Lung Cancer

CHICAGO – One of the main take-home messages in lung cancer this year is the efficacy and tolerability demonstrated in combining checkpoint inhibitors for small-cell lung cancer, Dr. Roy Herbst said in an interview at the annual meeting of the American Society of Clinical Oncology. Combining ipilimumab and nivolumab doubled the response rate in patients with progressive small-cell lung cancer, compared with those receiving only nivolumab.

“The evolution of immunotherapy studies continues to show that immunotherapies are here to stay,” Dr. Herbst said. The next step is to expand on how many respond to them. One possibility is to combine an antiangiogenesis agent with a checkpoint inhibitor to drive T cells into the tumor. Dr. Herbst discusses results he presented at the meeting showing safety and tolerability were achieved when combining pembrolizumab and ramucirumab in patients with non–small-cell lung cancer, and the response rate was close to 30%.

In the video interview, Dr. Herbst, professor and chief of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn., also discusses the evolution of EGFR and ALK inhibitors, a new antibody drug conjugate showing early promise in small cell lung cancer, and the future of liquid biopsies.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

CHICAGO – One of the main take-home messages in lung cancer this year is the efficacy and tolerability demonstrated in combining checkpoint inhibitors for small-cell lung cancer, Dr. Roy Herbst said in an interview at the annual meeting of the American Society of Clinical Oncology. Combining ipilimumab and nivolumab doubled the response rate in patients with progressive small-cell lung cancer, compared with those receiving only nivolumab.

“The evolution of immunotherapy studies continues to show that immunotherapies are here to stay,” Dr. Herbst said. The next step is to expand on how many respond to them. One possibility is to combine an antiangiogenesis agent with a checkpoint inhibitor to drive T cells into the tumor. Dr. Herbst discusses results he presented at the meeting showing safety and tolerability were achieved when combining pembrolizumab and ramucirumab in patients with non–small-cell lung cancer, and the response rate was close to 30%.

In the video interview, Dr. Herbst, professor and chief of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn., also discusses the evolution of EGFR and ALK inhibitors, a new antibody drug conjugate showing early promise in small cell lung cancer, and the future of liquid biopsies.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

CHICAGO – One of the main take-home messages in lung cancer this year is the efficacy and tolerability demonstrated in combining checkpoint inhibitors for small-cell lung cancer, Dr. Roy Herbst said in an interview at the annual meeting of the American Society of Clinical Oncology. Combining ipilimumab and nivolumab doubled the response rate in patients with progressive small-cell lung cancer, compared with those receiving only nivolumab.

“The evolution of immunotherapy studies continues to show that immunotherapies are here to stay,” Dr. Herbst said. The next step is to expand on how many respond to them. One possibility is to combine an antiangiogenesis agent with a checkpoint inhibitor to drive T cells into the tumor. Dr. Herbst discusses results he presented at the meeting showing safety and tolerability were achieved when combining pembrolizumab and ramucirumab in patients with non–small-cell lung cancer, and the response rate was close to 30%.

In the video interview, Dr. Herbst, professor and chief of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn., also discusses the evolution of EGFR and ALK inhibitors, a new antibody drug conjugate showing early promise in small cell lung cancer, and the future of liquid biopsies.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

Patients had significantly better outcomes when treatments were selected based on biomarker analysis of their tumors, in a meta-analysis of 346 phase I trials involving 351 study arms and 13,203 cancer patients.

Up to now, the purpose of phase I trials has been to determine safety based on adverse effects and tolerability. “Our analysis really shows that these days it is completely outdated and that with biomarker selection and especially genomic biomarkers, we can reach high response rates even in phase I trials,” Maria Schwaederle, Pharm.D., of the center for personalized cancer therapy at the University of California, San Diego, said in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.

For the meta-analysis, Dr. Schwaederle and her colleagues performed a PubMed search on phase I clinical trials in cancer published in the years 2011-2013. They included studies using a single agent that reported adequate efficacy endpoints for response rate and progression-free survival (PSF). Overall survival was rarely reported and so was excluded.

Personalized therapy was defined as molecular biomarker–based selection of a treatment or at least half the patients in a trial having a specific tumor known to harbor the biomarker. The study compared outcomes based on a personalized strategy with those that were not.

“We think that the results were striking here,” Dr. Schwaederle said. “We can see that personalized therapy that is [based on] biomarker-selected treatments was really associated with significantly higher response rates and progression-free survival.” Multivariable analysis showed that response rates were sixfold higher with the personalized approach (30.6%, n = 58 in the personalized trials, vs. 4.9%, n = 293 in those not personalized; P less than .0001), and median PFS practically doubled (5.7 months, n = 7 in personalized trials vs. 2.95 months, n = 38 in those not personalized; P = .0002).

Most (98.3%) of the personalized arms used targeted agents. However, 76% of the arms using targeted agents did not select patients using a related biomarker and were thus nonpersonalized in their approach to treatment. A subanalysis showed that targeted drugs that were applied in a nontargeted manner had much worse response rates than targeted therapies applied using biomarker-based selection and were equivalent to cytotoxic therapies (personalized approach, 31.1%; nontargeted approach, 5.1%; P less than 0.0001; cytotoxic drugs, 4.7%, P = .63 vs. nonpersonalized approach). The median PFS was also similar for the nonpersonalized and cytotoxic strategies (3.3 vs. 2.5 months, P = .22).

Better targeting with genomic biomarkers

The investigators found that patients selected based on genomic (DNA) biomarkers had almost double the response rates (42%) of patients selected based on protein biomarkers (22.4%, P = .001). The reasons for this difference were not clear. “We might think that the target in the end is a protein, so we would expect maybe to see better results with protein expression,” Dr. Schwaederle said. But she pointed to the example of patients with lung cancer and epidermal growth factor receptor genetic alterations. If looking only for epidermal growth factor receptor protein overexpression, she said, “we wouldn’t see any response, but only the patients that have specific alterations in this gene respond very well.” So in that case, genetic detection appears to be more sensitive than a protein biomarker–based test.

Dr. Schwaederle addressed the question that has often arisen of whether targeted agents are just better therapies. “Our analysis showed that it is not just that the therapies are better but that targeted therapies must be given to the right patients,” she said. “Indeed, when targeted therapies were given to patients without a biomarker selection, the response rates were only about 5%.”

The response rate in the range of 40% using genetic biomarkers in these phase I trials suggests that incorporating such targeted approaches even at this early stage of drug testing may potentially yield useful information on efficacy.

