Genitourinary Cancer

CHICAGO – Combining two immunotherapies, one inhibiting immune suppression and the other stimulating immune activation, is well tolerated and shows activity for a variety of solid tumor types, according to a phase I trial presented at the annual meeting of the American Association of Clinical Oncology.

Investigators enrolled 51 patients with locally advanced or metastatic solid tumors of any type after progression on standard therapy to a phase Ib dose-escalation study using atezolizumab, a monoclonal antibody checkpoint inhibitor that targets PD-L1, in combination with MOXR0916 (MOXR), an agonist IgG1 monoclonal antibody targeting OX40, a costimulatory receptor. Atezolizumab received Food and Drug Administration approval in May 2016 for use in certain patients with urothelial carcinoma. There were 28 patients in a dose-escalation cohort of the study and 23 in a serial biopsy cohort. The dose of the drug combination was started at 12 mg and escalated to understand pharmacodynamic changes in the tumors.

“The pharmacokinetics of both MOXR0916 and atezolizumab were similar to their single-agent data, suggesting no interaction,” reported Dr. Jeffrey Infante of the Sarah Cannon Research Institute in Nashville, Tenn.

The drug combination was well tolerated through the entire escalation range of MOXR. There were no dose-limiting toxicities, and no maximal tolerated dose was reached. There were also no drug-related deaths or grade 4 toxicities or drug-related treatment discontinuations. One case of grade 3 pneumonitis, successfully managed with methylprednisolone and antibiotics, occurred at the MOXR 40-mg dose on cycle 4 of treatment in a patient with non–small-cell lung cancer, he said.

About half the patients (53%) experienced any form of adverse event on the drug combination, and only 8% were grade 2 or 3. There were very few adverse events of any one type, and they did not appear to cluster among patients on the higher MOXR doses. The most prevalent adverse events were nausea, fever, fatigue, and rash, and each was in the 8%-14% range and almost always grade 1.

Many patients showed efficacy of the regimens out to 6-7 cycles regardless of tumor type, and 8 of the 51 patients were still receiving the therapy past cycle 7 with partial responses.

The stimulatory molecule OX40 is not normally expressed on T cells, but it is expressed when antigen interacts with the T-cell receptor, and it can then interact with its ligand, OX40L. The result is production of inflammatory cytokines such as gamma-interferon, activation and survival of effector T cells, and production of memory T cells. At the same time, OX40 activity blocks the suppressive function of regulatory T cells.

“So a molecule that can be a cancer therapeutic such as an OX40 agonist has dual mechanisms of action,” Dr. Infante said. “It can costimulate effector T cells and at the same time inhibit regulatory T cells. Furthermore, there is a reduced risk of toxicity, potentially, as its activity is linked to antigen recognition.”

There is good rationale for using an OX40 agonist such as MOXR, either for its immune stimulatory function or to deactivate immune suppression by regulatory T cells, or both, said discussant Dr. Jedd Wolchok, chief, melanoma and immunotherapeutics service, Memorial Sloan-Kettering Cancer Center, New York. Dr. Infante’s dose-escalation study was “very nicely designed and showed quite good safety,” Dr. Wolchok said, though one thing he would have liked to have seen was a quantification of regulatory T cells in tumor biopsies.

“This [study] is very important considering that this is an agonist antibody, and the agonist agents need to be dosed very deliberatively, as was done here, to ensure safety of patients,” Dr. Wolchok said, adding that further research needs to target “optimal combinatorial partners” and explore other mechanistic biomarkers.

MOXR was given in this trial at escalating doses on a 3+3 design (0.8-1,200 mg) on the same day as atezolizumab 1,200 mg IV once every 3 weeks with a 21-day window for assessment of MOXR dose-limiting toxicities. MOXR doses of 300 mg maintained trough concentrations sufficient to saturate OX40 receptors. An expansion regimen using 300 mg MOXR with atezolizumab 1,200 mg every 3 weeks is underway and will assess efficacy in the treatment of melanoma, renal cell carcinoma, non–small-cell lung cancer, urothelial carcinoma, and triple-negative breast cancer.

The study was sponsored by Roche. Dr. Infante reported having no relevant financial disclosures. Dr. Wolchok owns stock in Potenza Therapeutics and Vesuvius Pharmaceuticals, has received travel expenses and/or has an advisory role with several other companies, and is a coinventor on an issued patent for DNA vaccines for the treatment of cancer in companion animals.

CHICAGO – Combining two immunotherapies, one inhibiting immune suppression and the other stimulating immune activation, is well tolerated and shows activity for a variety of solid tumor types, according to a phase I trial presented at the annual meeting of the American Association of Clinical Oncology.

Investigators enrolled 51 patients with locally advanced or metastatic solid tumors of any type after progression on standard therapy to a phase Ib dose-escalation study using atezolizumab, a monoclonal antibody checkpoint inhibitor that targets PD-L1, in combination with MOXR0916 (MOXR), an agonist IgG1 monoclonal antibody targeting OX40, a costimulatory receptor. Atezolizumab received Food and Drug Administration approval in May 2016 for use in certain patients with urothelial carcinoma. There were 28 patients in a dose-escalation cohort of the study and 23 in a serial biopsy cohort. The dose of the drug combination was started at 12 mg and escalated to understand pharmacodynamic changes in the tumors.

“The pharmacokinetics of both MOXR0916 and atezolizumab were similar to their single-agent data, suggesting no interaction,” reported Dr. Jeffrey Infante of the Sarah Cannon Research Institute in Nashville, Tenn.

The drug combination was well tolerated through the entire escalation range of MOXR. There were no dose-limiting toxicities, and no maximal tolerated dose was reached. There were also no drug-related deaths or grade 4 toxicities or drug-related treatment discontinuations. One case of grade 3 pneumonitis, successfully managed with methylprednisolone and antibiotics, occurred at the MOXR 40-mg dose on cycle 4 of treatment in a patient with non–small-cell lung cancer, he said.

About half the patients (53%) experienced any form of adverse event on the drug combination, and only 8% were grade 2 or 3. There were very few adverse events of any one type, and they did not appear to cluster among patients on the higher MOXR doses. The most prevalent adverse events were nausea, fever, fatigue, and rash, and each was in the 8%-14% range and almost always grade 1.

Many patients showed efficacy of the regimens out to 6-7 cycles regardless of tumor type, and 8 of the 51 patients were still receiving the therapy past cycle 7 with partial responses.

