data cut-off. PD-L1 expression was evaluable in 84% of patients and there was no discernable variation in the response rates according to the levels of PD-L1 expression on the tumor.
The most common adverse events (AEs) that occurred in at least 20% of patients included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection (UTI). Serious AEs occurred in 41% of patients and most commonly involved UTI, abdominal pain, musculoskeletal pain, creatinine increase/renal failure, dehydration, hematuria, intestinal obstruction, and pyrexia. Deaths owing to AEs occurred in 6% of patients and were related to pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal AEs.
Durvalumab approval
The agency’s approval of durvalumab rested on the results of an ongoing single-arm phase 1/2 trial (Study 1108).4 Eligibility criteria were the same as for the avelumab study. Patients were ineligible for the trial if they had received any immunotherapy within the previous 4 weeks, any monoclonal antibody within the previous 6 weeks, or had received concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy.
Durvalumab was administered as an intravenous infusion at a dose of 10 mg/kg every 2 weeks, for up to 12 months or until disease progression or unacceptable toxicity. PD-L1 expression was evaluated by immunohistochemistry in tumor tissue obtained before treatment using the Ventana PD-L1 (SP263) assay (Ventana Medical Systems), which was approved by the FDA alongside durvalumab as a companion diagnostic. The first 20 patients were enrolled regardless of their PD-L1 expression, and the subsequent 43 patients were required to have PD-L1 expression of at least 5% of their tumor cells, but that requirement was removed at an interim analysis when objective responses occurred in patients with a PD-L1 expression of lessthan 5%.
In the most up-to-date analysis, published after FDA approval, a total of 191 patients had been treated. The ORR as assessed by blinded independent central review per RECIST-1.1, was 17.8%, including 7 CRs (3.7%). In patients with high PD-L1 expression, the ORR was 27.6%, compared with 5.1% in those with low or no PD-L1 expression. Responses were observed across all subgroups, including patients with a poor prognosis. The ORRs in patients with visceral and liver metastases were 15.3% and 7.3%, respectively. The median time to response was 1.41 months, and the median duration of response had not yet been reached.
The most common AEs experienced by patients treated with durvalumab included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and UTI. Serious treatment-related AEs occurred in 4.7% of patients, and treatment-related AEs leading to death occurred in 2 patients owing to autoimmune hepatitis and pneumonitis.
Toxicities and warnings for both therapies
Avelumab is marketed as Bavencio by EMD Serono, and durvalumab as Imfinzi by AstraZeneca. According to the prescribing information for both drugs, the recommended dose is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks.5,6
Both drugs are associated with serious or potentially life-threatening toxicities for which warnings and precautions are detailed in the prescribing information, predominantly for immune-mediated toxicities such as pneumonitis, hepatitis, colitis, nephritis, and endocrinpathy. Patients should be monitored for signs and symptoms of these toxicities and managed appropriately. Avelumab and durvalumab should both be withheld for grade 2 or higher pneumonitis, hepatitis, colitis, severe or life-threatening adrenal insufficiency, thyroid disorders or hyperglycemia, and moderate or severe nephritis or renal dysfunction.
These drugs should be permanently discontinued in the event of life-threatening or recurrent AEs. Immune-mediated pneumonitis, colitis, and hepatitis and adrenal insufficiency can be managed with corticosteroids; hypothyroidism, with hormone-replacement therapy; and hyperglycemia, with hyperglycemics or insulin.
To manage infusion-related reactions, patients should be premedicated with antihistamines and acetaminophen before the first 4 infusions and closely monitored for symptoms such as pyrexia, chills, flushing, hypotension, and dyspnea. Infusion can be interrupted or slowed for mild to moderate infusion-related reactions, but should be stopped and the drug discontinued for severe or life-threatening reactions.
Durvalumab is also associated with a risk of infection and patients should be monitored for signs and symptoms of infection and treated with anti-infectives. Durvalumab should be withheld for grade 3 infections. Patients being treated with durvalumab or avelumab should also be warned of the potential for embryofetal toxicity and advised to take appropriate precautions.
1. United States Food and Drug Administration. FDA grants accelerated approval to avelumab for urothelial carcinoma. US FDA Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm557162.htm. Last updated May 9, 2017. Accessed September 15, 2017.
2. United States Food and Drug Administration. Durvalumab (Imfinzi). US FDA Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm555930.htm. Last updated May 1, 2017. Accessed September 15, 2017
3. Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, et al. Avelumab for metastatic or locally advanced previously treated solid tumors (JAVELIN Solid Tumos): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18(5):587-598.
4. Powles T, O’Donnell PH, Massard C, Arkenau H-T, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma. Updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(8):e172411.
5. Bavencio (avelumab) injection, for intravenous use. Prescribing information. EMD Serono Inc. https://www.bavencio.com/en_US/document/Prescribing-Information.pdf. Revised October 2017. Accessed September 18th, 2017.
6. Imfinzi (durvalumab) injection, for intravenous use. Prescribing information. AstraZeneca Pharmaceuticals. https://www.azpicentral.com/imfinzi/imfinzi.pdf#page=1. Revised May 2017. Accessed September 18, 2017.
1. United States Food and Drug Administration. FDA grants accelerated approval to avelumab for urothelial carcinoma. US FDA Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm557162.htm. Last updated May 9, 2017. Accessed September 15, 2017.
2. United States Food and Drug Administration. Durvalumab (Imfinzi). US FDA Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm555930.htm. Last updated May 1, 2017. Accessed September 15, 2017
3. Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, et al. Avelumab for metastatic or locally advanced previously treated solid tumors (JAVELIN Solid Tumos): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18(5):587-598.
4. Powles T, O’Donnell PH, Massard C, Arkenau H-T, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma. Updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(8):e172411.
5. Bavencio (avelumab) injection, for intravenous use. Prescribing information. EMD Serono Inc. https://www.bavencio.com/en_US/document/Prescribing-Information.pdf. Revised October 2017. Accessed September 18th, 2017.
6. Imfinzi (durvalumab) injection, for intravenous use. Prescribing information. AstraZeneca Pharmaceuticals. https://www.azpicentral.com/imfinzi/imfinzi.pdf#page=1. Revised May 2017. Accessed September 18, 2017.