Dr. Don Dizon, presscast moderator and chair of ASCO’s Cancer Communications Committee, said that precision medicine “is here and that we can use patient selection using either changes in a tumor’s DNA, called genomic changes, or even protein biomarkers and do much better than we have done in the past.”

Dr. Schwaederle noted that one limitation of her study is that more recent trials, unpublished at the time of her analysis, could influence the results today.

The study received funding from the Joan and Irwin Jacobs Philanthropic Fund. Two coauthors reported extensive financial relationships with pharmaceutical or other commercial and noncommercial entities.

Patients had significantly better outcomes when treatments were selected based on biomarker analysis of their tumors, in a meta-analysis of 346 phase I trials involving 351 study arms and 13,203 cancer patients.

Up to now, the purpose of phase I trials has been to determine safety based on adverse effects and tolerability. “Our analysis really shows that these days it is completely outdated and that with biomarker selection and especially genomic biomarkers, we can reach high response rates even in phase I trials,” Maria Schwaederle, Pharm.D., of the center for personalized cancer therapy at the University of California, San Diego, said in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.

For the meta-analysis, Dr. Schwaederle and her colleagues performed a PubMed search on phase I clinical trials in cancer published in the years 2011-2013. They included studies using a single agent that reported adequate efficacy endpoints for response rate and progression-free survival (PSF). Overall survival was rarely reported and so was excluded.

Personalized therapy was defined as molecular biomarker–based selection of a treatment or at least half the patients in a trial having a specific tumor known to harbor the biomarker. The study compared outcomes based on a personalized strategy with those that were not.

“We think that the results were striking here,” Dr. Schwaederle said. “We can see that personalized therapy that is [based on] biomarker-selected treatments was really associated with significantly higher response rates and progression-free survival.” Multivariable analysis showed that response rates were sixfold higher with the personalized approach (30.6%, n = 58 in the personalized trials, vs. 4.9%, n = 293 in those not personalized; P less than .0001), and median PFS practically doubled (5.7 months, n = 7 in personalized trials vs. 2.95 months, n = 38 in those not personalized; P = .0002).

Most (98.3%) of the personalized arms used targeted agents. However, 76% of the arms using targeted agents did not select patients using a related biomarker and were thus nonpersonalized in their approach to treatment. A subanalysis showed that targeted drugs that were applied in a nontargeted manner had much worse response rates than targeted therapies applied using biomarker-based selection and were equivalent to cytotoxic therapies (personalized approach, 31.1%; nontargeted approach, 5.1%; P less than 0.0001; cytotoxic drugs, 4.7%, P = .63 vs. nonpersonalized approach). The median PFS was also similar for the nonpersonalized and cytotoxic strategies (3.3 vs. 2.5 months, P = .22).

Better targeting with genomic biomarkers

The investigators found that patients selected based on genomic (DNA) biomarkers had almost double the response rates (42%) of patients selected based on protein biomarkers (22.4%, P = .001). The reasons for this difference were not clear. “We might think that the target in the end is a protein, so we would expect maybe to see better results with protein expression,” Dr. Schwaederle said. But she pointed to the example of patients with lung cancer and epidermal growth factor receptor genetic alterations. If looking only for epidermal growth factor receptor protein overexpression, she said, “we wouldn’t see any response, but only the patients that have specific alterations in this gene respond very well.” So in that case, genetic detection appears to be more sensitive than a protein biomarker–based test.

Dr. Schwaederle addressed the question that has often arisen of whether targeted agents are just better therapies. “Our analysis showed that it is not just that the therapies are better but that targeted therapies must be given to the right patients,” she said. “Indeed, when targeted therapies were given to patients without a biomarker selection, the response rates were only about 5%.”

The response rate in the range of 40% using genetic biomarkers in these phase I trials suggests that incorporating such targeted approaches even at this early stage of drug testing may potentially yield useful information on efficacy.

Dr. Don Dizon, presscast moderator and chair of ASCO’s Cancer Communications Committee, said that precision medicine “is here and that we can use patient selection using either changes in a tumor’s DNA, called genomic changes, or even protein biomarkers and do much better than we have done in the past.”

Dr. Schwaederle noted that one limitation of her study is that more recent trials, unpublished at the time of her analysis, could influence the results today.

The study received funding from the Joan and Irwin Jacobs Philanthropic Fund. Two coauthors reported extensive financial relationships with pharmaceutical or other commercial and noncommercial entities.

Patients had significantly better outcomes when treatments were selected based on biomarker analysis of their tumors, in a meta-analysis of 346 phase I trials involving 351 study arms and 13,203 cancer patients.

Up to now, the purpose of phase I trials has been to determine safety based on adverse effects and tolerability. “Our analysis really shows that these days it is completely outdated and that with biomarker selection and especially genomic biomarkers, we can reach high response rates even in phase I trials,” Maria Schwaederle, Pharm.D., of the center for personalized cancer therapy at the University of California, San Diego, said in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.

For the meta-analysis, Dr. Schwaederle and her colleagues performed a PubMed search on phase I clinical trials in cancer published in the years 2011-2013. They included studies using a single agent that reported adequate efficacy endpoints for response rate and progression-free survival (PSF). Overall survival was rarely reported and so was excluded.

Personalized therapy was defined as molecular biomarker–based selection of a treatment or at least half the patients in a trial having a specific tumor known to harbor the biomarker. The study compared outcomes based on a personalized strategy with those that were not.

“We think that the results were striking here,” Dr. Schwaederle said. “We can see that personalized therapy that is [based on] biomarker-selected treatments was really associated with significantly higher response rates and progression-free survival.” Multivariable analysis showed that response rates were sixfold higher with the personalized approach (30.6%, n = 58 in the personalized trials, vs. 4.9%, n = 293 in those not personalized; P less than .0001), and median PFS practically doubled (5.7 months, n = 7 in personalized trials vs. 2.95 months, n = 38 in those not personalized; P = .0002).

Most (98.3%) of the personalized arms used targeted agents. However, 76% of the arms using targeted agents did not select patients using a related biomarker and were thus nonpersonalized in their approach to treatment. A subanalysis showed that targeted drugs that were applied in a nontargeted manner had much worse response rates than targeted therapies applied using biomarker-based selection and were equivalent to cytotoxic therapies (personalized approach, 31.1%; nontargeted approach, 5.1%; P less than 0.0001; cytotoxic drugs, 4.7%, P = .63 vs. nonpersonalized approach). The median PFS was also similar for the nonpersonalized and cytotoxic strategies (3.3 vs. 2.5 months, P = .22).

