User login
Test goes wide and deep to detect free tumor DNA in blood
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
AT ASCO 2017
Key clinical point: High-intensity sequencing of plasma samples appears capable of detecting actionable tumor mutations in a large proportion of samples.
Major finding: In 89% of patients with advanced cancers, genetic variants were identified in both tumor samples and circulating free DNA testing.
Data source: Prospective study of tissue and plasma samples from 124 patients with non–small cell lung cancer or metastatic breast and prostate cancers.
Disclosures: The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
VIDEO: Abiraterone improves survival in high-risk prostate cancer
CHICAGO – Adding abiraterone acetate plus prednisone to androgen deprivation therapy in hormone-naive high-risk prostate cancer patients significantly improves overall survival, according to “practice-changing” results from the phase III LATITUDE trial and the multiarm, multistage STAMPEDE trial.
In the double-blind, randomized, placebo-controlled LATITUDE trial, 597 patients with newly diagnosed high-risk metastatic prostate cancer who received 1,000 mg of abiraterone acetate daily plus 5 mg of prednisone daily in addition to androgen deprivation therapy experienced a 38% reduction in the risk of death and a 53% reduction in the risk of radiographic progression or death at a median follow-up of 30.4 months, compared with 602 such patients who received placebo and androgen deprivation, Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Villejuif, France, reported at the annual meeting of the American Society of Clinical Oncology.
Significant improvements also were seen in the treatment vs. placebo group for all secondary endpoints, including time to prostate-specific-antigen progression (hazard ratio, 0.30), time to pain progression (HR, 0.70), time to next symptomatic skeletal event (HR, 0.70), time to chemotherapy (HR, 0.44), and time to subsequent prostate cancer therapy (HR, 0.42), Dr. Fizazi said.
He discussed the findings, including side effects, and ongoing and future studies, in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Based on these findings, I believe that using abiraterone up front, together with androgen deprivation therapy, will become the next standard of care for these men,” he said.
Similarly, in the STAMPEDE trial, abiraterone acetate plus prednisone was associated with significantly improved overall survival in 960 high-risk prostate cancer patients starting hormone therapy, compared with 957 such patients receiving placebo and standard-of-care hormone therapy, according to Nicholas D. James, BSc MBBS, PhD, of the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Overall, we’ve got about a 30% improvement in survival times for the upfront use of abiraterone. For our metastatic patients, we haven’t reached the median survival yet for the abiraterone patients, but it’s around 3.5 years median survival in the control arm, and we’re projecting that’s going to go up to 6.5 or 7 years in the abiraterone patients,” he said in a video interview, adding that he and his colleagues think this will be one of the biggest survival gains ever reported in adults in such a setting.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. James also discussed findings with respect to secondary endpoints, including a 70% improvement in failure-free survival in the treatment vs. placebo group – an improvement that he called an “absolutely spectacularly big gain” – and skeletal-related events, which decreased by 55% in the treatment group.
Both investigators discussed ongoing and recently completed studies that could shed additional light on the use of abiraterone in prostate cancer patients, including plans to look at the effects of giving both abiraterone and docetaxel together.
“My prediction will be that we will be giving both treatments in due course,” Dr. James said, adding, “I think these findings will certainly be practice changing.”
CHICAGO – Adding abiraterone acetate plus prednisone to androgen deprivation therapy in hormone-naive high-risk prostate cancer patients significantly improves overall survival, according to “practice-changing” results from the phase III LATITUDE trial and the multiarm, multistage STAMPEDE trial.
In the double-blind, randomized, placebo-controlled LATITUDE trial, 597 patients with newly diagnosed high-risk metastatic prostate cancer who received 1,000 mg of abiraterone acetate daily plus 5 mg of prednisone daily in addition to androgen deprivation therapy experienced a 38% reduction in the risk of death and a 53% reduction in the risk of radiographic progression or death at a median follow-up of 30.4 months, compared with 602 such patients who received placebo and androgen deprivation, Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Villejuif, France, reported at the annual meeting of the American Society of Clinical Oncology.
Significant improvements also were seen in the treatment vs. placebo group for all secondary endpoints, including time to prostate-specific-antigen progression (hazard ratio, 0.30), time to pain progression (HR, 0.70), time to next symptomatic skeletal event (HR, 0.70), time to chemotherapy (HR, 0.44), and time to subsequent prostate cancer therapy (HR, 0.42), Dr. Fizazi said.
He discussed the findings, including side effects, and ongoing and future studies, in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Based on these findings, I believe that using abiraterone up front, together with androgen deprivation therapy, will become the next standard of care for these men,” he said.
Similarly, in the STAMPEDE trial, abiraterone acetate plus prednisone was associated with significantly improved overall survival in 960 high-risk prostate cancer patients starting hormone therapy, compared with 957 such patients receiving placebo and standard-of-care hormone therapy, according to Nicholas D. James, BSc MBBS, PhD, of the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Overall, we’ve got about a 30% improvement in survival times for the upfront use of abiraterone. For our metastatic patients, we haven’t reached the median survival yet for the abiraterone patients, but it’s around 3.5 years median survival in the control arm, and we’re projecting that’s going to go up to 6.5 or 7 years in the abiraterone patients,” he said in a video interview, adding that he and his colleagues think this will be one of the biggest survival gains ever reported in adults in such a setting.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. James also discussed findings with respect to secondary endpoints, including a 70% improvement in failure-free survival in the treatment vs. placebo group – an improvement that he called an “absolutely spectacularly big gain” – and skeletal-related events, which decreased by 55% in the treatment group.
Both investigators discussed ongoing and recently completed studies that could shed additional light on the use of abiraterone in prostate cancer patients, including plans to look at the effects of giving both abiraterone and docetaxel together.
“My prediction will be that we will be giving both treatments in due course,” Dr. James said, adding, “I think these findings will certainly be practice changing.”