The stimulatory molecule OX40 is not normally expressed on T cells, but it is expressed when antigen interacts with the T-cell receptor, and it can then interact with its ligand, OX40L. The result is production of inflammatory cytokines such as gamma-interferon, activation and survival of effector T cells, and production of memory T cells. At the same time, OX40 activity blocks the suppressive function of regulatory T cells.

“So a molecule that can be a cancer therapeutic such as an OX40 agonist has dual mechanisms of action,” Dr. Infante said. “It can costimulate effector T cells and at the same time inhibit regulatory T cells. Furthermore, there is a reduced risk of toxicity, potentially, as its activity is linked to antigen recognition.”

There is good rationale for using an OX40 agonist such as MOXR, either for its immune stimulatory function or to deactivate immune suppression by regulatory T cells, or both, said discussant Dr. Jedd Wolchok, chief, melanoma and immunotherapeutics service, Memorial Sloan-Kettering Cancer Center, New York. Dr. Infante’s dose-escalation study was “very nicely designed and showed quite good safety,” Dr. Wolchok said, though one thing he would have liked to have seen was a quantification of regulatory T cells in tumor biopsies.

“This [study] is very important considering that this is an agonist antibody, and the agonist agents need to be dosed very deliberatively, as was done here, to ensure safety of patients,” Dr. Wolchok said, adding that further research needs to target “optimal combinatorial partners” and explore other mechanistic biomarkers.

MOXR was given in this trial at escalating doses on a 3+3 design (0.8-1,200 mg) on the same day as atezolizumab 1,200 mg IV once every 3 weeks with a 21-day window for assessment of MOXR dose-limiting toxicities. MOXR doses of 300 mg maintained trough concentrations sufficient to saturate OX40 receptors. An expansion regimen using 300 mg MOXR with atezolizumab 1,200 mg every 3 weeks is underway and will assess efficacy in the treatment of melanoma, renal cell carcinoma, non–small-cell lung cancer, urothelial carcinoma, and triple-negative breast cancer.

The study was sponsored by Roche. Dr. Infante reported having no relevant financial disclosures. Dr. Wolchok owns stock in Potenza Therapeutics and Vesuvius Pharmaceuticals, has received travel expenses and/or has an advisory role with several other companies, and is a coinventor on an issued patent for DNA vaccines for the treatment of cancer in companion animals.

CHICAGO – Combining two immunotherapies, one inhibiting immune suppression and the other stimulating immune activation, is well tolerated and shows activity for a variety of solid tumor types, according to a phase I trial presented at the annual meeting of the American Association of Clinical Oncology.

Investigators enrolled 51 patients with locally advanced or metastatic solid tumors of any type after progression on standard therapy to a phase Ib dose-escalation study using atezolizumab, a monoclonal antibody checkpoint inhibitor that targets PD-L1, in combination with MOXR0916 (MOXR), an agonist IgG1 monoclonal antibody targeting OX40, a costimulatory receptor. Atezolizumab received Food and Drug Administration approval in May 2016 for use in certain patients with urothelial carcinoma. There were 28 patients in a dose-escalation cohort of the study and 23 in a serial biopsy cohort. The dose of the drug combination was started at 12 mg and escalated to understand pharmacodynamic changes in the tumors.

“The pharmacokinetics of both MOXR0916 and atezolizumab were similar to their single-agent data, suggesting no interaction,” reported Dr. Jeffrey Infante of the Sarah Cannon Research Institute in Nashville, Tenn.

The drug combination was well tolerated through the entire escalation range of MOXR. There were no dose-limiting toxicities, and no maximal tolerated dose was reached. There were also no drug-related deaths or grade 4 toxicities or drug-related treatment discontinuations. One case of grade 3 pneumonitis, successfully managed with methylprednisolone and antibiotics, occurred at the MOXR 40-mg dose on cycle 4 of treatment in a patient with non–small-cell lung cancer, he said.

About half the patients (53%) experienced any form of adverse event on the drug combination, and only 8% were grade 2 or 3. There were very few adverse events of any one type, and they did not appear to cluster among patients on the higher MOXR doses. The most prevalent adverse events were nausea, fever, fatigue, and rash, and each was in the 8%-14% range and almost always grade 1.

Many patients showed efficacy of the regimens out to 6-7 cycles regardless of tumor type, and 8 of the 51 patients were still receiving the therapy past cycle 7 with partial responses.

The stimulatory molecule OX40 is not normally expressed on T cells, but it is expressed when antigen interacts with the T-cell receptor, and it can then interact with its ligand, OX40L. The result is production of inflammatory cytokines such as gamma-interferon, activation and survival of effector T cells, and production of memory T cells. At the same time, OX40 activity blocks the suppressive function of regulatory T cells.

“So a molecule that can be a cancer therapeutic such as an OX40 agonist has dual mechanisms of action,” Dr. Infante said. “It can costimulate effector T cells and at the same time inhibit regulatory T cells. Furthermore, there is a reduced risk of toxicity, potentially, as its activity is linked to antigen recognition.”

There is good rationale for using an OX40 agonist such as MOXR, either for its immune stimulatory function or to deactivate immune suppression by regulatory T cells, or both, said discussant Dr. Jedd Wolchok, chief, melanoma and immunotherapeutics service, Memorial Sloan-Kettering Cancer Center, New York. Dr. Infante’s dose-escalation study was “very nicely designed and showed quite good safety,” Dr. Wolchok said, though one thing he would have liked to have seen was a quantification of regulatory T cells in tumor biopsies.

“This [study] is very important considering that this is an agonist antibody, and the agonist agents need to be dosed very deliberatively, as was done here, to ensure safety of patients,” Dr. Wolchok said, adding that further research needs to target “optimal combinatorial partners” and explore other mechanistic biomarkers.

MOXR was given in this trial at escalating doses on a 3+3 design (0.8-1,200 mg) on the same day as atezolizumab 1,200 mg IV once every 3 weeks with a 21-day window for assessment of MOXR dose-limiting toxicities. MOXR doses of 300 mg maintained trough concentrations sufficient to saturate OX40 receptors. An expansion regimen using 300 mg MOXR with atezolizumab 1,200 mg every 3 weeks is underway and will assess efficacy in the treatment of melanoma, renal cell carcinoma, non–small-cell lung cancer, urothelial carcinoma, and triple-negative breast cancer.

The study was sponsored by Roche. Dr. Infante reported having no relevant financial disclosures. Dr. Wolchok owns stock in Potenza Therapeutics and Vesuvius Pharmaceuticals, has received travel expenses and/or has an advisory role with several other companies, and is a coinventor on an issued patent for DNA vaccines for the treatment of cancer in companion animals.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

tor@frontlinemedcom.com

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

tor@frontlinemedcom.com

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

tor@frontlinemedcom.com

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

CHICAGO – Agents that target the HER2, BRAF, Hedgehog, or EGFR pathways show promise in nonindicated tumor types that harbor these molecular alterations, according to early findings from the MyPathway study.