Better targeting with genomic biomarkers

The investigators found that patients selected based on genomic (DNA) biomarkers had almost double the response rates (42%) of patients selected based on protein biomarkers (22.4%, P = .001). The reasons for this difference were not clear. “We might think that the target in the end is a protein, so we would expect maybe to see better results with protein expression,” Dr. Schwaederle said. But she pointed to the example of patients with lung cancer and epidermal growth factor receptor genetic alterations. If looking only for epidermal growth factor receptor protein overexpression, she said, “we wouldn’t see any response, but only the patients that have specific alterations in this gene respond very well.” So in that case, genetic detection appears to be more sensitive than a protein biomarker–based test.

Dr. Schwaederle addressed the question that has often arisen of whether targeted agents are just better therapies. “Our analysis showed that it is not just that the therapies are better but that targeted therapies must be given to the right patients,” she said. “Indeed, when targeted therapies were given to patients without a biomarker selection, the response rates were only about 5%.”

The response rate in the range of 40% using genetic biomarkers in these phase I trials suggests that incorporating such targeted approaches even at this early stage of drug testing may potentially yield useful information on efficacy.

Dr. Don Dizon, presscast moderator and chair of ASCO’s Cancer Communications Committee, said that precision medicine “is here and that we can use patient selection using either changes in a tumor’s DNA, called genomic changes, or even protein biomarkers and do much better than we have done in the past.”

Dr. Schwaederle noted that one limitation of her study is that more recent trials, unpublished at the time of her analysis, could influence the results today.

The study received funding from the Joan and Irwin Jacobs Philanthropic Fund. Two coauthors reported extensive financial relationships with pharmaceutical or other commercial and noncommercial entities.

Current and former cigarette smoking were associated with a longer hospital stay for patients with lung cancer, chronic obstructive pulmonary disease, or ischemic heart disease, according to a report published in Hospital Practice.

Researchers assessed factors influencing hospital length of stay (LOS) as a first step toward shortening that measure, improving inpatient services, and cutting hospital costs in Iran, where this issue has not been studied previously. The overall prevalence of smoking in Iran is 12.5%, and it is much more common among men than women, said Satar Rezaei, Ph.D., of the Research Centre for Environmental Determinants of Health, Kermanshah (Iran) University of Medical Sciences, and his associates.

©ricky_68fr/fotolia.com

They assessed LOS in 1,271 patients aged 35-93 years (mean age, 63 years) who were hospitalized at 11 Tehran medical centers during a 1-year period. Slightly more than half (54%) of these patients had never smoked, while 34% were current smokers and 12% were former smokers. A total of 415 (32%) had lung cancer, 427 (34%) had COPD, and 429 (34%) had ischemic heart disease. The overall mean LOS was 7.3 days, with a range from 1 to 45 days.

The mean LOS was 48% longer among current smokers and 15% longer among former smokers than among nonsmokers. It was 9.4 days for current smokers and 7.3 days for former smokers, compared with 6.0 days for nonsmokers, Dr. Rezaei and his associates said (Hosp. Pract. 2016. doi: 10.1080/21548331.2016.1178579).

Patient cigarette smoking imposes a heavy financial burden on these hospitals and contributes to their shortage of resources. Hospital-based smoking cessation programs would be useful in shortening LOS and sparing hospital resources, the researchers added.

This study was supported by Tehran University of Medical Sciences. Dr. Rezaei and his associates reported having no relevant financial disclosures.

Current and former cigarette smoking were associated with a longer hospital stay for patients with lung cancer, chronic obstructive pulmonary disease, or ischemic heart disease, according to a report published in Hospital Practice.

Researchers assessed factors influencing hospital length of stay (LOS) as a first step toward shortening that measure, improving inpatient services, and cutting hospital costs in Iran, where this issue has not been studied previously. The overall prevalence of smoking in Iran is 12.5%, and it is much more common among men than women, said Satar Rezaei, Ph.D., of the Research Centre for Environmental Determinants of Health, Kermanshah (Iran) University of Medical Sciences, and his associates.

©ricky_68fr/fotolia.com

They assessed LOS in 1,271 patients aged 35-93 years (mean age, 63 years) who were hospitalized at 11 Tehran medical centers during a 1-year period. Slightly more than half (54%) of these patients had never smoked, while 34% were current smokers and 12% were former smokers. A total of 415 (32%) had lung cancer, 427 (34%) had COPD, and 429 (34%) had ischemic heart disease. The overall mean LOS was 7.3 days, with a range from 1 to 45 days.

The mean LOS was 48% longer among current smokers and 15% longer among former smokers than among nonsmokers. It was 9.4 days for current smokers and 7.3 days for former smokers, compared with 6.0 days for nonsmokers, Dr. Rezaei and his associates said (Hosp. Pract. 2016. doi: 10.1080/21548331.2016.1178579).

Patient cigarette smoking imposes a heavy financial burden on these hospitals and contributes to their shortage of resources. Hospital-based smoking cessation programs would be useful in shortening LOS and sparing hospital resources, the researchers added.

This study was supported by Tehran University of Medical Sciences. Dr. Rezaei and his associates reported having no relevant financial disclosures.

Current and former cigarette smoking were associated with a longer hospital stay for patients with lung cancer, chronic obstructive pulmonary disease, or ischemic heart disease, according to a report published in Hospital Practice.

Researchers assessed factors influencing hospital length of stay (LOS) as a first step toward shortening that measure, improving inpatient services, and cutting hospital costs in Iran, where this issue has not been studied previously. The overall prevalence of smoking in Iran is 12.5%, and it is much more common among men than women, said Satar Rezaei, Ph.D., of the Research Centre for Environmental Determinants of Health, Kermanshah (Iran) University of Medical Sciences, and his associates.

©ricky_68fr/fotolia.com

They assessed LOS in 1,271 patients aged 35-93 years (mean age, 63 years) who were hospitalized at 11 Tehran medical centers during a 1-year period. Slightly more than half (54%) of these patients had never smoked, while 34% were current smokers and 12% were former smokers. A total of 415 (32%) had lung cancer, 427 (34%) had COPD, and 429 (34%) had ischemic heart disease. The overall mean LOS was 7.3 days, with a range from 1 to 45 days.