CHICAGO – Adding abiraterone acetate plus prednisone to androgen deprivation therapy in hormone-naive high-risk prostate cancer patients significantly improves overall survival, according to “practice-changing” results from the phase III LATITUDE trial and the multiarm, multistage STAMPEDE trial.
In the double-blind, randomized, placebo-controlled LATITUDE trial, 597 patients with newly diagnosed high-risk metastatic prostate cancer who received 1,000 mg of abiraterone acetate daily plus 5 mg of prednisone daily in addition to androgen deprivation therapy experienced a 38% reduction in the risk of death and a 53% reduction in the risk of radiographic progression or death at a median follow-up of 30.4 months, compared with 602 such patients who received placebo and androgen deprivation, Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Villejuif, France, reported at the annual meeting of the American Society of Clinical Oncology.
Significant improvements also were seen in the treatment vs. placebo group for all secondary endpoints, including time to prostate-specific-antigen progression (hazard ratio, 0.30), time to pain progression (HR, 0.70), time to next symptomatic skeletal event (HR, 0.70), time to chemotherapy (HR, 0.44), and time to subsequent prostate cancer therapy (HR, 0.42), Dr. Fizazi said.
He discussed the findings, including side effects, and ongoing and future studies, in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Based on these findings, I believe that using abiraterone up front, together with androgen deprivation therapy, will become the next standard of care for these men,” he said.
Similarly, in the STAMPEDE trial, abiraterone acetate plus prednisone was associated with significantly improved overall survival in 960 high-risk prostate cancer patients starting hormone therapy, compared with 957 such patients receiving placebo and standard-of-care hormone therapy, according to Nicholas D. James, BSc MBBS, PhD, of the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Overall, we’ve got about a 30% improvement in survival times for the upfront use of abiraterone. For our metastatic patients, we haven’t reached the median survival yet for the abiraterone patients, but it’s around 3.5 years median survival in the control arm, and we’re projecting that’s going to go up to 6.5 or 7 years in the abiraterone patients,” he said in a video interview, adding that he and his colleagues think this will be one of the biggest survival gains ever reported in adults in such a setting.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. James also discussed findings with respect to secondary endpoints, including a 70% improvement in failure-free survival in the treatment vs. placebo group – an improvement that he called an “absolutely spectacularly big gain” – and skeletal-related events, which decreased by 55% in the treatment group.
Both investigators discussed ongoing and recently completed studies that could shed additional light on the use of abiraterone in prostate cancer patients, including plans to look at the effects of giving both abiraterone and docetaxel together.
“My prediction will be that we will be giving both treatments in due course,” Dr. James said, adding, “I think these findings will certainly be practice changing.”
AT ASCO 2017
VIDEO: Low testosterone common after testicular cancer
CHICAGO – More than one-third of testicular cancer survivors have hypogonadism, according to an analysis of nearly 500 male patients conducted by the Platinum Study Group.
Lead author Mohammad Abu Zaid, MBBS, of Indiana University, Indianapolis, discusses the implications for long-term health, screening during follow-up, testing, and testosterone replacement therapy in a video interview at the annual meeting of the American Society of Clinical Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – More than one-third of testicular cancer survivors have hypogonadism, according to an analysis of nearly 500 male patients conducted by the Platinum Study Group.
Lead author Mohammad Abu Zaid, MBBS, of Indiana University, Indianapolis, discusses the implications for long-term health, screening during follow-up, testing, and testosterone replacement therapy in a video interview at the annual meeting of the American Society of Clinical Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – More than one-third of testicular cancer survivors have hypogonadism, according to an analysis of nearly 500 male patients conducted by the Platinum Study Group.
Lead author Mohammad Abu Zaid, MBBS, of Indiana University, Indianapolis, discusses the implications for long-term health, screening during follow-up, testing, and testosterone replacement therapy in a video interview at the annual meeting of the American Society of Clinical Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
FDA approves pembrolizumab for advanced urothelial carcinoma
The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
Approval of pembrolizumab for the second-line indication was based on an improvement in overall survival and objective response rate (ORR) in the KEYNOTE-045 trial. Median overall survival was 10.3 months for patients randomized to receive pembrolizumab (n = 270) every 3 weeks, compared with 7.4 months for patients randomized to receive the investigator’s choice of a chemotherapy regimen (paclitaxel [n = 84], docetaxel [n = 84], or vinflunine [n = 87]) every 3 weeks (hazard ratio, 0.73; 95% confidence interval: 0.59-0.91, P =.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (P = .002). All patients had locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. No statistically significant difference in progression-free survival between the two arms was observed, the FDA said in a statement.
The accelerated approval for the first-line indication was based on an ORR of 28.6% (95% CI, 24-34) in KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. The median response duration was not reached (range, 1.4+-17.8+ months).
The most common adverse reactions reported for those receiving pembrolizumab in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab occurred in 8% of patients in KEYNOTE-045 and in 11% in KEYNOTE-052. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients, the FDA said.
The recommended pembrolizumab dose and schedule for the treatment of urothelial carcinoma is 200 mg as an intravenous infusion over 30 minutes every 3 weeks. Full prescribing information is available the FDA website.
The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
Approval of pembrolizumab for the second-line indication was based on an improvement in overall survival and objective response rate (ORR) in the KEYNOTE-045 trial. Median overall survival was 10.3 months for patients randomized to receive pembrolizumab (n = 270) every 3 weeks, compared with 7.4 months for patients randomized to receive the investigator’s choice of a chemotherapy regimen (paclitaxel [n = 84], docetaxel [n = 84], or vinflunine [n = 87]) every 3 weeks (hazard ratio, 0.73; 95% confidence interval: 0.59-0.91, P =.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (P = .002). All patients had locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. No statistically significant difference in progression-free survival between the two arms was observed, the FDA said in a statement.