Of 129 patients enrolled in the multicenter, open-label, phase IIa study, 29 had a major response, defined as tumor shrinkage of at least 30%, to such treatment. One of those patients had a complete response, and 28 had a partial response. An additional 40 patients had stable disease on treatment. Fourteen of the 29 patients progressed after a median of 6 months’ follow-up, and 15 responses were ongoing at up to 11 months, Dr. John D. Hainsworth reported at the annual meeting of the American Society of Clinical Oncology.

©Gio_tto/Thinkstock.com

No new safety signals were observed, said Dr. Hainsworth of Sarah Cannon Research Institute in Nashville, Tenn.

Treatments evaluated in MyPathway included:

• Trastuzumab + pertuzumab, which targets the HER2 pathway and is currently indicated for breast cancer.

• Vemurafenib, which targets the BRAF pathway and is currently indicated for melanoma.

• Vismodegib, which targets the Hedgehog pathway and is currently indicated for basal cell carcinoma of the skin.

• Erlotinib, which targets the EGFR pathway and is indicated for non–small-cell lung cancer.

Responses have been seen with all four of the treatments, but the best responses were seen among patients with HER2 and BRAF abnormalities.

Among 61 cancers with HER2 amplification/overexpression, trastuzumab + pertuzumab provided a benefit for colorectal, bladder, biliary, non–small-cell lung, pancreas, and head/neck cancers.

Of 20 colorectal tumors, 7 (35%) showed complete or partial response, and 3 (15%) remained stable for at least 120 days (clinical benefit rate, 50%). Complete/partial responses and stable disease, respectively, were also seen in three and two of eight bladder tumors (clinical benefit rate, 63%), in three and three of six biliary tumors (clinical benefit rate, 100%), in two and zero of seven non–small-cell lung tumors (clinical benefit rate, 29%), one and zero of six pancreas tumors (clinical benefit rate, 17%), and one and zero of three head and neck tumors (34%). One of 11 other types of tumors showed disease stability at 120 days (clinical benefit rate, 9%). The overall clinical benefit rate in the study was 43%, Dr. Hainsworth said.

Among 33 cancers with the BRAF mutation, vemurafenib showed activity for non–small-cell lung, ovary, unknown primary, colorectal, pancreas, and head/neck tumors. Of 15 non–small-cell lung tumors, 3 (20%) showed complete or partial responses and 2 (13%) remained stable for at least 120 days (clinical benefit rate, 33%). Complete/partial responses and stable disease, respectively, were also seen in one and two of four ovary tumors (clinical benefit rate, 75%), and complete or partial responses were seen in one each of three unknown primary tumors, two colorectal tumors, two pancreas tumors, and one head/neck tumor (clinical benefit rates of 33%, 50%, 50%, and 100%, respectively). No benefit was seen with tumors at other sites (total clinical benefit rate, 36%), Dr. Hainsworth said.

“Of interest in this group [of patients with BRAF mutations], seven of the eight responses were in V600E mutations, and as you know, that’s the mutation that’s been specifically correlated with high response to BRAF inhibition in melanoma where this treatment is now approved,” he said, adding that the response rate in those patients was 38%.

Based on these early results, enrollment of patients with HER2 abnormalities and colorectal, bladder, or biliary cancer, and of patients with BRAF mutations and lung cancer, will be expanded, he said.

Subjects enrolled in MyPathway have advanced cancer showing abnormalities in any of the pathways of interest. The first 129 received a mean of three prior therapies, and in the 29 who responded, 12 different types of cancer responded to the targeted treatment.

“An increasing number of targeted agents for advanced cancer are in use now based on the presence of molecular abnormalities in the cancer. … We’ve known that the same mutations that are in those cancers are found in a wide variety of other cancers, although at a lower incidence, and it’s been difficult to test how effective these same treatments are for the other cancers due to the difficulty in identifying the patient population,” he said, explaining that an increase in comprehensive genomic profiling in recent years has allowed for identification of more and more of these mutations in other cancers.

“I think we’ve shown now that this trial design is feasible, where patients are selected on the basis of molecular abnormalities in their cancers rather than on their primary tumor type or primary site, and certainly offers opportunities for patients with these molecular abnormalities,” Dr. Hainsworth concluded.

Thus far, MyPathway has enrolled more than 200 patients, and is designed to accrue up to 500, with adjustment of treatment groups based on response rates. Emerging new regimens that target these pathways, such as the MEK inhibitor cobemetinib, will also be added, as will new agents targeting additional molecular abnormalities.

The study design, using this “tumor-agnostic approach,” mirrors that of the ASCO-led TAPUR trial, according to ASCO spokesperson Dr. Sumanta Kumar Pal.

The findings of these and other precision medicine trials may ultimately shift the longstanding cancer treatment paradigm, Dr. Pal said.

MyPathway received funding from Genentech. Dr. Hainsworth reported that his institution has received research funding from Astellas Pharma, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Lilly, and Novartis.

sworcester@frontlinemedcom.com

CHICAGO – Agents that target the HER2, BRAF, Hedgehog, or EGFR pathways show promise in nonindicated tumor types that harbor these molecular alterations, according to early findings from the MyPathway study.

Of 129 patients enrolled in the multicenter, open-label, phase IIa study, 29 had a major response, defined as tumor shrinkage of at least 30%, to such treatment. One of those patients had a complete response, and 28 had a partial response. An additional 40 patients had stable disease on treatment. Fourteen of the 29 patients progressed after a median of 6 months’ follow-up, and 15 responses were ongoing at up to 11 months, Dr. John D. Hainsworth reported at the annual meeting of the American Society of Clinical Oncology.

©Gio_tto/Thinkstock.com

No new safety signals were observed, said Dr. Hainsworth of Sarah Cannon Research Institute in Nashville, Tenn.

Treatments evaluated in MyPathway included:

• Trastuzumab + pertuzumab, which targets the HER2 pathway and is currently indicated for breast cancer.

• Vemurafenib, which targets the BRAF pathway and is currently indicated for melanoma.

• Vismodegib, which targets the Hedgehog pathway and is currently indicated for basal cell carcinoma of the skin.

• Erlotinib, which targets the EGFR pathway and is indicated for non–small-cell lung cancer.