The mean LOS was 48% longer among current smokers and 15% longer among former smokers than among nonsmokers. It was 9.4 days for current smokers and 7.3 days for former smokers, compared with 6.0 days for nonsmokers, Dr. Rezaei and his associates said (Hosp. Pract. 2016. doi: 10.1080/21548331.2016.1178579).

Patient cigarette smoking imposes a heavy financial burden on these hospitals and contributes to their shortage of resources. Hospital-based smoking cessation programs would be useful in shortening LOS and sparing hospital resources, the researchers added.

This study was supported by Tehran University of Medical Sciences. Dr. Rezaei and his associates reported having no relevant financial disclosures.

A 2-mg/kg dosage of pembrolizumab given to adult patients with non–small-cell lung cancer (NSCLC) every 3 weeks is optimal to both reduce tumor size and avoid treatment-related adverse events, according to a new method of analysis.

Current methods for determining the maximum tolerated dose (MTD) based on dose-limiting toxicities may be outmoded for targeted therapies and immunotherapies, where the biologically effective dose (BED) may be much lower than the MTD.

“Using the MTD rather than the BED could expose patients to a higher dose than that necessary to achieve clinical effect and may increase toxicity, which could lower overall clinical effectiveness. Therefore, dose determination in oncology should use a multifactorial approach that includes not only clinical data from the first treatment cycle but extended clinical data, preclinical models, pharmacokinetics, pharmacodynamics, and integrated modeling and simulation,” said Dr. Manash Chatterjee of Merck, and associates (Ann Oncol. 2016 April 26. doi: 10.1093/annonc/mdw174).

Dr. Chatterjee and associates analyzed data from KEYNOTE-001 using various statistical and mathematical modeling techniques to determine the lowest effective drug dosage of pembrolizumab, a highly selective humanized IgG4 monoclonal antibody that targets the programmed death-1 receptor, for treatment of patients with NSCLC.

Patients enrolled in the KEYNOTE-001 trial received pembrolizumab at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression or intolerable toxicity, or until the patient or investigator decided to stop treatment. Sixty-one patients were treated with pembrolizumab at 2 mg/kg every 3 weeks, 287 patients were treated at 10 mg/kg every 3 weeks, and 202 patients were treated at 10 mg/kg every 2 weeks. PD-1 expression was assessed from biopsy samples using a prototype assay.

Decreases from baseline tumor size were observed for 67% of patients with known PD-L1 expression treated with pembrolizumab at 2 mg/kg every 3 weeks, 66% for patients treated at 10 mg/kg every 3 weeks, and 63% for patients treated at 10 mg/kg every 2 weeks.

Data on occurrence and severity of adverse events were collected throughout the study and up to 60 days after treatment was discontinued. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.0). Treatment-related adverse events were reported for 47% of patients treated at 2 mg/kg every 3 weeks. The frequency and severity of adverse events were similar for all dosages, the investigators reported.

Exposure-efficacy was evaluated by way of exploratory regression analyses followed by nonlinear mixed effects modeling. The model found no significant difference in the exposure-efficacy relationship based on dosage. PD-L1 expression and EGFR mutation were the only two factors that explained a significant portion of interindividual variability in tumor size decrease.

Exposure-safety was evaluated via logistic regression modeling where safety was defined as the frequency of adverse events. The model revealed that there was no significant relationship between adverse events and exposure to pembrolizumab or dosage. Overall duration of treatment was the only factor that was significantly related to adverse events.

“These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC,” the investigators concluded.

jcraig@frontlinemedcom.com

On Twitter@jess_craig94

A 2-mg/kg dosage of pembrolizumab given to adult patients with non–small-cell lung cancer (NSCLC) every 3 weeks is optimal to both reduce tumor size and avoid treatment-related adverse events, according to a new method of analysis.

Current methods for determining the maximum tolerated dose (MTD) based on dose-limiting toxicities may be outmoded for targeted therapies and immunotherapies, where the biologically effective dose (BED) may be much lower than the MTD.

“Using the MTD rather than the BED could expose patients to a higher dose than that necessary to achieve clinical effect and may increase toxicity, which could lower overall clinical effectiveness. Therefore, dose determination in oncology should use a multifactorial approach that includes not only clinical data from the first treatment cycle but extended clinical data, preclinical models, pharmacokinetics, pharmacodynamics, and integrated modeling and simulation,” said Dr. Manash Chatterjee of Merck, and associates (Ann Oncol. 2016 April 26. doi: 10.1093/annonc/mdw174).

Dr. Chatterjee and associates analyzed data from KEYNOTE-001 using various statistical and mathematical modeling techniques to determine the lowest effective drug dosage of pembrolizumab, a highly selective humanized IgG4 monoclonal antibody that targets the programmed death-1 receptor, for treatment of patients with NSCLC.

Patients enrolled in the KEYNOTE-001 trial received pembrolizumab at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression or intolerable toxicity, or until the patient or investigator decided to stop treatment. Sixty-one patients were treated with pembrolizumab at 2 mg/kg every 3 weeks, 287 patients were treated at 10 mg/kg every 3 weeks, and 202 patients were treated at 10 mg/kg every 2 weeks. PD-1 expression was assessed from biopsy samples using a prototype assay.

Decreases from baseline tumor size were observed for 67% of patients with known PD-L1 expression treated with pembrolizumab at 2 mg/kg every 3 weeks, 66% for patients treated at 10 mg/kg every 3 weeks, and 63% for patients treated at 10 mg/kg every 2 weeks.

Data on occurrence and severity of adverse events were collected throughout the study and up to 60 days after treatment was discontinued. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.0). Treatment-related adverse events were reported for 47% of patients treated at 2 mg/kg every 3 weeks. The frequency and severity of adverse events were similar for all dosages, the investigators reported.

Exposure-efficacy was evaluated by way of exploratory regression analyses followed by nonlinear mixed effects modeling. The model found no significant difference in the exposure-efficacy relationship based on dosage. PD-L1 expression and EGFR mutation were the only two factors that explained a significant portion of interindividual variability in tumor size decrease.

Exposure-safety was evaluated via logistic regression modeling where safety was defined as the frequency of adverse events. The model revealed that there was no significant relationship between adverse events and exposure to pembrolizumab or dosage. Overall duration of treatment was the only factor that was significantly related to adverse events.

“These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC,” the investigators concluded.

jcraig@frontlinemedcom.com

On Twitter@jess_craig94

A 2-mg/kg dosage of pembrolizumab given to adult patients with non–small-cell lung cancer (NSCLC) every 3 weeks is optimal to both reduce tumor size and avoid treatment-related adverse events, according to a new method of analysis.