The accelerated approval for the first-line indication was based on an ORR of 28.6% (95% CI, 24-34) in KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. The median response duration was not reached (range, 1.4+-17.8+ months).
The most common adverse reactions reported for those receiving pembrolizumab in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab occurred in 8% of patients in KEYNOTE-045 and in 11% in KEYNOTE-052. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients, the FDA said.
The recommended pembrolizumab dose and schedule for the treatment of urothelial carcinoma is 200 mg as an intravenous infusion over 30 minutes every 3 weeks. Full prescribing information is available the FDA website.
The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
Approval of pembrolizumab for the second-line indication was based on an improvement in overall survival and objective response rate (ORR) in the KEYNOTE-045 trial. Median overall survival was 10.3 months for patients randomized to receive pembrolizumab (n = 270) every 3 weeks, compared with 7.4 months for patients randomized to receive the investigator’s choice of a chemotherapy regimen (paclitaxel [n = 84], docetaxel [n = 84], or vinflunine [n = 87]) every 3 weeks (hazard ratio, 0.73; 95% confidence interval: 0.59-0.91, P =.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (P = .002). All patients had locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. No statistically significant difference in progression-free survival between the two arms was observed, the FDA said in a statement.
The accelerated approval for the first-line indication was based on an ORR of 28.6% (95% CI, 24-34) in KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. The median response duration was not reached (range, 1.4+-17.8+ months).
The most common adverse reactions reported for those receiving pembrolizumab in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab occurred in 8% of patients in KEYNOTE-045 and in 11% in KEYNOTE-052. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients, the FDA said.
The recommended pembrolizumab dose and schedule for the treatment of urothelial carcinoma is 200 mg as an intravenous infusion over 30 minutes every 3 weeks. Full prescribing information is available the FDA website.
Alternating therapy in renal cell carcinoma fails to show an advantage
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
FROM JAMA ONCOLOGY
Key clinical point:
Major finding: The median time to progression or death was 7.4 months for the combination versus 9.4 months for pazopanib alone (P = .37).
Data source: Randomized, multicenter controlled trial.
Disclosures: The principal investigator Dr. Cirkel reports travel expenses from Novartis, which, along with GlaxoSmithKline, provided funding for this study.
More early-stage cancer diagnosis since ACA implementation
Implementation of the Affordable Care Act (ACA) has been associated with a shift toward earlier stage at diagnosis for common screenable cancers, finds an analysis of nearly 273,000 patients reported in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.
“Extensive evidence has shown that people without insurance are more likely to be diagnosed at later stage, especially for the cancers that can be detected earlier through screening or symptoms,” said lead study author Xuesong Han, PhD, strategic director of health policy and health care delivery research at the American Cancer Society in Atlanta. “In 2014, two major components of the Affordable Care Act – Medicaid expansion and marketplace exchange – were implemented. As a result, insurance coverage has substantially increased for nonelderly Americans.”
Study findings showed that, for four of five screenable cancers – breast and cervical cancer in women and lung and colorectal cancer in both sexes combined – the proportion of cancers that were stage I at diagnosis, and hence most curable, increased by an absolute 1% or so after the ACA was implemented. Prostate cancer was the outlier: the value for this malignancy decreased by 1%.
“The increases for the first four cancers were consistent with our hypothesis, with more people gaining insurance and access to screening services or access to physicians to detect early symptoms,” Dr. Han summarized. “But what about prostate cancer? We think [that pattern] may reflect the recent USPSTF recommendations against routine prostate cancer screening.”
“We think that this is an important study,” commented ASCO president-elect Bruce E. Johnson, MD, who is also chief clinical research officer and an institute physician at the Dana-Farber Cancer Institute in Boston. “Obviously, the changes are not enormous; they are not dramatic. But … because the uptake of screening is relatively slow, this is certainly consistent with the idea that, by doing additional screening, you can potentially find more stage I patients, and, the earlier the stage, the more likely one is to be cured.”
“The other important thing is that ASCO strongly supports the relative ease of access to screening capabilities, and that’s one of the characteristics of the Affordable Care Act, that most of the cancer screening is covered,” he further stated. “Whatever form our health care takes over the next several years, we advocate for patients to have early access to screening, which can identify cancers at an earlier stage in their more curable forms.”
Study details
For the study, the investigators used the National Cancer Database – which captures 70% of newly diagnosed cases in the United States – to identify patients younger than 65 who were eligible for cancer screening and who received a diagnosis of any of the five screenable cancers in 2013 or 2014. They compared stage distribution before ACA implementation (first nine months of 2013) and afterward (last nine months of 2014).
Analyses were based on data from 121,402 female breast cancer patients aged 40-64 years, 39,418 colorectal cancer patients aged 50-64 years, 11,190 cervical cancer patients aged 21-64 years, 59,210 prostate cancer patients aged 50-64 years, and 41,436 lung cancer patients aged 55-64 years.
Results showed that the proportion of cancers that were stage I at diagnosis increased after ACA implementation from 47.8% to 48.9% for breast cancer (adjusted prevalence ratio, 1.02) and from 47.3% to 48.8% for cervical cancer (APR, 1.02) in women, and from 16.6% to 17.7% for lung cancer (APR, 1.07) and from 22.8% to 23.7% for colorectal cancer (APR, 1.04) in men and women combined, Dr. Han reported.
Prostate cancer was the exception, with the proportion of cases that were stage I at diagnosis falling from 18.5% to 17.2% (APR, 0.93).
In a stratified analysis, the significant downshift in lung and colorectal cancer stage were seen only in states that had actually adopted the Medicaid expansion component of the ACA, which covers low-income individuals, according to Dr. Han. The downshift in female breast cancer stage and upshift in prostate cancer stage occurred regardless of whether states had done so.