Responses have been seen with all four of the treatments, but the best responses were seen among patients with HER2 and BRAF abnormalities.

Among 61 cancers with HER2 amplification/overexpression, trastuzumab + pertuzumab provided a benefit for colorectal, bladder, biliary, non–small-cell lung, pancreas, and head/neck cancers.

Of 20 colorectal tumors, 7 (35%) showed complete or partial response, and 3 (15%) remained stable for at least 120 days (clinical benefit rate, 50%). Complete/partial responses and stable disease, respectively, were also seen in three and two of eight bladder tumors (clinical benefit rate, 63%), in three and three of six biliary tumors (clinical benefit rate, 100%), in two and zero of seven non–small-cell lung tumors (clinical benefit rate, 29%), one and zero of six pancreas tumors (clinical benefit rate, 17%), and one and zero of three head and neck tumors (34%). One of 11 other types of tumors showed disease stability at 120 days (clinical benefit rate, 9%). The overall clinical benefit rate in the study was 43%, Dr. Hainsworth said.

Among 33 cancers with the BRAF mutation, vemurafenib showed activity for non–small-cell lung, ovary, unknown primary, colorectal, pancreas, and head/neck tumors. Of 15 non–small-cell lung tumors, 3 (20%) showed complete or partial responses and 2 (13%) remained stable for at least 120 days (clinical benefit rate, 33%). Complete/partial responses and stable disease, respectively, were also seen in one and two of four ovary tumors (clinical benefit rate, 75%), and complete or partial responses were seen in one each of three unknown primary tumors, two colorectal tumors, two pancreas tumors, and one head/neck tumor (clinical benefit rates of 33%, 50%, 50%, and 100%, respectively). No benefit was seen with tumors at other sites (total clinical benefit rate, 36%), Dr. Hainsworth said.

“Of interest in this group [of patients with BRAF mutations], seven of the eight responses were in V600E mutations, and as you know, that’s the mutation that’s been specifically correlated with high response to BRAF inhibition in melanoma where this treatment is now approved,” he said, adding that the response rate in those patients was 38%.

Based on these early results, enrollment of patients with HER2 abnormalities and colorectal, bladder, or biliary cancer, and of patients with BRAF mutations and lung cancer, will be expanded, he said.

Subjects enrolled in MyPathway have advanced cancer showing abnormalities in any of the pathways of interest. The first 129 received a mean of three prior therapies, and in the 29 who responded, 12 different types of cancer responded to the targeted treatment.

“An increasing number of targeted agents for advanced cancer are in use now based on the presence of molecular abnormalities in the cancer. … We’ve known that the same mutations that are in those cancers are found in a wide variety of other cancers, although at a lower incidence, and it’s been difficult to test how effective these same treatments are for the other cancers due to the difficulty in identifying the patient population,” he said, explaining that an increase in comprehensive genomic profiling in recent years has allowed for identification of more and more of these mutations in other cancers.

“I think we’ve shown now that this trial design is feasible, where patients are selected on the basis of molecular abnormalities in their cancers rather than on their primary tumor type or primary site, and certainly offers opportunities for patients with these molecular abnormalities,” Dr. Hainsworth concluded.

Thus far, MyPathway has enrolled more than 200 patients, and is designed to accrue up to 500, with adjustment of treatment groups based on response rates. Emerging new regimens that target these pathways, such as the MEK inhibitor cobemetinib, will also be added, as will new agents targeting additional molecular abnormalities.

The study design, using this “tumor-agnostic approach,” mirrors that of the ASCO-led TAPUR trial, according to ASCO spokesperson Dr. Sumanta Kumar Pal.

The findings of these and other precision medicine trials may ultimately shift the longstanding cancer treatment paradigm, Dr. Pal said.

MyPathway received funding from Genentech. Dr. Hainsworth reported that his institution has received research funding from Astellas Pharma, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Lilly, and Novartis.

sworcester@frontlinemedcom.com

CHICAGO – Agents that target the HER2, BRAF, Hedgehog, or EGFR pathways show promise in nonindicated tumor types that harbor these molecular alterations, according to early findings from the MyPathway study.

Of 129 patients enrolled in the multicenter, open-label, phase IIa study, 29 had a major response, defined as tumor shrinkage of at least 30%, to such treatment. One of those patients had a complete response, and 28 had a partial response. An additional 40 patients had stable disease on treatment. Fourteen of the 29 patients progressed after a median of 6 months’ follow-up, and 15 responses were ongoing at up to 11 months, Dr. John D. Hainsworth reported at the annual meeting of the American Society of Clinical Oncology.

©Gio_tto/Thinkstock.com

No new safety signals were observed, said Dr. Hainsworth of Sarah Cannon Research Institute in Nashville, Tenn.

Treatments evaluated in MyPathway included:

• Trastuzumab + pertuzumab, which targets the HER2 pathway and is currently indicated for breast cancer.

• Vemurafenib, which targets the BRAF pathway and is currently indicated for melanoma.

• Vismodegib, which targets the Hedgehog pathway and is currently indicated for basal cell carcinoma of the skin.

• Erlotinib, which targets the EGFR pathway and is indicated for non–small-cell lung cancer.

Responses have been seen with all four of the treatments, but the best responses were seen among patients with HER2 and BRAF abnormalities.

Among 61 cancers with HER2 amplification/overexpression, trastuzumab + pertuzumab provided a benefit for colorectal, bladder, biliary, non–small-cell lung, pancreas, and head/neck cancers.

Of 20 colorectal tumors, 7 (35%) showed complete or partial response, and 3 (15%) remained stable for at least 120 days (clinical benefit rate, 50%). Complete/partial responses and stable disease, respectively, were also seen in three and two of eight bladder tumors (clinical benefit rate, 63%), in three and three of six biliary tumors (clinical benefit rate, 100%), in two and zero of seven non–small-cell lung tumors (clinical benefit rate, 29%), one and zero of six pancreas tumors (clinical benefit rate, 17%), and one and zero of three head and neck tumors (34%). One of 11 other types of tumors showed disease stability at 120 days (clinical benefit rate, 9%). The overall clinical benefit rate in the study was 43%, Dr. Hainsworth said.

Among 33 cancers with the BRAF mutation, vemurafenib showed activity for non–small-cell lung, ovary, unknown primary, colorectal, pancreas, and head/neck tumors. Of 15 non–small-cell lung tumors, 3 (20%) showed complete or partial responses and 2 (13%) remained stable for at least 120 days (clinical benefit rate, 33%). Complete/partial responses and stable disease, respectively, were also seen in one and two of four ovary tumors (clinical benefit rate, 75%), and complete or partial responses were seen in one each of three unknown primary tumors, two colorectal tumors, two pancreas tumors, and one head/neck tumor (clinical benefit rates of 33%, 50%, 50%, and 100%, respectively). No benefit was seen with tumors at other sites (total clinical benefit rate, 36%), Dr. Hainsworth said.