Current methods for determining the maximum tolerated dose (MTD) based on dose-limiting toxicities may be outmoded for targeted therapies and immunotherapies, where the biologically effective dose (BED) may be much lower than the MTD.

“Using the MTD rather than the BED could expose patients to a higher dose than that necessary to achieve clinical effect and may increase toxicity, which could lower overall clinical effectiveness. Therefore, dose determination in oncology should use a multifactorial approach that includes not only clinical data from the first treatment cycle but extended clinical data, preclinical models, pharmacokinetics, pharmacodynamics, and integrated modeling and simulation,” said Dr. Manash Chatterjee of Merck, and associates (Ann Oncol. 2016 April 26. doi: 10.1093/annonc/mdw174).

Dr. Chatterjee and associates analyzed data from KEYNOTE-001 using various statistical and mathematical modeling techniques to determine the lowest effective drug dosage of pembrolizumab, a highly selective humanized IgG4 monoclonal antibody that targets the programmed death-1 receptor, for treatment of patients with NSCLC.

Patients enrolled in the KEYNOTE-001 trial received pembrolizumab at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression or intolerable toxicity, or until the patient or investigator decided to stop treatment. Sixty-one patients were treated with pembrolizumab at 2 mg/kg every 3 weeks, 287 patients were treated at 10 mg/kg every 3 weeks, and 202 patients were treated at 10 mg/kg every 2 weeks. PD-1 expression was assessed from biopsy samples using a prototype assay.

Decreases from baseline tumor size were observed for 67% of patients with known PD-L1 expression treated with pembrolizumab at 2 mg/kg every 3 weeks, 66% for patients treated at 10 mg/kg every 3 weeks, and 63% for patients treated at 10 mg/kg every 2 weeks.

Data on occurrence and severity of adverse events were collected throughout the study and up to 60 days after treatment was discontinued. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.0). Treatment-related adverse events were reported for 47% of patients treated at 2 mg/kg every 3 weeks. The frequency and severity of adverse events were similar for all dosages, the investigators reported.

Exposure-efficacy was evaluated by way of exploratory regression analyses followed by nonlinear mixed effects modeling. The model found no significant difference in the exposure-efficacy relationship based on dosage. PD-L1 expression and EGFR mutation were the only two factors that explained a significant portion of interindividual variability in tumor size decrease.

Exposure-safety was evaluated via logistic regression modeling where safety was defined as the frequency of adverse events. The model revealed that there was no significant relationship between adverse events and exposure to pembrolizumab or dosage. Overall duration of treatment was the only factor that was significantly related to adverse events.

“These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC,” the investigators concluded.

jcraig@frontlinemedcom.com

On Twitter@jess_craig94

The Molecular Immunology Center is a campus of concrete and stone buildings with dark-tinted windows set against palm trees and pink tropical flowers. The buildings are imposing and seem to stretch endlessly along the flat terrain of Havana, Cuba. The research institute, like most buildings in Cuba, is just a few minutes’ walk to the Atlantic Ocean coastline. Inside the research and development building, investigators are working on creating 18 new cancer immunotherapy treatments from vaccines to monoclonal antibodies to synthetic cytokines. A few buildings down, in an almost 50,000–square foot manufacturing plant, a positive pressure air gradient system whirs, and stirred tank bioreactors clank in continuous motion. It is here that the CIMAvax-EGF, a therapeutic vaccine used to treat non–small-cell lung cancer (NSCLC), is manufactured, formulated, and packaged into 40-L sterile bulk bags.

©Konstik/Thinkstock

The Molecular Immunology Center, also called the Center of Molecular Immunology or Centro de Immunologia Molecular, was founded in the early 1990’s and the research that eventually led to CIMAvax-EGF began almost immediately, spurred by Cuba’s high rate of lung cancer–related deaths (at the time the second leading cause of death and the leading cause of cancer mortality in the country).

The vaccine works by stimulating a patient’s own immune system to make antibodies against epidermal growth factor (EGF), which depletes circulating EGF levels and prevents EGF from binding to its receptor. “The epidermal growth factor receptor (EGFR) is a well-known oncogene. Its overactivation can induce malignant transformation of a normal cell, signaling inhibition of apoptosis, cell proliferation, angiogenesis, metastasis, and tumor-induced proinflammatory and immunosuppressive processes,” wrote Dr. Pedro Rodríguez and his associates at the Molecular Immunology Center in Cuba (MEDICC Rev. 2010;12:17-23).

“The EGFR signaling and transduction pathway can be efficiently interrupted by EGF deprivation, direct specific mAb [monoclonal antibody] receptor inhibition, or low-molecular-weight molecules competing intracellularly with adenosine triphosphate for the receptor’s tyrosine kinase activity site, with negative repercussions on cell proliferation and, consequently, on tumor development. Inducing EGF deprivation by active immunotherapy is an emerging concept developed by Cuban researchers that involves manipulating an individual’s immune response to release its own effector antibodies against EGF, thereby reducing tumor size or preventing its progression,” the investigators wrote.

Early preclinical studies for vaccine formulation began in Cuba in 1992. Over the next few years, researchers perfected the vaccine’s formula: EGF along with two immunopotentiating molecules, an adjuvant called Montanide ISA 51 and the virulent protein P64k from the microbial organism Neisseria meningitidis (Ann Oncol. 1998;9:431-5; Ann Oncol. 2003;14:461-6).

Together, the adjuvant and the virulent protein activate the immune system while the overabundance of EGF in the body directs antibodies to be made specifically against EGF and not virulent protein P64k. Although some antibodies bind the EGF introduced by the vaccine, other antibodies target cancerous cells where EGFR is overexpressed.

NSCLC was selected “because of its frequency and because EGFR is overexpressed in tissues during development and progression of lung neoplasms,” reported the investigators.

Subsequent clinical trials focused on fine-tuning administration route, dose, dosing interval, optimal combinations with other established therapies, and reducing vaccine-related side effects, which include fever, chills, nausea, headache, asthenia, and tremor.

Researchers found that administering the vaccine in “high but fractioned dose[s] in multiple anatomical sites (such as the 2 deltoid and 2 gluteal regions), thereby bringing the EGF vaccine closer to regional lymph nodes and synergizing the immune response” resulted in the best patient outcomes. In addition, significantly better patient outcomes were achieved when the vaccine was administered before and after chemotherapy.