Implementation of the Affordable Care Act (ACA) has been associated with a shift toward earlier stage at diagnosis for common screenable cancers, finds an analysis of nearly 273,000 patients reported in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.
“Extensive evidence has shown that people without insurance are more likely to be diagnosed at later stage, especially for the cancers that can be detected earlier through screening or symptoms,” said lead study author Xuesong Han, PhD, strategic director of health policy and health care delivery research at the American Cancer Society in Atlanta. “In 2014, two major components of the Affordable Care Act – Medicaid expansion and marketplace exchange – were implemented. As a result, insurance coverage has substantially increased for nonelderly Americans.”
Study findings showed that, for four of five screenable cancers – breast and cervical cancer in women and lung and colorectal cancer in both sexes combined – the proportion of cancers that were stage I at diagnosis, and hence most curable, increased by an absolute 1% or so after the ACA was implemented. Prostate cancer was the outlier: the value for this malignancy decreased by 1%.
“The increases for the first four cancers were consistent with our hypothesis, with more people gaining insurance and access to screening services or access to physicians to detect early symptoms,” Dr. Han summarized. “But what about prostate cancer? We think [that pattern] may reflect the recent USPSTF recommendations against routine prostate cancer screening.”
“We think that this is an important study,” commented ASCO president-elect Bruce E. Johnson, MD, who is also chief clinical research officer and an institute physician at the Dana-Farber Cancer Institute in Boston. “Obviously, the changes are not enormous; they are not dramatic. But … because the uptake of screening is relatively slow, this is certainly consistent with the idea that, by doing additional screening, you can potentially find more stage I patients, and, the earlier the stage, the more likely one is to be cured.”
“The other important thing is that ASCO strongly supports the relative ease of access to screening capabilities, and that’s one of the characteristics of the Affordable Care Act, that most of the cancer screening is covered,” he further stated. “Whatever form our health care takes over the next several years, we advocate for patients to have early access to screening, which can identify cancers at an earlier stage in their more curable forms.”
Study details
For the study, the investigators used the National Cancer Database – which captures 70% of newly diagnosed cases in the United States – to identify patients younger than 65 who were eligible for cancer screening and who received a diagnosis of any of the five screenable cancers in 2013 or 2014. They compared stage distribution before ACA implementation (first nine months of 2013) and afterward (last nine months of 2014).
Analyses were based on data from 121,402 female breast cancer patients aged 40-64 years, 39,418 colorectal cancer patients aged 50-64 years, 11,190 cervical cancer patients aged 21-64 years, 59,210 prostate cancer patients aged 50-64 years, and 41,436 lung cancer patients aged 55-64 years.
Results showed that the proportion of cancers that were stage I at diagnosis increased after ACA implementation from 47.8% to 48.9% for breast cancer (adjusted prevalence ratio, 1.02) and from 47.3% to 48.8% for cervical cancer (APR, 1.02) in women, and from 16.6% to 17.7% for lung cancer (APR, 1.07) and from 22.8% to 23.7% for colorectal cancer (APR, 1.04) in men and women combined, Dr. Han reported.
Prostate cancer was the exception, with the proportion of cases that were stage I at diagnosis falling from 18.5% to 17.2% (APR, 0.93).
In a stratified analysis, the significant downshift in lung and colorectal cancer stage were seen only in states that had actually adopted the Medicaid expansion component of the ACA, which covers low-income individuals, according to Dr. Han. The downshift in female breast cancer stage and upshift in prostate cancer stage occurred regardless of whether states had done so.
Implementation of the Affordable Care Act (ACA) has been associated with a shift toward earlier stage at diagnosis for common screenable cancers, finds an analysis of nearly 273,000 patients reported in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.
“Extensive evidence has shown that people without insurance are more likely to be diagnosed at later stage, especially for the cancers that can be detected earlier through screening or symptoms,” said lead study author Xuesong Han, PhD, strategic director of health policy and health care delivery research at the American Cancer Society in Atlanta. “In 2014, two major components of the Affordable Care Act – Medicaid expansion and marketplace exchange – were implemented. As a result, insurance coverage has substantially increased for nonelderly Americans.”
Study findings showed that, for four of five screenable cancers – breast and cervical cancer in women and lung and colorectal cancer in both sexes combined – the proportion of cancers that were stage I at diagnosis, and hence most curable, increased by an absolute 1% or so after the ACA was implemented. Prostate cancer was the outlier: the value for this malignancy decreased by 1%.
“The increases for the first four cancers were consistent with our hypothesis, with more people gaining insurance and access to screening services or access to physicians to detect early symptoms,” Dr. Han summarized. “But what about prostate cancer? We think [that pattern] may reflect the recent USPSTF recommendations against routine prostate cancer screening.”
“We think that this is an important study,” commented ASCO president-elect Bruce E. Johnson, MD, who is also chief clinical research officer and an institute physician at the Dana-Farber Cancer Institute in Boston. “Obviously, the changes are not enormous; they are not dramatic. But … because the uptake of screening is relatively slow, this is certainly consistent with the idea that, by doing additional screening, you can potentially find more stage I patients, and, the earlier the stage, the more likely one is to be cured.”
“The other important thing is that ASCO strongly supports the relative ease of access to screening capabilities, and that’s one of the characteristics of the Affordable Care Act, that most of the cancer screening is covered,” he further stated. “Whatever form our health care takes over the next several years, we advocate for patients to have early access to screening, which can identify cancers at an earlier stage in their more curable forms.”
Study details
For the study, the investigators used the National Cancer Database – which captures 70% of newly diagnosed cases in the United States – to identify patients younger than 65 who were eligible for cancer screening and who received a diagnosis of any of the five screenable cancers in 2013 or 2014. They compared stage distribution before ACA implementation (first nine months of 2013) and afterward (last nine months of 2014).