“Of interest in this group [of patients with BRAF mutations], seven of the eight responses were in V600E mutations, and as you know, that’s the mutation that’s been specifically correlated with high response to BRAF inhibition in melanoma where this treatment is now approved,” he said, adding that the response rate in those patients was 38%.

Based on these early results, enrollment of patients with HER2 abnormalities and colorectal, bladder, or biliary cancer, and of patients with BRAF mutations and lung cancer, will be expanded, he said.

Subjects enrolled in MyPathway have advanced cancer showing abnormalities in any of the pathways of interest. The first 129 received a mean of three prior therapies, and in the 29 who responded, 12 different types of cancer responded to the targeted treatment.

“An increasing number of targeted agents for advanced cancer are in use now based on the presence of molecular abnormalities in the cancer. … We’ve known that the same mutations that are in those cancers are found in a wide variety of other cancers, although at a lower incidence, and it’s been difficult to test how effective these same treatments are for the other cancers due to the difficulty in identifying the patient population,” he said, explaining that an increase in comprehensive genomic profiling in recent years has allowed for identification of more and more of these mutations in other cancers.

“I think we’ve shown now that this trial design is feasible, where patients are selected on the basis of molecular abnormalities in their cancers rather than on their primary tumor type or primary site, and certainly offers opportunities for patients with these molecular abnormalities,” Dr. Hainsworth concluded.

Thus far, MyPathway has enrolled more than 200 patients, and is designed to accrue up to 500, with adjustment of treatment groups based on response rates. Emerging new regimens that target these pathways, such as the MEK inhibitor cobemetinib, will also be added, as will new agents targeting additional molecular abnormalities.

The study design, using this “tumor-agnostic approach,” mirrors that of the ASCO-led TAPUR trial, according to ASCO spokesperson Dr. Sumanta Kumar Pal.

The findings of these and other precision medicine trials may ultimately shift the longstanding cancer treatment paradigm, Dr. Pal said.

MyPathway received funding from Genentech. Dr. Hainsworth reported that his institution has received research funding from Astellas Pharma, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Lilly, and Novartis.

sworcester@frontlinemedcom.com

CHICAGO – Atezolizumab, an antibody that targets PD-L1, achieves a median survival of 14.8 months in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, according to findings of the IMvigor210 trial’s cohort 1. Researchers presented the findings this week at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, lead author Dr. Arjun Vasant Balar of the department of medicine at the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, discussed the study and its implications. In particular, he weighed in on key issues, such as whether PD-L1 status predicts benefit and where atezolizumab may ultimately fit into the treatment armamentarium for this disease.

tor@frontlinemedcom.com

On Twitter @OncologyPractic

CHICAGO – Atezolizumab, an antibody that targets PD-L1, achieves a median survival of 14.8 months in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, according to findings of the IMvigor210 trial’s cohort 1. Researchers presented the findings this week at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, lead author Dr. Arjun Vasant Balar of the department of medicine at the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, discussed the study and its implications. In particular, he weighed in on key issues, such as whether PD-L1 status predicts benefit and where atezolizumab may ultimately fit into the treatment armamentarium for this disease.

tor@frontlinemedcom.com

On Twitter @OncologyPractic

CHICAGO – Atezolizumab, an antibody that targets PD-L1, achieves a median survival of 14.8 months in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, according to findings of the IMvigor210 trial’s cohort 1. Researchers presented the findings this week at the annual meeting of the American Society of Clinical Oncology.

In an interview at the meeting, lead author Dr. Arjun Vasant Balar of the department of medicine at the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, discussed the study and its implications. In particular, he weighed in on key issues, such as whether PD-L1 status predicts benefit and where atezolizumab may ultimately fit into the treatment armamentarium for this disease.

tor@frontlinemedcom.com

On Twitter @OncologyPractic

The Food and Drug Administration has granted accelerated approval to atezolizumab for the treatment of locally advanced or metastatic urothelial carcinoma in patients who experienced disease progression during or following platinum-based chemotherapy, along with a complementary diagnostic.

Atezolizumab, marketed as Tecentriq by Genentech, is the first and only FDA-approved anti-PDL1 immunotherapy for urothelial carcinoma.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

This accelerated approval is based on a 14.8% overall response rate (95% confidence interval, 11.1-19.3) reported from the open-label, multicenter, phase II IMvigor clinical trial of 310 patients, the FDA said in a written statement.

Just over one-fourth (26%) of participants who tested positive for PD-L1 expression experienced a tumor response, compared with 9.5% of participants who were negative for PD-L1 expression. The FDA, therefore, also approved the Ventana PD-L1 (SP142) assay to detect PD-L1 protein expression levels on patients’ tumor-infiltrating immune cells, which will help guide treatment decisions.

The most common adverse events reported in the single-arm trail of atezolizumab were urinary tract infection (9%), anemia (8%), fatigue (6%), and difficulty breathing (4%). Other serious side effects included pneumonitis, hepatitis, colitis, hormone gland problems, neuropathy, meningocephalitis, eye problems, severe infections, and severe infusion reactions. Three people (0.9%) experienced sepsis, pneumonitis, or intestinal obstruction that led to death, Genentech reported in a written statement.

jcraig@frontlinemedcom.com

On Twitter @JessCraig_OP

The Food and Drug Administration has granted accelerated approval to atezolizumab for the treatment of locally advanced or metastatic urothelial carcinoma in patients who experienced disease progression during or following platinum-based chemotherapy, along with a complementary diagnostic.

Atezolizumab, marketed as Tecentriq by Genentech, is the first and only FDA-approved anti-PDL1 immunotherapy for urothelial carcinoma.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

This accelerated approval is based on a 14.8% overall response rate (95% confidence interval, 11.1-19.3) reported from the open-label, multicenter, phase II IMvigor clinical trial of 310 patients, the FDA said in a written statement.

Just over one-fourth (26%) of participants who tested positive for PD-L1 expression experienced a tumor response, compared with 9.5% of participants who were negative for PD-L1 expression. The FDA, therefore, also approved the Ventana PD-L1 (SP142) assay to detect PD-L1 protein expression levels on patients’ tumor-infiltrating immune cells, which will help guide treatment decisions.