By 1995, Cuban researchers had successfully completed five separate phase I/II clinical trials and one phase II clinical trial.

Pooling the results from the various clinical trials, non–small-cell lung cancer patients who received the vaccine and who were under the age of 60, lived an average of 4-6 months longer than patients who did not receive the vaccine or were older than 60.

By 2009 “more than 700 patients [had] received the vaccine over the years, many of them in seven clinical trials in Cuba, Canada, and the U.K.,” reported an online Cuban newspaper, Cuba Headlines.

It wasn’t until September 2011 that Cuban researchers officially began distributing the vaccine to Cuban citizens.

“The drug could turn the cancer into a manageable, chronic disease by generating antibodies against the proteins, which triggered the uncontrolled cell proliferation,” Dr. Gisela Gonzalez of the Center of Molecular Immunology said in an interview in 2009 following the official launch of the vaccine.

Today, ongoing clinical trials continue in Cuba and are also underway (at various stages) in several other countries, including the United States. The vaccine still has a long way to go before it can be hailed as a true “cancer cure,” a sentiment that many American publications expressed and one that the researchers at Roswell Park Cancer Institute who are leading the U.S. clinical trials are vehemently trying to quell. Nonetheless, the now global reach of CIMAvax may mark a promising paradigm shift in the field of oncology.

jcraig@frontlinemedcom.com

On Twitter @jess_craig94

The Molecular Immunology Center is a campus of concrete and stone buildings with dark-tinted windows set against palm trees and pink tropical flowers. The buildings are imposing and seem to stretch endlessly along the flat terrain of Havana, Cuba. The research institute, like most buildings in Cuba, is just a few minutes’ walk to the Atlantic Ocean coastline. Inside the research and development building, investigators are working on creating 18 new cancer immunotherapy treatments from vaccines to monoclonal antibodies to synthetic cytokines. A few buildings down, in an almost 50,000–square foot manufacturing plant, a positive pressure air gradient system whirs, and stirred tank bioreactors clank in continuous motion. It is here that the CIMAvax-EGF, a therapeutic vaccine used to treat non–small-cell lung cancer (NSCLC), is manufactured, formulated, and packaged into 40-L sterile bulk bags.

©Konstik/Thinkstock

The Molecular Immunology Center, also called the Center of Molecular Immunology or Centro de Immunologia Molecular, was founded in the early 1990’s and the research that eventually led to CIMAvax-EGF began almost immediately, spurred by Cuba’s high rate of lung cancer–related deaths (at the time the second leading cause of death and the leading cause of cancer mortality in the country).

The vaccine works by stimulating a patient’s own immune system to make antibodies against epidermal growth factor (EGF), which depletes circulating EGF levels and prevents EGF from binding to its receptor. “The epidermal growth factor receptor (EGFR) is a well-known oncogene. Its overactivation can induce malignant transformation of a normal cell, signaling inhibition of apoptosis, cell proliferation, angiogenesis, metastasis, and tumor-induced proinflammatory and immunosuppressive processes,” wrote Dr. Pedro Rodríguez and his associates at the Molecular Immunology Center in Cuba (MEDICC Rev. 2010;12:17-23).

“The EGFR signaling and transduction pathway can be efficiently interrupted by EGF deprivation, direct specific mAb [monoclonal antibody] receptor inhibition, or low-molecular-weight molecules competing intracellularly with adenosine triphosphate for the receptor’s tyrosine kinase activity site, with negative repercussions on cell proliferation and, consequently, on tumor development. Inducing EGF deprivation by active immunotherapy is an emerging concept developed by Cuban researchers that involves manipulating an individual’s immune response to release its own effector antibodies against EGF, thereby reducing tumor size or preventing its progression,” the investigators wrote.

Early preclinical studies for vaccine formulation began in Cuba in 1992. Over the next few years, researchers perfected the vaccine’s formula: EGF along with two immunopotentiating molecules, an adjuvant called Montanide ISA 51 and the virulent protein P64k from the microbial organism Neisseria meningitidis (Ann Oncol. 1998;9:431-5; Ann Oncol. 2003;14:461-6).

Together, the adjuvant and the virulent protein activate the immune system while the overabundance of EGF in the body directs antibodies to be made specifically against EGF and not virulent protein P64k. Although some antibodies bind the EGF introduced by the vaccine, other antibodies target cancerous cells where EGFR is overexpressed.

NSCLC was selected “because of its frequency and because EGFR is overexpressed in tissues during development and progression of lung neoplasms,” reported the investigators.

Subsequent clinical trials focused on fine-tuning administration route, dose, dosing interval, optimal combinations with other established therapies, and reducing vaccine-related side effects, which include fever, chills, nausea, headache, asthenia, and tremor.

Researchers found that administering the vaccine in “high but fractioned dose[s] in multiple anatomical sites (such as the 2 deltoid and 2 gluteal regions), thereby bringing the EGF vaccine closer to regional lymph nodes and synergizing the immune response” resulted in the best patient outcomes. In addition, significantly better patient outcomes were achieved when the vaccine was administered before and after chemotherapy.

By 1995, Cuban researchers had successfully completed five separate phase I/II clinical trials and one phase II clinical trial.

Pooling the results from the various clinical trials, non–small-cell lung cancer patients who received the vaccine and who were under the age of 60, lived an average of 4-6 months longer than patients who did not receive the vaccine or were older than 60.

By 2009 “more than 700 patients [had] received the vaccine over the years, many of them in seven clinical trials in Cuba, Canada, and the U.K.,” reported an online Cuban newspaper, Cuba Headlines.

It wasn’t until September 2011 that Cuban researchers officially began distributing the vaccine to Cuban citizens.

“The drug could turn the cancer into a manageable, chronic disease by generating antibodies against the proteins, which triggered the uncontrolled cell proliferation,” Dr. Gisela Gonzalez of the Center of Molecular Immunology said in an interview in 2009 following the official launch of the vaccine.