Analyses were based on data from 121,402 female breast cancer patients aged 40-64 years, 39,418 colorectal cancer patients aged 50-64 years, 11,190 cervical cancer patients aged 21-64 years, 59,210 prostate cancer patients aged 50-64 years, and 41,436 lung cancer patients aged 55-64 years.
Results showed that the proportion of cancers that were stage I at diagnosis increased after ACA implementation from 47.8% to 48.9% for breast cancer (adjusted prevalence ratio, 1.02) and from 47.3% to 48.8% for cervical cancer (APR, 1.02) in women, and from 16.6% to 17.7% for lung cancer (APR, 1.07) and from 22.8% to 23.7% for colorectal cancer (APR, 1.04) in men and women combined, Dr. Han reported.
Prostate cancer was the exception, with the proportion of cases that were stage I at diagnosis falling from 18.5% to 17.2% (APR, 0.93).
In a stratified analysis, the significant downshift in lung and colorectal cancer stage were seen only in states that had actually adopted the Medicaid expansion component of the ACA, which covers low-income individuals, according to Dr. Han. The downshift in female breast cancer stage and upshift in prostate cancer stage occurred regardless of whether states had done so.
FROM THE 2017 ASCO ANNUAL MEETING
Key clinical point:
Major finding: The proportion of cancers that were stage I when diagnosed increased by about 1% after ACA implementation for breast, cervical, lung, and colorectal cancer, while it decreased by 1% for prostate cancer.
Data source: A cohort study of 272,656 patients with these five cancers from the National Cancer Database.
Disclosures: Dr. Han reported that she had no disclosures.
FDA approves avelumab for advanced urothelial carcinoma
The Food and Drug Administration has granted accelerated approval to avelumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
Approval was based on a confirmed overall response rate (ORR) of 16.1% in 26 patients who had been followed for at least 6 months in a single-arm, multicenter study that enrolled 242 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed following platinum-containing neoadjuvant or adjuvant chemotherapy. The ORR was 13.3% among 30 patients who had been followed for at least 13 weeks. Median time to response was 2.0 months (range 1.3-11.0). The median response duration had not been reached in patients followed for at least 13 weeks or at least 6 months, but ranged from 1.4+ to 17.4+ months in both groups, the FDA said in a statement.
Serious adverse reactions, including urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestinal obstruction, and pyrexia, were reported in 41% of patients, causing death in 6% of patients. The most common adverse reactions were infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.
The FDA recommended an intravenous infusion of 10 mg/kg over 60 minutes every 2 weeks, and premedication with an antihistamine and acetaminophen prior to the first four infusions of avelumab.
Full prescribing information is available here.
The drug is being marketed as Bavencio by EMD Serono.
The Food and Drug Administration has granted accelerated approval to avelumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
Approval was based on a confirmed overall response rate (ORR) of 16.1% in 26 patients who had been followed for at least 6 months in a single-arm, multicenter study that enrolled 242 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed following platinum-containing neoadjuvant or adjuvant chemotherapy. The ORR was 13.3% among 30 patients who had been followed for at least 13 weeks. Median time to response was 2.0 months (range 1.3-11.0). The median response duration had not been reached in patients followed for at least 13 weeks or at least 6 months, but ranged from 1.4+ to 17.4+ months in both groups, the FDA said in a statement.
Serious adverse reactions, including urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestinal obstruction, and pyrexia, were reported in 41% of patients, causing death in 6% of patients. The most common adverse reactions were infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.
The FDA recommended an intravenous infusion of 10 mg/kg over 60 minutes every 2 weeks, and premedication with an antihistamine and acetaminophen prior to the first four infusions of avelumab.
Full prescribing information is available here.
The drug is being marketed as Bavencio by EMD Serono.
The Food and Drug Administration has granted accelerated approval to avelumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
Approval was based on a confirmed overall response rate (ORR) of 16.1% in 26 patients who had been followed for at least 6 months in a single-arm, multicenter study that enrolled 242 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed following platinum-containing neoadjuvant or adjuvant chemotherapy. The ORR was 13.3% among 30 patients who had been followed for at least 13 weeks. Median time to response was 2.0 months (range 1.3-11.0). The median response duration had not been reached in patients followed for at least 13 weeks or at least 6 months, but ranged from 1.4+ to 17.4+ months in both groups, the FDA said in a statement.
Serious adverse reactions, including urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestinal obstruction, and pyrexia, were reported in 41% of patients, causing death in 6% of patients. The most common adverse reactions were infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.
The FDA recommended an intravenous infusion of 10 mg/kg over 60 minutes every 2 weeks, and premedication with an antihistamine and acetaminophen prior to the first four infusions of avelumab.
Full prescribing information is available here.
The drug is being marketed as Bavencio by EMD Serono.
Novel agent varlilumab shows activity in RCC
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: A novel, first-in-class, agonist anti-CD27 monoclonal antibody showed activity in solid tumors when used as monotherapy.
Major finding: Two patients with advanced renal cell carcinoma experienced tumor shrinkage and durable responses while eight achieved stable disease.
Data source: Phase I first-in-human study comprising 56 patients with advanced colorectal cancer, renal cell carcinoma, and melanoma.
Disclosures: The study was supported by Celldex Therapeutics. Dr. Burris has no disclosures, and several coauthors have declared relationships with the industry.
Durvalumab approved for advanced urothelial carcinoma
for patients with locally advanced or metastatic urothelial carcinoma who have disease progression after prior treatment with a platinum-containing chemotherapy.
The agency also approved a complementary diagnostic for the assessment of the PD-L1 protein the tumor tissue.
The most common adverse reactions were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes also occurred in patients taking durvalumab.
The recommended dose of durvalumab is 10 mg/kg IV over a period of 60 minutes, every 2 weeks, until disease progression or unacceptable toxicity occurs. Full prescribing information is available here.