The most common adverse events reported in the single-arm trail of atezolizumab were urinary tract infection (9%), anemia (8%), fatigue (6%), and difficulty breathing (4%). Other serious side effects included pneumonitis, hepatitis, colitis, hormone gland problems, neuropathy, meningocephalitis, eye problems, severe infections, and severe infusion reactions. Three people (0.9%) experienced sepsis, pneumonitis, or intestinal obstruction that led to death, Genentech reported in a written statement.

jcraig@frontlinemedcom.com

On Twitter @JessCraig_OP

The Food and Drug Administration has granted accelerated approval to atezolizumab for the treatment of locally advanced or metastatic urothelial carcinoma in patients who experienced disease progression during or following platinum-based chemotherapy, along with a complementary diagnostic.

Atezolizumab, marketed as Tecentriq by Genentech, is the first and only FDA-approved anti-PDL1 immunotherapy for urothelial carcinoma.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

This accelerated approval is based on a 14.8% overall response rate (95% confidence interval, 11.1-19.3) reported from the open-label, multicenter, phase II IMvigor clinical trial of 310 patients, the FDA said in a written statement.

Just over one-fourth (26%) of participants who tested positive for PD-L1 expression experienced a tumor response, compared with 9.5% of participants who were negative for PD-L1 expression. The FDA, therefore, also approved the Ventana PD-L1 (SP142) assay to detect PD-L1 protein expression levels on patients’ tumor-infiltrating immune cells, which will help guide treatment decisions.

The most common adverse events reported in the single-arm trail of atezolizumab were urinary tract infection (9%), anemia (8%), fatigue (6%), and difficulty breathing (4%). Other serious side effects included pneumonitis, hepatitis, colitis, hormone gland problems, neuropathy, meningocephalitis, eye problems, severe infections, and severe infusion reactions. Three people (0.9%) experienced sepsis, pneumonitis, or intestinal obstruction that led to death, Genentech reported in a written statement.

jcraig@frontlinemedcom.com

On Twitter @JessCraig_OP

The Food and Drug Administration has approved lenvatinib capsules, in combination with everolimus, for the treatment of patients with advanced renal cell carcinoma following one prior antiangiogenic therapy.

Approval was based on prolonged progression-free survival (PFS) in a randomized, phase II, open-label multicenter clinical trial of 153 patients, the FDA said in a written statement.

Patients who received lenvatinib plus everolimus (n = 51) had significantly prolonged PFS, compared with patients who received only everolimus (n = 50) (14.6 months vs. 5.5 months; HR, 0.40; 95% CI, 0.24-0.68; P = .0005) but not compared with patients who received lenvatinib alone (n = 52) (7.4 months; HR, 0.66; 95% CI, 0.30-1.10; P = .12). Of patients receiving the combination of drugs, 71% experienced adverse events, compared with 79% of patients receiving lenvatinib alone and 50% of patients receiving everolimus alone. The most common treatment-related adverse events reported included diarrhea, decreased appetite, and severe fatigue.

The FDA previously granted lenvatinib, marketed as Lenvima by Eisai, a breakthrough therapy designation and priority review.

“This is the only combination regimen to significantly prolong progression-free survival … when compared with a standard of care in patients with advanced renal cell carcinoma,” representatives from Eisai said in a written statement.

Lenvatinib was previously approved for the treatment of recurrent, progressive, radioactive iodine-refractory differentiated thyroid cancer in early 2015. However, in April 2016, the FDA released a safety warning about lenvatinib capsules for oral use.

“Serious tumor-related bleeds, including fatal hemorrhagic events in Lenvima-treated patients, have occurred in clinical trials and been reported in postmarketing experience,” reported the FDA in a written statement.

The recommended lenvatinib dosage for renal cell carcinoma patients is 18 mg/day, lower than the 24 mg/day that was recommended to thyroid cancer patients prior to the FDA’s warning.

jcraig@frontlinemedcom.com

On Twitter @JessCraig_OP

The Food and Drug Administration has approved lenvatinib capsules, in combination with everolimus, for the treatment of patients with advanced renal cell carcinoma following one prior antiangiogenic therapy.

Approval was based on prolonged progression-free survival (PFS) in a randomized, phase II, open-label multicenter clinical trial of 153 patients, the FDA said in a written statement.

Patients who received lenvatinib plus everolimus (n = 51) had significantly prolonged PFS, compared with patients who received only everolimus (n = 50) (14.6 months vs. 5.5 months; HR, 0.40; 95% CI, 0.24-0.68; P = .0005) but not compared with patients who received lenvatinib alone (n = 52) (7.4 months; HR, 0.66; 95% CI, 0.30-1.10; P = .12). Of patients receiving the combination of drugs, 71% experienced adverse events, compared with 79% of patients receiving lenvatinib alone and 50% of patients receiving everolimus alone. The most common treatment-related adverse events reported included diarrhea, decreased appetite, and severe fatigue.

The FDA previously granted lenvatinib, marketed as Lenvima by Eisai, a breakthrough therapy designation and priority review.

“This is the only combination regimen to significantly prolong progression-free survival … when compared with a standard of care in patients with advanced renal cell carcinoma,” representatives from Eisai said in a written statement.

Lenvatinib was previously approved for the treatment of recurrent, progressive, radioactive iodine-refractory differentiated thyroid cancer in early 2015. However, in April 2016, the FDA released a safety warning about lenvatinib capsules for oral use.

“Serious tumor-related bleeds, including fatal hemorrhagic events in Lenvima-treated patients, have occurred in clinical trials and been reported in postmarketing experience,” reported the FDA in a written statement.

The recommended lenvatinib dosage for renal cell carcinoma patients is 18 mg/day, lower than the 24 mg/day that was recommended to thyroid cancer patients prior to the FDA’s warning.

jcraig@frontlinemedcom.com

On Twitter @JessCraig_OP

The Food and Drug Administration has approved lenvatinib capsules, in combination with everolimus, for the treatment of patients with advanced renal cell carcinoma following one prior antiangiogenic therapy.

Approval was based on prolonged progression-free survival (PFS) in a randomized, phase II, open-label multicenter clinical trial of 153 patients, the FDA said in a written statement.

Patients who received lenvatinib plus everolimus (n = 51) had significantly prolonged PFS, compared with patients who received only everolimus (n = 50) (14.6 months vs. 5.5 months; HR, 0.40; 95% CI, 0.24-0.68; P = .0005) but not compared with patients who received lenvatinib alone (n = 52) (7.4 months; HR, 0.66; 95% CI, 0.30-1.10; P = .12). Of patients receiving the combination of drugs, 71% experienced adverse events, compared with 79% of patients receiving lenvatinib alone and 50% of patients receiving everolimus alone. The most common treatment-related adverse events reported included diarrhea, decreased appetite, and severe fatigue.