Today, ongoing clinical trials continue in Cuba and are also underway (at various stages) in several other countries, including the United States. The vaccine still has a long way to go before it can be hailed as a true “cancer cure,” a sentiment that many American publications expressed and one that the researchers at Roswell Park Cancer Institute who are leading the U.S. clinical trials are vehemently trying to quell. Nonetheless, the now global reach of CIMAvax may mark a promising paradigm shift in the field of oncology.

jcraig@frontlinemedcom.com

On Twitter @jess_craig94

The Molecular Immunology Center is a campus of concrete and stone buildings with dark-tinted windows set against palm trees and pink tropical flowers. The buildings are imposing and seem to stretch endlessly along the flat terrain of Havana, Cuba. The research institute, like most buildings in Cuba, is just a few minutes’ walk to the Atlantic Ocean coastline. Inside the research and development building, investigators are working on creating 18 new cancer immunotherapy treatments from vaccines to monoclonal antibodies to synthetic cytokines. A few buildings down, in an almost 50,000–square foot manufacturing plant, a positive pressure air gradient system whirs, and stirred tank bioreactors clank in continuous motion. It is here that the CIMAvax-EGF, a therapeutic vaccine used to treat non–small-cell lung cancer (NSCLC), is manufactured, formulated, and packaged into 40-L sterile bulk bags.

©Konstik/Thinkstock

The Molecular Immunology Center, also called the Center of Molecular Immunology or Centro de Immunologia Molecular, was founded in the early 1990’s and the research that eventually led to CIMAvax-EGF began almost immediately, spurred by Cuba’s high rate of lung cancer–related deaths (at the time the second leading cause of death and the leading cause of cancer mortality in the country).

The vaccine works by stimulating a patient’s own immune system to make antibodies against epidermal growth factor (EGF), which depletes circulating EGF levels and prevents EGF from binding to its receptor. “The epidermal growth factor receptor (EGFR) is a well-known oncogene. Its overactivation can induce malignant transformation of a normal cell, signaling inhibition of apoptosis, cell proliferation, angiogenesis, metastasis, and tumor-induced proinflammatory and immunosuppressive processes,” wrote Dr. Pedro Rodríguez and his associates at the Molecular Immunology Center in Cuba (MEDICC Rev. 2010;12:17-23).

“The EGFR signaling and transduction pathway can be efficiently interrupted by EGF deprivation, direct specific mAb [monoclonal antibody] receptor inhibition, or low-molecular-weight molecules competing intracellularly with adenosine triphosphate for the receptor’s tyrosine kinase activity site, with negative repercussions on cell proliferation and, consequently, on tumor development. Inducing EGF deprivation by active immunotherapy is an emerging concept developed by Cuban researchers that involves manipulating an individual’s immune response to release its own effector antibodies against EGF, thereby reducing tumor size or preventing its progression,” the investigators wrote.

Early preclinical studies for vaccine formulation began in Cuba in 1992. Over the next few years, researchers perfected the vaccine’s formula: EGF along with two immunopotentiating molecules, an adjuvant called Montanide ISA 51 and the virulent protein P64k from the microbial organism Neisseria meningitidis (Ann Oncol. 1998;9:431-5; Ann Oncol. 2003;14:461-6).

Together, the adjuvant and the virulent protein activate the immune system while the overabundance of EGF in the body directs antibodies to be made specifically against EGF and not virulent protein P64k. Although some antibodies bind the EGF introduced by the vaccine, other antibodies target cancerous cells where EGFR is overexpressed.

NSCLC was selected “because of its frequency and because EGFR is overexpressed in tissues during development and progression of lung neoplasms,” reported the investigators.

Subsequent clinical trials focused on fine-tuning administration route, dose, dosing interval, optimal combinations with other established therapies, and reducing vaccine-related side effects, which include fever, chills, nausea, headache, asthenia, and tremor.

Researchers found that administering the vaccine in “high but fractioned dose[s] in multiple anatomical sites (such as the 2 deltoid and 2 gluteal regions), thereby bringing the EGF vaccine closer to regional lymph nodes and synergizing the immune response” resulted in the best patient outcomes. In addition, significantly better patient outcomes were achieved when the vaccine was administered before and after chemotherapy.

By 1995, Cuban researchers had successfully completed five separate phase I/II clinical trials and one phase II clinical trial.

Pooling the results from the various clinical trials, non–small-cell lung cancer patients who received the vaccine and who were under the age of 60, lived an average of 4-6 months longer than patients who did not receive the vaccine or were older than 60.

By 2009 “more than 700 patients [had] received the vaccine over the years, many of them in seven clinical trials in Cuba, Canada, and the U.K.,” reported an online Cuban newspaper, Cuba Headlines.

It wasn’t until September 2011 that Cuban researchers officially began distributing the vaccine to Cuban citizens.

“The drug could turn the cancer into a manageable, chronic disease by generating antibodies against the proteins, which triggered the uncontrolled cell proliferation,” Dr. Gisela Gonzalez of the Center of Molecular Immunology said in an interview in 2009 following the official launch of the vaccine.

Today, ongoing clinical trials continue in Cuba and are also underway (at various stages) in several other countries, including the United States. The vaccine still has a long way to go before it can be hailed as a true “cancer cure,” a sentiment that many American publications expressed and one that the researchers at Roswell Park Cancer Institute who are leading the U.S. clinical trials are vehemently trying to quell. Nonetheless, the now global reach of CIMAvax may mark a promising paradigm shift in the field of oncology.

jcraig@frontlinemedcom.com

On Twitter @jess_craig94

The prevalence of mutations in oncogenic driver genes is correlated to smoking dose and body mass index, according to a prospective epidemiology study of environmental factors and mutation frequencies in non–small-cell lung cancer that was published online May 9.

In the Japan Molecular Epidemiology for Lung Cancer study, Dr. Tomoya Kawaguchi and colleagues found that increased mutation frequencies in TP53, KRAS, and NFE2L2 correlated with smoking dose (P < .001 for all), whereas decreased mutation frequencies were observed in EGFR (P < .001) and CTNNB1 (P = .030). The number of KRAS mutations in smokers increased in proportion to body-mass index (BMI) increases (P = .026).

©Sebastian Kaulitzki/Thinkstock

Simultaneous mutations in EGFR and CTNNB1 suggested possible biological relevance; 88% of CTNNB1 mutations (15/17) occurred with EGFR mutations. TP53 and NFE2L2 mutations were more frequent in advanced-stage disease, wrote Dr. Kawaguchi of the department of respiratory medicine at Osaka (Japan) City University and colleagues (J Clin Oncol. 2016 May 9. doi: 10.1200/JCO.2015.64.2322).