Durvalumab is marketed as Imfinzi by AstraZeneca. The complementary diagnostic is the Ventana PD-L1 (SP263) Assay from Ventana Medical Systems.
for patients with locally advanced or metastatic urothelial carcinoma who have disease progression after prior treatment with a platinum-containing chemotherapy.
The agency also approved a complementary diagnostic for the assessment of the PD-L1 protein the tumor tissue.
The most common adverse reactions were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes also occurred in patients taking durvalumab.
The recommended dose of durvalumab is 10 mg/kg IV over a period of 60 minutes, every 2 weeks, until disease progression or unacceptable toxicity occurs. Full prescribing information is available here.
Durvalumab is marketed as Imfinzi by AstraZeneca. The complementary diagnostic is the Ventana PD-L1 (SP263) Assay from Ventana Medical Systems.
for patients with locally advanced or metastatic urothelial carcinoma who have disease progression after prior treatment with a platinum-containing chemotherapy.
The agency also approved a complementary diagnostic for the assessment of the PD-L1 protein the tumor tissue.
The most common adverse reactions were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. Pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes also occurred in patients taking durvalumab.
The recommended dose of durvalumab is 10 mg/kg IV over a period of 60 minutes, every 2 weeks, until disease progression or unacceptable toxicity occurs. Full prescribing information is available here.
Durvalumab is marketed as Imfinzi by AstraZeneca. The complementary diagnostic is the Ventana PD-L1 (SP263) Assay from Ventana Medical Systems.
Lenvatinib expands its reach into renal cell carcinoma
The US Food and Drug Administration (FDA) expanded the approval of the multitargeted tyrosine kinase inhibitor lenvatinib to a second indication in 2016. In addition to thyroid cancer, the drug is now approved in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for the treatment of advanced renal cell carcinoma (RCC) after one prior anti-angiogenic therapy.
The current approval was based on the demonstration of synergistic efficacy and a manageable toxicity profile for the combination in a randomized, open-label, phase 2 clinical trial performed at 37 centers in 5 countries. Patients were eligible for the study if they were aged 18 years or older and had histologically verified clear cell RCC, measurable disease as assessed by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, radiographic evidence of progression or metastasis
From March 16, 2012 to June 19, 2013, 153 patients were randomly assigned in a 1:1:1 ratio to 3 treatment arms; lenvatinib 18 mg plus everolimus 5 mg, lenvatinib 24 mg monotherapy, or everolimus 10 mg monotherapy, all administered once daily. Randomization was stratified according to hemoglobin (men ≤130 g/L and >130 g/L; women ≤115 g/L and >115 g/L) and corrected serum calcium (≥2.5 mmol/L and <2.5 mmol/L).
Radiographic tumor response assessments were performed every 8 weeks from randomization until disease progression or the start of another anticancer treatment. To enable pharmacokinetic analyses, 6 blood samples were obtained on day 1 of the first 3 treatment cycles for all patients. In addition, 9 samples were obtained over a 24-hour period for 9-12 patients in each treatment group to provide intensive samples.
The primary endpoint of the study was progression-free survival (PFS), which was significantly improved with a combination of lenvatinib and everolimus, compared with single-agent everolimus. Median PFS was 14.6 months, compared with 5.5 months, respectively (hazard ratio [HR], 0.40; P = .0005), translating into a 63% reduction in the risk of disease progression or death. In the lenvatinib monotherapy group, median PFS was 7.4 months.
Over a median follow-up of 24.2 months there was also a significant difference in overall survival (OS) between the combination arm and single-agent everolimus (24.2 months vs 15.4 months, respectively). Objective responses were seen in 43% of patients in the combination arm and 6% and 27% of patients in the everolimus and lenvatinib monotherapy arms, respectively. The median duration of response was 13 months, 8.5 months, and 7.5 months in the 3 treatment arms, respectively.
All patients had at least 1 treatment-related adverse event (AE), almost all considered to be related to the study drug. Among patients treated with lenvatinib and everolimus, 24% discontinued therapy because of AEs, whereas the rate of discontinuation was 12% and 25% among patients treated with everolimus or lenvatinib monotherapy, respectively. There was 1 instance of a trans-arterial embolization leading to death that was judged to be probably treatment related in the combination arm, compared with 2 in the everolimus arm, neither judged treatment-related, and 3 in the lenvatinib arm, 1 of which was considered to be possibly treatment related.
The rates of grade 3/4 AEs were 71% for combination therapy, compared with 50% and 79%, respectively, among patients treated with everolimus or lenvatinib alone. Most commonly, in the combination arm, these included renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%).
The prescribing information carries warnings and precautions about hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, renal failure and impairment, gastrointestinal perforation, and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, and impairment of thyroid stimulating hormone suppression or thyroid dysfunction, all of which have been reported in clinical trials of lenvatinib and everolimus. Patients should also be warned about the risk of fetal harm.
Blood pressure should be closely monitored prior to treatment, after 1 week and then every 2 weeks for the first 2 months, then at least monthly thereafter during treatment. Patients should be monitored for signs of cardiac decompensation and proteinuria. Liver function should be monitored before initiating therapy, every 2 weeks for the first 2 months and then at least monthly while treatment continues. Electrolyte abnormalities should be monitored and corrected, blood calcium levels should be monitored at least monthly, and thyroid function should be evaluated before and at least monthly during treatment.
The prescribing information details dose reductions and modifications for AEs. Treatment should be withheld for grade 3 hypertension, grade 3 cardiac dysfunction, grade 3 or greater hepatotoxicity, proteinuria >2 g/24 hours, grade 3 diarrhea, grade 3/4 renal failure or impairment, corrected QT interval prolongation >500 ms, hypocalcemia as necessary, reversible posterior leukoencephalopathy syndrome confirmed by magnetic resonance imaging, and grade 3 hemorrhagic events.