The FDA previously granted lenvatinib, marketed as Lenvima by Eisai, a breakthrough therapy designation and priority review.

“This is the only combination regimen to significantly prolong progression-free survival … when compared with a standard of care in patients with advanced renal cell carcinoma,” representatives from Eisai said in a written statement.

Lenvatinib was previously approved for the treatment of recurrent, progressive, radioactive iodine-refractory differentiated thyroid cancer in early 2015. However, in April 2016, the FDA released a safety warning about lenvatinib capsules for oral use.

“Serious tumor-related bleeds, including fatal hemorrhagic events in Lenvima-treated patients, have occurred in clinical trials and been reported in postmarketing experience,” reported the FDA in a written statement.

The recommended lenvatinib dosage for renal cell carcinoma patients is 18 mg/day, lower than the 24 mg/day that was recommended to thyroid cancer patients prior to the FDA’s warning.

jcraig@frontlinemedcom.com

On Twitter @JessCraig_OP

More reason, if any is needed, to encourage patients to kick the habit comes from a study showing an association between cigarette smoking and tumor DNA methylation changes.

In a study of tumor tissue from men with prostate cancer (PCa) who underwent radical prostatectomy, smoking was associated with differential methylation across 40 genetic regions, and at least 10 of the regions significantly correlated with levels of messenger RNA (mRNA) expression in corresponding genes.

Brett Mulcahy/ThinkStock

Men whose tumors had the highest levels of smoking-associated methylation were more likely to have higher Gleason grade tumors or regional vs. local stage disease, reported Dr. Irene M. Shui of the Fred Hutchinson Cancer Research Center in Seattle and her colleagues.

“[O]ur results provide support for the hypothesis that smoking-induced changes in DNA methylation may underlie the association of smoking with PCa recurrence and mortality,” they wrote (Cancer 2016 May 3. doi: 10.1002/cncr.30045).

To see whether DNA methylation could at least partly explain the association of smoking with increased PCa progression and mortality, the investigators looked at tumor methylation and long-term follow-up data on 523 patients, 469 of whom (90%) had matched tumor gene expression data available. In all, 43% of the men were never smokers, 47% were former smokers, and 10% were current smokers.

The investigators examined tumor methylation profiles by smoking status, with the goals of determining whether smoking-associated changes in methylation are linked to mRNA expression, and whether they are related to disease prognosis.

They found that 40 DNA methylation regions were associated with smoking, and that 10 of the regions were strongly correlated with mRNA expression. They then used these 10 regions to create a smoking-related methylation score.

As noted before, the score was associated with adverse outcomes, with men in the highest third having an odds ratio (OR) for disease recurrence of 2.29 (P = .0007), and an OR of 4.21 for death from prostate cancer (P = .004)

The associations between smoking-related methylation scores and worse outcomes were slightly less strong but still significant after adjustment for Gleason score and pathologic stage.

“Importantly, there is evidence that smoking-related methylation changes in blood may be reversible; men who quit smoking for longer periods of time have methylation profiles similar to those of never-smokers,” the authors wrote.

More reason, if any is needed, to encourage patients to kick the habit comes from a study showing an association between cigarette smoking and tumor DNA methylation changes.

In a study of tumor tissue from men with prostate cancer (PCa) who underwent radical prostatectomy, smoking was associated with differential methylation across 40 genetic regions, and at least 10 of the regions significantly correlated with levels of messenger RNA (mRNA) expression in corresponding genes.

Brett Mulcahy/ThinkStock

Men whose tumors had the highest levels of smoking-associated methylation were more likely to have higher Gleason grade tumors or regional vs. local stage disease, reported Dr. Irene M. Shui of the Fred Hutchinson Cancer Research Center in Seattle and her colleagues.

“[O]ur results provide support for the hypothesis that smoking-induced changes in DNA methylation may underlie the association of smoking with PCa recurrence and mortality,” they wrote (Cancer 2016 May 3. doi: 10.1002/cncr.30045).

To see whether DNA methylation could at least partly explain the association of smoking with increased PCa progression and mortality, the investigators looked at tumor methylation and long-term follow-up data on 523 patients, 469 of whom (90%) had matched tumor gene expression data available. In all, 43% of the men were never smokers, 47% were former smokers, and 10% were current smokers.

The investigators examined tumor methylation profiles by smoking status, with the goals of determining whether smoking-associated changes in methylation are linked to mRNA expression, and whether they are related to disease prognosis.

They found that 40 DNA methylation regions were associated with smoking, and that 10 of the regions were strongly correlated with mRNA expression. They then used these 10 regions to create a smoking-related methylation score.

As noted before, the score was associated with adverse outcomes, with men in the highest third having an odds ratio (OR) for disease recurrence of 2.29 (P = .0007), and an OR of 4.21 for death from prostate cancer (P = .004)

The associations between smoking-related methylation scores and worse outcomes were slightly less strong but still significant after adjustment for Gleason score and pathologic stage.

“Importantly, there is evidence that smoking-related methylation changes in blood may be reversible; men who quit smoking for longer periods of time have methylation profiles similar to those of never-smokers,” the authors wrote.

More reason, if any is needed, to encourage patients to kick the habit comes from a study showing an association between cigarette smoking and tumor DNA methylation changes.

In a study of tumor tissue from men with prostate cancer (PCa) who underwent radical prostatectomy, smoking was associated with differential methylation across 40 genetic regions, and at least 10 of the regions significantly correlated with levels of messenger RNA (mRNA) expression in corresponding genes.

Brett Mulcahy/ThinkStock

Men whose tumors had the highest levels of smoking-associated methylation were more likely to have higher Gleason grade tumors or regional vs. local stage disease, reported Dr. Irene M. Shui of the Fred Hutchinson Cancer Research Center in Seattle and her colleagues.

“[O]ur results provide support for the hypothesis that smoking-induced changes in DNA methylation may underlie the association of smoking with PCa recurrence and mortality,” they wrote (Cancer 2016 May 3. doi: 10.1002/cncr.30045).

To see whether DNA methylation could at least partly explain the association of smoking with increased PCa progression and mortality, the investigators looked at tumor methylation and long-term follow-up data on 523 patients, 469 of whom (90%) had matched tumor gene expression data available. In all, 43% of the men were never smokers, 47% were former smokers, and 10% were current smokers.