Although smoking is the most studied cause of lung cancer, about one-quarter of lung cancers worldwide occur in never-smokers.“It remains elusive which environmental factors contribute to the EGFR mutations that are frequently observed in never-smokers,” the investigators wrote. “In this study, the prevalence of EGFR mutations was higher in those who had more [environmental tobacco smoke], although this difference did not reach the level of statistical significance in the sample size. More detailed methods to detect the mutations (e.g., digital polymerase chain reaction) might yield more precise information.”

Levels of sex hormones were not significant factors in mutation frequencies, but the investigators found that estrogen receptor was more highly expressed in never-smokers than smokers, and the presence of estrogen receptor was associated with EGFR mutations in younger patients.

The investigators studied environmental influences on lung cancer by collecting information by questionnaire and by detecting mutations in 72 candidate genes from 876 patients with stage I to IIIB non–small-cell lung cancer (441 ever- and 435 never-smokers). In total, 622 patients had at least one mutation, and 860 mutations were observed. Dr. Kawaguchi and colleagues also examined patterns of estrogen-receptor expression by immunohistochemical staining and evidence of human papillomavirus (HPV) infection by a polymerase chain reaction–based microarray system.

Contrary to retrospective analyses that had pointed to a link between HPV and NSCLC, this prospective study showed little evidence for HPV in early NSCLC.

Dr. Kawaguchi reported having financial ties to Chugai Pharmaceutical and Eli Lilly. Several coauthors reported tis to industry sources.

The prevalence of mutations in oncogenic driver genes is correlated to smoking dose and body mass index, according to a prospective epidemiology study of environmental factors and mutation frequencies in non–small-cell lung cancer that was published online May 9.

In the Japan Molecular Epidemiology for Lung Cancer study, Dr. Tomoya Kawaguchi and colleagues found that increased mutation frequencies in TP53, KRAS, and NFE2L2 correlated with smoking dose (P < .001 for all), whereas decreased mutation frequencies were observed in EGFR (P < .001) and CTNNB1 (P = .030). The number of KRAS mutations in smokers increased in proportion to body-mass index (BMI) increases (P = .026).

©Sebastian Kaulitzki/Thinkstock

Simultaneous mutations in EGFR and CTNNB1 suggested possible biological relevance; 88% of CTNNB1 mutations (15/17) occurred with EGFR mutations. TP53 and NFE2L2 mutations were more frequent in advanced-stage disease, wrote Dr. Kawaguchi of the department of respiratory medicine at Osaka (Japan) City University and colleagues (J Clin Oncol. 2016 May 9. doi: 10.1200/JCO.2015.64.2322).

Although smoking is the most studied cause of lung cancer, about one-quarter of lung cancers worldwide occur in never-smokers.“It remains elusive which environmental factors contribute to the EGFR mutations that are frequently observed in never-smokers,” the investigators wrote. “In this study, the prevalence of EGFR mutations was higher in those who had more [environmental tobacco smoke], although this difference did not reach the level of statistical significance in the sample size. More detailed methods to detect the mutations (e.g., digital polymerase chain reaction) might yield more precise information.”

Levels of sex hormones were not significant factors in mutation frequencies, but the investigators found that estrogen receptor was more highly expressed in never-smokers than smokers, and the presence of estrogen receptor was associated with EGFR mutations in younger patients.

The investigators studied environmental influences on lung cancer by collecting information by questionnaire and by detecting mutations in 72 candidate genes from 876 patients with stage I to IIIB non–small-cell lung cancer (441 ever- and 435 never-smokers). In total, 622 patients had at least one mutation, and 860 mutations were observed. Dr. Kawaguchi and colleagues also examined patterns of estrogen-receptor expression by immunohistochemical staining and evidence of human papillomavirus (HPV) infection by a polymerase chain reaction–based microarray system.

Contrary to retrospective analyses that had pointed to a link between HPV and NSCLC, this prospective study showed little evidence for HPV in early NSCLC.

Dr. Kawaguchi reported having financial ties to Chugai Pharmaceutical and Eli Lilly. Several coauthors reported tis to industry sources.

The prevalence of mutations in oncogenic driver genes is correlated to smoking dose and body mass index, according to a prospective epidemiology study of environmental factors and mutation frequencies in non–small-cell lung cancer that was published online May 9.

In the Japan Molecular Epidemiology for Lung Cancer study, Dr. Tomoya Kawaguchi and colleagues found that increased mutation frequencies in TP53, KRAS, and NFE2L2 correlated with smoking dose (P < .001 for all), whereas decreased mutation frequencies were observed in EGFR (P < .001) and CTNNB1 (P = .030). The number of KRAS mutations in smokers increased in proportion to body-mass index (BMI) increases (P = .026).

©Sebastian Kaulitzki/Thinkstock

Simultaneous mutations in EGFR and CTNNB1 suggested possible biological relevance; 88% of CTNNB1 mutations (15/17) occurred with EGFR mutations. TP53 and NFE2L2 mutations were more frequent in advanced-stage disease, wrote Dr. Kawaguchi of the department of respiratory medicine at Osaka (Japan) City University and colleagues (J Clin Oncol. 2016 May 9. doi: 10.1200/JCO.2015.64.2322).

Although smoking is the most studied cause of lung cancer, about one-quarter of lung cancers worldwide occur in never-smokers.“It remains elusive which environmental factors contribute to the EGFR mutations that are frequently observed in never-smokers,” the investigators wrote. “In this study, the prevalence of EGFR mutations was higher in those who had more [environmental tobacco smoke], although this difference did not reach the level of statistical significance in the sample size. More detailed methods to detect the mutations (e.g., digital polymerase chain reaction) might yield more precise information.”

Levels of sex hormones were not significant factors in mutation frequencies, but the investigators found that estrogen receptor was more highly expressed in never-smokers than smokers, and the presence of estrogen receptor was associated with EGFR mutations in younger patients.

The investigators studied environmental influences on lung cancer by collecting information by questionnaire and by detecting mutations in 72 candidate genes from 876 patients with stage I to IIIB non–small-cell lung cancer (441 ever- and 435 never-smokers). In total, 622 patients had at least one mutation, and 860 mutations were observed. Dr. Kawaguchi and colleagues also examined patterns of estrogen-receptor expression by immunohistochemical staining and evidence of human papillomavirus (HPV) infection by a polymerase chain reaction–based microarray system.

Contrary to retrospective analyses that had pointed to a link between HPV and NSCLC, this prospective study showed little evidence for HPV in early NSCLC.

Dr. Kawaguchi reported having financial ties to Chugai Pharmaceutical and Eli Lilly. Several coauthors reported tis to industry sources.