Treatment discontinuation should occur in the event of life-threatening hypertension, grade 4 cardiac dysfunction, arterial thromboembolic events, hepatic failure, grade 3 diarrhea that persists despite medical management, severe or persistent renal impairment, gastrointestinal perforation or life-threatening fistula formation, severe and persistent neurologic symptoms, and grade 4 hemorrhage. The recommended dose for lenvatinib, which is marketed as Lenvima by Eisai Inc, is 18 mg (1 x 10 mg capsule and 2 x 4 mg capsules) in combination with 5 mg everolimus orally taken daily, with or without food, until disease progression or unacceptable toxicity.
1. Lenvima (lenvatinib) capsules, for oral use. Prescribing information. Woodcliff Lake, NJ: Eisai Inc: 2016. http://www.lenvima.com/pdfs/prescribing-information.pdf. Accessed November 17, 2016.
2. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473-1482.
3. US Food and Drug Administration. Lenvatinib in combination with everolimus. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501070.htm. Last updated May 16, 2016. Accessed November 17, 2016.
The US Food and Drug Administration (FDA) expanded the approval of the multitargeted tyrosine kinase inhibitor lenvatinib to a second indication in 2016. In addition to thyroid cancer, the drug is now approved in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for the treatment of advanced renal cell carcinoma (RCC) after one prior anti-angiogenic therapy.
The current approval was based on the demonstration of synergistic efficacy and a manageable toxicity profile for the combination in a randomized, open-label, phase 2 clinical trial performed at 37 centers in 5 countries. Patients were eligible for the study if they were aged 18 years or older and had histologically verified clear cell RCC, measurable disease as assessed by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, radiographic evidence of progression or metastasis
From March 16, 2012 to June 19, 2013, 153 patients were randomly assigned in a 1:1:1 ratio to 3 treatment arms; lenvatinib 18 mg plus everolimus 5 mg, lenvatinib 24 mg monotherapy, or everolimus 10 mg monotherapy, all administered once daily. Randomization was stratified according to hemoglobin (men ≤130 g/L and >130 g/L; women ≤115 g/L and >115 g/L) and corrected serum calcium (≥2.5 mmol/L and <2.5 mmol/L).
Radiographic tumor response assessments were performed every 8 weeks from randomization until disease progression or the start of another anticancer treatment. To enable pharmacokinetic analyses, 6 blood samples were obtained on day 1 of the first 3 treatment cycles for all patients. In addition, 9 samples were obtained over a 24-hour period for 9-12 patients in each treatment group to provide intensive samples.
The primary endpoint of the study was progression-free survival (PFS), which was significantly improved with a combination of lenvatinib and everolimus, compared with single-agent everolimus. Median PFS was 14.6 months, compared with 5.5 months, respectively (hazard ratio [HR], 0.40; P = .0005), translating into a 63% reduction in the risk of disease progression or death. In the lenvatinib monotherapy group, median PFS was 7.4 months.
Over a median follow-up of 24.2 months there was also a significant difference in overall survival (OS) between the combination arm and single-agent everolimus (24.2 months vs 15.4 months, respectively). Objective responses were seen in 43% of patients in the combination arm and 6% and 27% of patients in the everolimus and lenvatinib monotherapy arms, respectively. The median duration of response was 13 months, 8.5 months, and 7.5 months in the 3 treatment arms, respectively.
All patients had at least 1 treatment-related adverse event (AE), almost all considered to be related to the study drug. Among patients treated with lenvatinib and everolimus, 24% discontinued therapy because of AEs, whereas the rate of discontinuation was 12% and 25% among patients treated with everolimus or lenvatinib monotherapy, respectively. There was 1 instance of a trans-arterial embolization leading to death that was judged to be probably treatment related in the combination arm, compared with 2 in the everolimus arm, neither judged treatment-related, and 3 in the lenvatinib arm, 1 of which was considered to be possibly treatment related.
The rates of grade 3/4 AEs were 71% for combination therapy, compared with 50% and 79%, respectively, among patients treated with everolimus or lenvatinib alone. Most commonly, in the combination arm, these included renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%).
The prescribing information carries warnings and precautions about hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, renal failure and impairment, gastrointestinal perforation, and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, and impairment of thyroid stimulating hormone suppression or thyroid dysfunction, all of which have been reported in clinical trials of lenvatinib and everolimus. Patients should also be warned about the risk of fetal harm.
Blood pressure should be closely monitored prior to treatment, after 1 week and then every 2 weeks for the first 2 months, then at least monthly thereafter during treatment. Patients should be monitored for signs of cardiac decompensation and proteinuria. Liver function should be monitored before initiating therapy, every 2 weeks for the first 2 months and then at least monthly while treatment continues. Electrolyte abnormalities should be monitored and corrected, blood calcium levels should be monitored at least monthly, and thyroid function should be evaluated before and at least monthly during treatment.
The prescribing information details dose reductions and modifications for AEs. Treatment should be withheld for grade 3 hypertension, grade 3 cardiac dysfunction, grade 3 or greater hepatotoxicity, proteinuria >2 g/24 hours, grade 3 diarrhea, grade 3/4 renal failure or impairment, corrected QT interval prolongation >500 ms, hypocalcemia as necessary, reversible posterior leukoencephalopathy syndrome confirmed by magnetic resonance imaging, and grade 3 hemorrhagic events.
Treatment discontinuation should occur in the event of life-threatening hypertension, grade 4 cardiac dysfunction, arterial thromboembolic events, hepatic failure, grade 3 diarrhea that persists despite medical management, severe or persistent renal impairment, gastrointestinal perforation or life-threatening fistula formation, severe and persistent neurologic symptoms, and grade 4 hemorrhage. The recommended dose for lenvatinib, which is marketed as Lenvima by Eisai Inc, is 18 mg (1 x 10 mg capsule and 2 x 4 mg capsules) in combination with 5 mg everolimus orally taken daily, with or without food, until disease progression or unacceptable toxicity.
The US Food and Drug Administration (FDA) expanded the approval of the multitargeted tyrosine kinase inhibitor lenvatinib to a second indication in 2016. In addition to thyroid cancer, the drug is now approved in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for the treatment of advanced renal cell carcinoma (RCC) after one prior anti-angiogenic therapy.
The current approval was based on the demonstration of synergistic efficacy and a manageable toxicity profile for the combination in a randomized, open-label, phase 2 clinical trial performed at 37 centers in 5 countries. Patients were eligible for the study if they were aged 18 years or older and had histologically verified clear cell RCC, measurable disease as assessed by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, radiographic evidence of progression or metastasis
From March 16, 2012 to June 19, 2013, 153 patients were randomly assigned in a 1:1:1 ratio to 3 treatment arms; lenvatinib 18 mg plus everolimus 5 mg, lenvatinib 24 mg monotherapy, or everolimus 10 mg monotherapy, all administered once daily. Randomization was stratified according to hemoglobin (men ≤130 g/L and >130 g/L; women ≤115 g/L and >115 g/L) and corrected serum calcium (≥2.5 mmol/L and <2.5 mmol/L).
Radiographic tumor response assessments were performed every 8 weeks from randomization until disease progression or the start of another anticancer treatment. To enable pharmacokinetic analyses, 6 blood samples were obtained on day 1 of the first 3 treatment cycles for all patients. In addition, 9 samples were obtained over a 24-hour period for 9-12 patients in each treatment group to provide intensive samples.
The primary endpoint of the study was progression-free survival (PFS), which was significantly improved with a combination of lenvatinib and everolimus, compared with single-agent everolimus. Median PFS was 14.6 months, compared with 5.5 months, respectively (hazard ratio [HR], 0.40; P = .0005), translating into a 63% reduction in the risk of disease progression or death. In the lenvatinib monotherapy group, median PFS was 7.4 months.
Over a median follow-up of 24.2 months there was also a significant difference in overall survival (OS) between the combination arm and single-agent everolimus (24.2 months vs 15.4 months, respectively). Objective responses were seen in 43% of patients in the combination arm and 6% and 27% of patients in the everolimus and lenvatinib monotherapy arms, respectively. The median duration of response was 13 months, 8.5 months, and 7.5 months in the 3 treatment arms, respectively.
All patients had at least 1 treatment-related adverse event (AE), almost all considered to be related to the study drug. Among patients treated with lenvatinib and everolimus, 24% discontinued therapy because of AEs, whereas the rate of discontinuation was 12% and 25% among patients treated with everolimus or lenvatinib monotherapy, respectively. There was 1 instance of a trans-arterial embolization leading to death that was judged to be probably treatment related in the combination arm, compared with 2 in the everolimus arm, neither judged treatment-related, and 3 in the lenvatinib arm, 1 of which was considered to be possibly treatment related.
The rates of grade 3/4 AEs were 71% for combination therapy, compared with 50% and 79%, respectively, among patients treated with everolimus or lenvatinib alone. Most commonly, in the combination arm, these included renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%).
The prescribing information carries warnings and precautions about hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, renal failure and impairment, gastrointestinal perforation, and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, and impairment of thyroid stimulating hormone suppression or thyroid dysfunction, all of which have been reported in clinical trials of lenvatinib and everolimus. Patients should also be warned about the risk of fetal harm.
Blood pressure should be closely monitored prior to treatment, after 1 week and then every 2 weeks for the first 2 months, then at least monthly thereafter during treatment. Patients should be monitored for signs of cardiac decompensation and proteinuria. Liver function should be monitored before initiating therapy, every 2 weeks for the first 2 months and then at least monthly while treatment continues. Electrolyte abnormalities should be monitored and corrected, blood calcium levels should be monitored at least monthly, and thyroid function should be evaluated before and at least monthly during treatment.
The prescribing information details dose reductions and modifications for AEs. Treatment should be withheld for grade 3 hypertension, grade 3 cardiac dysfunction, grade 3 or greater hepatotoxicity, proteinuria >2 g/24 hours, grade 3 diarrhea, grade 3/4 renal failure or impairment, corrected QT interval prolongation >500 ms, hypocalcemia as necessary, reversible posterior leukoencephalopathy syndrome confirmed by magnetic resonance imaging, and grade 3 hemorrhagic events.
Treatment discontinuation should occur in the event of life-threatening hypertension, grade 4 cardiac dysfunction, arterial thromboembolic events, hepatic failure, grade 3 diarrhea that persists despite medical management, severe or persistent renal impairment, gastrointestinal perforation or life-threatening fistula formation, severe and persistent neurologic symptoms, and grade 4 hemorrhage. The recommended dose for lenvatinib, which is marketed as Lenvima by Eisai Inc, is 18 mg (1 x 10 mg capsule and 2 x 4 mg capsules) in combination with 5 mg everolimus orally taken daily, with or without food, until disease progression or unacceptable toxicity.
1. Lenvima (lenvatinib) capsules, for oral use. Prescribing information. Woodcliff Lake, NJ: Eisai Inc: 2016. http://www.lenvima.com/pdfs/prescribing-information.pdf. Accessed November 17, 2016.
2. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473-1482.
3. US Food and Drug Administration. Lenvatinib in combination with everolimus. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501070.htm. Last updated May 16, 2016. Accessed November 17, 2016.
1. Lenvima (lenvatinib) capsules, for oral use. Prescribing information. Woodcliff Lake, NJ: Eisai Inc: 2016. http://www.lenvima.com/pdfs/prescribing-information.pdf. Accessed November 17, 2016.
2. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473-1482.
3. US Food and Drug Administration. Lenvatinib in combination with everolimus. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501070.htm. Last updated May 16, 2016. Accessed November 17, 2016.