The investigators examined tumor methylation profiles by smoking status, with the goals of determining whether smoking-associated changes in methylation are linked to mRNA expression, and whether they are related to disease prognosis.

They found that 40 DNA methylation regions were associated with smoking, and that 10 of the regions were strongly correlated with mRNA expression. They then used these 10 regions to create a smoking-related methylation score.

As noted before, the score was associated with adverse outcomes, with men in the highest third having an odds ratio (OR) for disease recurrence of 2.29 (P = .0007), and an OR of 4.21 for death from prostate cancer (P = .004)

The associations between smoking-related methylation scores and worse outcomes were slightly less strong but still significant after adjustment for Gleason score and pathologic stage.

“Importantly, there is evidence that smoking-related methylation changes in blood may be reversible; men who quit smoking for longer periods of time have methylation profiles similar to those of never-smokers,” the authors wrote.

Increased risk of bladder cancer in New England may be partly due to drinking water from private wells, particularly dug wells established during the first half of the 20th century, according to researchers from the National Cancer Institute. Bladder cancer mortality rates have been elevated in northern New England for at least 5 decades. Incidence rates in Maine, New Hampshire, and Vermont are about 20% higher than in the United States overall, researchers said in a press release.

To explore reasons for the elevated risk, NCI investigators and colleagues in New England compared well water consumption, smoking, occupation, ancestry, use of wood-burning stoves, and consumption of various foods for 1,213 people in New England who were newly diagnosed with bladder cancer, and 1,418 people without bladder cancer who were matched by geographic area.

©Sebastian Kaulitzki/thinkstock

The amount of arsenic ingested through drinking water was estimated based on current levels and historical information. Increasing cumulative exposure was associated with an increasing risk of bladder cancer. Among people who used private wells, people who drank the most water had twice the risk of those who drank the least. Highest risk was seen among those who drank water from dug wells established before 1960, when the use of arsenic-based pesticides was common.

“Arsenic is an established cause of bladder cancer, largely based on observations from earlier studies in highly exposed populations,” said Debra Silverman, Sc.D., chief of the Occupational and Environmental Epidemiology Branch of the NCI, Rockville, Md., and senior author on the study. “However, emerging evidence suggests that low to moderate levels of exposure may also increase risk,” she said in the press release.

“Although smoking and employment in high-risk occupations both showed their expected associations with bladder cancer risk in this population, they were similar to those found in other populations,” Dr. Silverman said. “This suggests that neither risk factor explains the excess occurrence of bladder cancer in northern New England.”

These study results indicate historical consumption of water from private wells, particularly dug wells in an era when arsenic-based pesticides were widely used, may have contributed to the excess rate in New England residents, Dr. Silverman and colleagues concluded.

The study was published in the Journal of the National Cancer Institute (2016;108[9]:djw099).

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

Increased risk of bladder cancer in New England may be partly due to drinking water from private wells, particularly dug wells established during the first half of the 20th century, according to researchers from the National Cancer Institute. Bladder cancer mortality rates have been elevated in northern New England for at least 5 decades. Incidence rates in Maine, New Hampshire, and Vermont are about 20% higher than in the United States overall, researchers said in a press release.

To explore reasons for the elevated risk, NCI investigators and colleagues in New England compared well water consumption, smoking, occupation, ancestry, use of wood-burning stoves, and consumption of various foods for 1,213 people in New England who were newly diagnosed with bladder cancer, and 1,418 people without bladder cancer who were matched by geographic area.

©Sebastian Kaulitzki/thinkstock

The amount of arsenic ingested through drinking water was estimated based on current levels and historical information. Increasing cumulative exposure was associated with an increasing risk of bladder cancer. Among people who used private wells, people who drank the most water had twice the risk of those who drank the least. Highest risk was seen among those who drank water from dug wells established before 1960, when the use of arsenic-based pesticides was common.

“Arsenic is an established cause of bladder cancer, largely based on observations from earlier studies in highly exposed populations,” said Debra Silverman, Sc.D., chief of the Occupational and Environmental Epidemiology Branch of the NCI, Rockville, Md., and senior author on the study. “However, emerging evidence suggests that low to moderate levels of exposure may also increase risk,” she said in the press release.

“Although smoking and employment in high-risk occupations both showed their expected associations with bladder cancer risk in this population, they were similar to those found in other populations,” Dr. Silverman said. “This suggests that neither risk factor explains the excess occurrence of bladder cancer in northern New England.”

These study results indicate historical consumption of water from private wells, particularly dug wells in an era when arsenic-based pesticides were widely used, may have contributed to the excess rate in New England residents, Dr. Silverman and colleagues concluded.

The study was published in the Journal of the National Cancer Institute (2016;108[9]:djw099).

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

Increased risk of bladder cancer in New England may be partly due to drinking water from private wells, particularly dug wells established during the first half of the 20th century, according to researchers from the National Cancer Institute. Bladder cancer mortality rates have been elevated in northern New England for at least 5 decades. Incidence rates in Maine, New Hampshire, and Vermont are about 20% higher than in the United States overall, researchers said in a press release.

To explore reasons for the elevated risk, NCI investigators and colleagues in New England compared well water consumption, smoking, occupation, ancestry, use of wood-burning stoves, and consumption of various foods for 1,213 people in New England who were newly diagnosed with bladder cancer, and 1,418 people without bladder cancer who were matched by geographic area.

©Sebastian Kaulitzki/thinkstock

The amount of arsenic ingested through drinking water was estimated based on current levels and historical information. Increasing cumulative exposure was associated with an increasing risk of bladder cancer. Among people who used private wells, people who drank the most water had twice the risk of those who drank the least. Highest risk was seen among those who drank water from dug wells established before 1960, when the use of arsenic-based pesticides was common.

“Arsenic is an established cause of bladder cancer, largely based on observations from earlier studies in highly exposed populations,” said Debra Silverman, Sc.D., chief of the Occupational and Environmental Epidemiology Branch of the NCI, Rockville, Md., and senior author on the study. “However, emerging evidence suggests that low to moderate levels of exposure may also increase risk,” she said in the press release.

“Although smoking and employment in high-risk occupations both showed their expected associations with bladder cancer risk in this population, they were similar to those found in other populations,” Dr. Silverman said. “This suggests that neither risk factor explains the excess occurrence of bladder cancer in northern New England.”

These study results indicate historical consumption of water from private wells, particularly dug wells in an era when arsenic-based pesticides were widely used, may have contributed to the excess rate in New England residents, Dr. Silverman and colleagues concluded.

The study was published in the Journal of the National Cancer Institute (2016;108[9]:djw099).

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura