AACR-IASLC Joint Conference

SAN DIEGO – Although the release of the U.S. Preventive Services Task Force grade B recommendations on lung cancer screening in December 2013 marked an important advance in the field, they are not the last words on the issue.

"There are innumerable other questions for which we don’t have great answers," Dr. Denise R. Aberle said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

These include lack of data on the optimal screening population, interpretation algorithms, and cost effectiveness, said Dr. Aberle, professor of radiology and bioengineering at the University of California, Los Angeles. "Because there remain many unanswered questions, and the implementation process is not standardized, the single most important thing we can do in screening programs is to collect the data that would be necessary to inform these questions."

The primary difference between the recommendations of the U.S. Preventive Services Task Force and those of the National Lung Screening Trial (NLST) is the USPSTF’s expanded age range of 55-80 years. The USPSTF "also added the caveat that screenings should be discontinued once patients are beyond the age of 80, if there is a smoking cessation history of greater than 15 years, or in the face of significant comorbidity that would likely be a factor in competing mortality or would render that person unable to tolerate treatment," she said.

USPSTF investigators used data from the Cancer Intervention and Surveillance Modeling Network (CISNET) to inform their decision-making. CISNET consists of investigators from five different institutions who have each developed independent, natural histories of lung cancer in modeling exercises. They used each of their five models, and tested at least 500 different strategies for screening based on differences in the frequency of screening (anywhere from annually to once every 3 years), start and stop ages, pack-year intensity, and the number of years since quitting smoking. By doing so, the USPSTF investigators determined that mortality reduction with screening was 15%, estimated that 50% of cancers would be early stage, and projected that 497 per 100,000 lung cancer deaths would be averted.

"We now have guidelines that we can build on," Dr. Aberle said of the USPSTF recommendations.

She characterized false positivity rates as "probably the most significant downside of CT screening" for lung cancer. "It results in unnecessary follow-up imaging and excess radiation, [and] unnecessary biopsies and surgical procedures with their attendant complications, costs, and unnecessary anxiety," she said.

In a study of NLST participants led by Dr. Aberle, 24% of all screens were positive based on the observation of a nodule of 4 mm or larger (N. Engl. J. Med. 2011;365:395-409). "It turns out that about two-thirds of positive screens were for a nodule that was 7 mm or smaller in size," she said. "Finally, 96% of positive screens were not associated with a lung cancer diagnosis. How do we address this? The easiest way to look at this is to look at nodule size, which remains the most durable of imaging biomarkers that we have thus far."

About 7% of all lung cancers occurred in nodules between 4 and 6 mm in diameter, but Dr. Aberle and her associates noticed two inflection points. First, relative to nodules 4-6 mm in diameter, nodules in the 7- to 10-mm diameter range translate into about a threefold increase in the numbers of lung cancers observed. Second, nodules greater than 10 mm in diameter roughly translate into a doubling in the number of lung cancers observed. "After 20 mm, the numbers of cancers decrease, as do the number of nodules," she said.

In subsequent analyses, Dr. Aberle and her associates found that using a 7-mm nodule as the threshold size for screen positivity would result in a delay in diagnosis of perhaps 2% of lung cancers relative to first observation. "This is clearly an area that we’ll be looking at when we look toward screening implementation," she said.

With respect to diagnostic algorithms, a number of organizations are looking to standardize interpretations, including the American College of Radiology, which is developing a standardized reporting system called LUNG-RADS. In this algorithm, category 1 = negative, 2 = benign, 3 = likely benign (not actionable), 4 = suspicious, 5 = highly suspicious, and S = significant/other. In categories 1-3, annual screening would be recommended. "Level 4 screens would dictate an early follow-up, generally within 4-6 months of the baseline CT scan," Dr. Aberle explained. "Nodules that are highly suspicious typically undergo some form of additional tissue sampling."

Dr. Aberle said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Although the release of the U.S. Preventive Services Task Force grade B recommendations on lung cancer screening in December 2013 marked an important advance in the field, they are not the last words on the issue.

"There are innumerable other questions for which we don’t have great answers," Dr. Denise R. Aberle said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

These include lack of data on the optimal screening population, interpretation algorithms, and cost effectiveness, said Dr. Aberle, professor of radiology and bioengineering at the University of California, Los Angeles. "Because there remain many unanswered questions, and the implementation process is not standardized, the single most important thing we can do in screening programs is to collect the data that would be necessary to inform these questions."

The primary difference between the recommendations of the U.S. Preventive Services Task Force and those of the National Lung Screening Trial (NLST) is the USPSTF’s expanded age range of 55-80 years. The USPSTF "also added the caveat that screenings should be discontinued once patients are beyond the age of 80, if there is a smoking cessation history of greater than 15 years, or in the face of significant comorbidity that would likely be a factor in competing mortality or would render that person unable to tolerate treatment," she said.

USPSTF investigators used data from the Cancer Intervention and Surveillance Modeling Network (CISNET) to inform their decision-making. CISNET consists of investigators from five different institutions who have each developed independent, natural histories of lung cancer in modeling exercises. They used each of their five models, and tested at least 500 different strategies for screening based on differences in the frequency of screening (anywhere from annually to once every 3 years), start and stop ages, pack-year intensity, and the number of years since quitting smoking. By doing so, the USPSTF investigators determined that mortality reduction with screening was 15%, estimated that 50% of cancers would be early stage, and projected that 497 per 100,000 lung cancer deaths would be averted.

"We now have guidelines that we can build on," Dr. Aberle said of the USPSTF recommendations.

She characterized false positivity rates as "probably the most significant downside of CT screening" for lung cancer. "It results in unnecessary follow-up imaging and excess radiation, [and] unnecessary biopsies and surgical procedures with their attendant complications, costs, and unnecessary anxiety," she said.

In a study of NLST participants led by Dr. Aberle, 24% of all screens were positive based on the observation of a nodule of 4 mm or larger (N. Engl. J. Med. 2011;365:395-409). "It turns out that about two-thirds of positive screens were for a nodule that was 7 mm or smaller in size," she said. "Finally, 96% of positive screens were not associated with a lung cancer diagnosis. How do we address this? The easiest way to look at this is to look at nodule size, which remains the most durable of imaging biomarkers that we have thus far."

About 7% of all lung cancers occurred in nodules between 4 and 6 mm in diameter, but Dr. Aberle and her associates noticed two inflection points. First, relative to nodules 4-6 mm in diameter, nodules in the 7- to 10-mm diameter range translate into about a threefold increase in the numbers of lung cancers observed. Second, nodules greater than 10 mm in diameter roughly translate into a doubling in the number of lung cancers observed. "After 20 mm, the numbers of cancers decrease, as do the number of nodules," she said.

In subsequent analyses, Dr. Aberle and her associates found that using a 7-mm nodule as the threshold size for screen positivity would result in a delay in diagnosis of perhaps 2% of lung cancers relative to first observation. "This is clearly an area that we’ll be looking at when we look toward screening implementation," she said.

With respect to diagnostic algorithms, a number of organizations are looking to standardize interpretations, including the American College of Radiology, which is developing a standardized reporting system called LUNG-RADS. In this algorithm, category 1 = negative, 2 = benign, 3 = likely benign (not actionable), 4 = suspicious, 5 = highly suspicious, and S = significant/other. In categories 1-3, annual screening would be recommended. "Level 4 screens would dictate an early follow-up, generally within 4-6 months of the baseline CT scan," Dr. Aberle explained. "Nodules that are highly suspicious typically undergo some form of additional tissue sampling."

Dr. Aberle said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Although the release of the U.S. Preventive Services Task Force grade B recommendations on lung cancer screening in December 2013 marked an important advance in the field, they are not the last words on the issue.

"There are innumerable other questions for which we don’t have great answers," Dr. Denise R. Aberle said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

These include lack of data on the optimal screening population, interpretation algorithms, and cost effectiveness, said Dr. Aberle, professor of radiology and bioengineering at the University of California, Los Angeles. "Because there remain many unanswered questions, and the implementation process is not standardized, the single most important thing we can do in screening programs is to collect the data that would be necessary to inform these questions."

The primary difference between the recommendations of the U.S. Preventive Services Task Force and those of the National Lung Screening Trial (NLST) is the USPSTF’s expanded age range of 55-80 years. The USPSTF "also added the caveat that screenings should be discontinued once patients are beyond the age of 80, if there is a smoking cessation history of greater than 15 years, or in the face of significant comorbidity that would likely be a factor in competing mortality or would render that person unable to tolerate treatment," she said.

USPSTF investigators used data from the Cancer Intervention and Surveillance Modeling Network (CISNET) to inform their decision-making. CISNET consists of investigators from five different institutions who have each developed independent, natural histories of lung cancer in modeling exercises. They used each of their five models, and tested at least 500 different strategies for screening based on differences in the frequency of screening (anywhere from annually to once every 3 years), start and stop ages, pack-year intensity, and the number of years since quitting smoking. By doing so, the USPSTF investigators determined that mortality reduction with screening was 15%, estimated that 50% of cancers would be early stage, and projected that 497 per 100,000 lung cancer deaths would be averted.

"We now have guidelines that we can build on," Dr. Aberle said of the USPSTF recommendations.

She characterized false positivity rates as "probably the most significant downside of CT screening" for lung cancer. "It results in unnecessary follow-up imaging and excess radiation, [and] unnecessary biopsies and surgical procedures with their attendant complications, costs, and unnecessary anxiety," she said.

In a study of NLST participants led by Dr. Aberle, 24% of all screens were positive based on the observation of a nodule of 4 mm or larger (N. Engl. J. Med. 2011;365:395-409). "It turns out that about two-thirds of positive screens were for a nodule that was 7 mm or smaller in size," she said. "Finally, 96% of positive screens were not associated with a lung cancer diagnosis. How do we address this? The easiest way to look at this is to look at nodule size, which remains the most durable of imaging biomarkers that we have thus far."

About 7% of all lung cancers occurred in nodules between 4 and 6 mm in diameter, but Dr. Aberle and her associates noticed two inflection points. First, relative to nodules 4-6 mm in diameter, nodules in the 7- to 10-mm diameter range translate into about a threefold increase in the numbers of lung cancers observed. Second, nodules greater than 10 mm in diameter roughly translate into a doubling in the number of lung cancers observed. "After 20 mm, the numbers of cancers decrease, as do the number of nodules," she said.

In subsequent analyses, Dr. Aberle and her associates found that using a 7-mm nodule as the threshold size for screen positivity would result in a delay in diagnosis of perhaps 2% of lung cancers relative to first observation. "This is clearly an area that we’ll be looking at when we look toward screening implementation," she said.

With respect to diagnostic algorithms, a number of organizations are looking to standardize interpretations, including the American College of Radiology, which is developing a standardized reporting system called LUNG-RADS. In this algorithm, category 1 = negative, 2 = benign, 3 = likely benign (not actionable), 4 = suspicious, 5 = highly suspicious, and S = significant/other. In categories 1-3, annual screening would be recommended. "Level 4 screens would dictate an early follow-up, generally within 4-6 months of the baseline CT scan," Dr. Aberle explained. "Nodules that are highly suspicious typically undergo some form of additional tissue sampling."

Dr. Aberle said that she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Results from studies conducted to date indicate that anti-PD-L1 therapy is well tolerated in patients with non–small cell lung cancer, with rapid response rates.

In fact, responses are "not only very rapid, they’re also very durable," Dr. Leora Horn said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

"We’re seeing continued responses even when treatment is discontinued. The response rates appear to be somewhat higher in tumors that express PD-L1, and we see no pneumonitis or treatment-related grade 5 adverse events to date."

The four anti-PD-L1 agents that have been investigated or are currently being investigated in patients with non–small cell lung cancer (NSCLC) are BMS-936559, MPDL3280A, MEDI-4736, and MSB0010718C, according to Dr. Horn, clinical director of the thoracic oncology research program at Vanderbilt University, Nashville, Tenn.

BMS-936559, developed by Bristol Myers-Squibb, was part of a phase IA dose study at 0.3, 1, 3, and 10 mg/kg in patients with multiple tumor types including NSCLC. Of the 207 patients enrolled, 75 had NSCLC (N. Engl. J. Med 2012;366:2455-65).

More than half of all patients (61%) had treatment-related adverse events, with fatigue the most common (16%), followed by infusion reaction (10%) and diarrhea (9%). Grade 3 and 4 adverse events occurred in 9% of patients. "One of the themes with anti-PD-L1 therapy is that we’re not seeing grade 3-5 pneumonitis in these like we have seen with anti-PD-1 agents," said Dr. Horn. "This may have to do with different expression of PD-1 and PD-2 within the body and the targets of PD-1 compared to anti-PD-L1 antibodies."

The response rate among NSCLC patients treated in the trial reached about 10%, and responses were seen in squamous and nonsquamous NSCLC. "This agent is not being further developed in NSCLC patients," Dr. Horn said. "Nivolumab, a PD-1 blocking antibody, has really taken over as far as development for Bristol-Myers Squibb."

The next agent she discussed, MPDL3280A, is being developed by Roche and Genentech. A phase I trial presented at the 2013 European Society for Medical Oncology (ESMO) Congress examined different doses in 85 patients with NSCLC ranging from 10 to 20 mg/kg once every week for just under 1 year. Key eligibility criteria were measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 and Eastern Cooperative Oncology Group Performance Status 0 or 1. Dr. Horn said that the majority of adverse events were grade 1-2 and did not require intervention. "There was also no maximum tolerated dose or dose-limiting toxicities, and no grade 3-5 pneumonitis was observed," she said.

In a study of MPDL3280A presented by Dr. Horn and her associates at the 2013 World Conference on Lung Cancer, the clinical impact was assessed in 53 patients with NSCLC. Patients first dosed at 1-20 mg/kg by Oct. 1, 2012, with data cutoff on April 30, 2013. The response rate was 83% among patients who had an immunohistochemistry (IHC) score of 3, 46% among those who were IHC 2 and 3, and 31% among those who were IHC 1, 2, and 3. "In all-comers the response rate was 23%," Dr. Horn said. "The responses in these patients are very rapid. We see them by their first or second CT [computed tomography] scan. The responses are also very durable regardless of their IHC status and in patients who are PD-L1 negative. They’ve also been responding even after treatment has been discontinued."

She and her associates examined the response rate to MPDL3280A based on smoking status and mutational status. The response rate was higher in patients who were current or former smokers compared with never smokers (26% vs. 10%, respectively). By molecular status, the response rate in EGFR [epidermal growth factor receptor] wild-type patients was 26%, compared with 17% in EGFR mutant patients. In addition, there was a 30% response rate in patients who were KRAS wild-type and a 10% response rate in KRAS mutant patients, although the numbers are very small, she noted.

According to Dr. Horn, there are three separate, ongoing studies looking at MPDL3280A in NSCLC patients: one in patients with PD-L1–positive NSCLC, one in combination with bevacizumab and/or chemotherapy, and one randomized phase III trial comparing the agent with docetaxel in patients after platinum failure.

Data on the next agent Dr. Horn discussed, MEDI4736 from MedImmune, are limited. A study of this agent was presented at the 2013 ESMO Congress and included 11 patients who received doses of 0.1, 0.3, and 1.0 mg/kg. The most common treatment-related adverse events were diarrhea, vomiting, and dizziness (18% each), and no grade 3 or 4 adverse events or pneumonitis have been reported to date.

Pharmacokinetic studies of MEDI4736 indicate a dose-dependent increase in target engagement, consistent with binding of the agent to PD-L1. Initial clinical data on eight patients demonstrated response at all different dose levels, ranging from 42% to 80%. "This involves small subsets of patients, so hopefully we’ll see more data on this agent in the next couple of years," Dr. Horn said.

The final anti-PD-L1 in clinical development is MSB0010718C from EMD Serono, but no data are available yet. A three-dose escalation study up to 10 mg/kg is underway. "Hopefully, we’ll see some data on this later this year," Dr. Horn said.

She concluded her remarks by noting that future directions in anti-PD-L1 therapy will involve determining its role in specific molecular cohorts and in patients with PD-L1–negative tumors; combination therapy with chemotherapy, other immune therapy, and targeted therapies; patients with prior radiation therapy to the chest; and patients with early-stage disease.

Dr. Horn disclosed that she is a speaker for Bristol-Myers Squibb, Theradex, and other companies.

[email protected]

SAN DIEGO – Results from studies conducted to date indicate that anti-PD-L1 therapy is well tolerated in patients with non–small cell lung cancer, with rapid response rates.

In fact, responses are "not only very rapid, they’re also very durable," Dr. Leora Horn said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

"We’re seeing continued responses even when treatment is discontinued. The response rates appear to be somewhat higher in tumors that express PD-L1, and we see no pneumonitis or treatment-related grade 5 adverse events to date."

The four anti-PD-L1 agents that have been investigated or are currently being investigated in patients with non–small cell lung cancer (NSCLC) are BMS-936559, MPDL3280A, MEDI-4736, and MSB0010718C, according to Dr. Horn, clinical director of the thoracic oncology research program at Vanderbilt University, Nashville, Tenn.

BMS-936559, developed by Bristol Myers-Squibb, was part of a phase IA dose study at 0.3, 1, 3, and 10 mg/kg in patients with multiple tumor types including NSCLC. Of the 207 patients enrolled, 75 had NSCLC (N. Engl. J. Med 2012;366:2455-65).

More than half of all patients (61%) had treatment-related adverse events, with fatigue the most common (16%), followed by infusion reaction (10%) and diarrhea (9%). Grade 3 and 4 adverse events occurred in 9% of patients. "One of the themes with anti-PD-L1 therapy is that we’re not seeing grade 3-5 pneumonitis in these like we have seen with anti-PD-1 agents," said Dr. Horn. "This may have to do with different expression of PD-1 and PD-2 within the body and the targets of PD-1 compared to anti-PD-L1 antibodies."

The response rate among NSCLC patients treated in the trial reached about 10%, and responses were seen in squamous and nonsquamous NSCLC. "This agent is not being further developed in NSCLC patients," Dr. Horn said. "Nivolumab, a PD-1 blocking antibody, has really taken over as far as development for Bristol-Myers Squibb."

The next agent she discussed, MPDL3280A, is being developed by Roche and Genentech. A phase I trial presented at the 2013 European Society for Medical Oncology (ESMO) Congress examined different doses in 85 patients with NSCLC ranging from 10 to 20 mg/kg once every week for just under 1 year. Key eligibility criteria were measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 and Eastern Cooperative Oncology Group Performance Status 0 or 1. Dr. Horn said that the majority of adverse events were grade 1-2 and did not require intervention. "There was also no maximum tolerated dose or dose-limiting toxicities, and no grade 3-5 pneumonitis was observed," she said.

In a study of MPDL3280A presented by Dr. Horn and her associates at the 2013 World Conference on Lung Cancer, the clinical impact was assessed in 53 patients with NSCLC. Patients first dosed at 1-20 mg/kg by Oct. 1, 2012, with data cutoff on April 30, 2013. The response rate was 83% among patients who had an immunohistochemistry (IHC) score of 3, 46% among those who were IHC 2 and 3, and 31% among those who were IHC 1, 2, and 3. "In all-comers the response rate was 23%," Dr. Horn said. "The responses in these patients are very rapid. We see them by their first or second CT [computed tomography] scan. The responses are also very durable regardless of their IHC status and in patients who are PD-L1 negative. They’ve also been responding even after treatment has been discontinued."

She and her associates examined the response rate to MPDL3280A based on smoking status and mutational status. The response rate was higher in patients who were current or former smokers compared with never smokers (26% vs. 10%, respectively). By molecular status, the response rate in EGFR [epidermal growth factor receptor] wild-type patients was 26%, compared with 17% in EGFR mutant patients. In addition, there was a 30% response rate in patients who were KRAS wild-type and a 10% response rate in KRAS mutant patients, although the numbers are very small, she noted.

According to Dr. Horn, there are three separate, ongoing studies looking at MPDL3280A in NSCLC patients: one in patients with PD-L1–positive NSCLC, one in combination with bevacizumab and/or chemotherapy, and one randomized phase III trial comparing the agent with docetaxel in patients after platinum failure.

Data on the next agent Dr. Horn discussed, MEDI4736 from MedImmune, are limited. A study of this agent was presented at the 2013 ESMO Congress and included 11 patients who received doses of 0.1, 0.3, and 1.0 mg/kg. The most common treatment-related adverse events were diarrhea, vomiting, and dizziness (18% each), and no grade 3 or 4 adverse events or pneumonitis have been reported to date.

Pharmacokinetic studies of MEDI4736 indicate a dose-dependent increase in target engagement, consistent with binding of the agent to PD-L1. Initial clinical data on eight patients demonstrated response at all different dose levels, ranging from 42% to 80%. "This involves small subsets of patients, so hopefully we’ll see more data on this agent in the next couple of years," Dr. Horn said.

The final anti-PD-L1 in clinical development is MSB0010718C from EMD Serono, but no data are available yet. A three-dose escalation study up to 10 mg/kg is underway. "Hopefully, we’ll see some data on this later this year," Dr. Horn said.

She concluded her remarks by noting that future directions in anti-PD-L1 therapy will involve determining its role in specific molecular cohorts and in patients with PD-L1–negative tumors; combination therapy with chemotherapy, other immune therapy, and targeted therapies; patients with prior radiation therapy to the chest; and patients with early-stage disease.

Dr. Horn disclosed that she is a speaker for Bristol-Myers Squibb, Theradex, and other companies.

[email protected]

SAN DIEGO – Results from studies conducted to date indicate that anti-PD-L1 therapy is well tolerated in patients with non–small cell lung cancer, with rapid response rates.

In fact, responses are "not only very rapid, they’re also very durable," Dr. Leora Horn said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

"We’re seeing continued responses even when treatment is discontinued. The response rates appear to be somewhat higher in tumors that express PD-L1, and we see no pneumonitis or treatment-related grade 5 adverse events to date."

The four anti-PD-L1 agents that have been investigated or are currently being investigated in patients with non–small cell lung cancer (NSCLC) are BMS-936559, MPDL3280A, MEDI-4736, and MSB0010718C, according to Dr. Horn, clinical director of the thoracic oncology research program at Vanderbilt University, Nashville, Tenn.

BMS-936559, developed by Bristol Myers-Squibb, was part of a phase IA dose study at 0.3, 1, 3, and 10 mg/kg in patients with multiple tumor types including NSCLC. Of the 207 patients enrolled, 75 had NSCLC (N. Engl. J. Med 2012;366:2455-65).

More than half of all patients (61%) had treatment-related adverse events, with fatigue the most common (16%), followed by infusion reaction (10%) and diarrhea (9%). Grade 3 and 4 adverse events occurred in 9% of patients. "One of the themes with anti-PD-L1 therapy is that we’re not seeing grade 3-5 pneumonitis in these like we have seen with anti-PD-1 agents," said Dr. Horn. "This may have to do with different expression of PD-1 and PD-2 within the body and the targets of PD-1 compared to anti-PD-L1 antibodies."

The response rate among NSCLC patients treated in the trial reached about 10%, and responses were seen in squamous and nonsquamous NSCLC. "This agent is not being further developed in NSCLC patients," Dr. Horn said. "Nivolumab, a PD-1 blocking antibody, has really taken over as far as development for Bristol-Myers Squibb."

The next agent she discussed, MPDL3280A, is being developed by Roche and Genentech. A phase I trial presented at the 2013 European Society for Medical Oncology (ESMO) Congress examined different doses in 85 patients with NSCLC ranging from 10 to 20 mg/kg once every week for just under 1 year. Key eligibility criteria were measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 and Eastern Cooperative Oncology Group Performance Status 0 or 1. Dr. Horn said that the majority of adverse events were grade 1-2 and did not require intervention. "There was also no maximum tolerated dose or dose-limiting toxicities, and no grade 3-5 pneumonitis was observed," she said.

In a study of MPDL3280A presented by Dr. Horn and her associates at the 2013 World Conference on Lung Cancer, the clinical impact was assessed in 53 patients with NSCLC. Patients first dosed at 1-20 mg/kg by Oct. 1, 2012, with data cutoff on April 30, 2013. The response rate was 83% among patients who had an immunohistochemistry (IHC) score of 3, 46% among those who were IHC 2 and 3, and 31% among those who were IHC 1, 2, and 3. "In all-comers the response rate was 23%," Dr. Horn said. "The responses in these patients are very rapid. We see them by their first or second CT [computed tomography] scan. The responses are also very durable regardless of their IHC status and in patients who are PD-L1 negative. They’ve also been responding even after treatment has been discontinued."

She and her associates examined the response rate to MPDL3280A based on smoking status and mutational status. The response rate was higher in patients who were current or former smokers compared with never smokers (26% vs. 10%, respectively). By molecular status, the response rate in EGFR [epidermal growth factor receptor] wild-type patients was 26%, compared with 17% in EGFR mutant patients. In addition, there was a 30% response rate in patients who were KRAS wild-type and a 10% response rate in KRAS mutant patients, although the numbers are very small, she noted.

According to Dr. Horn, there are three separate, ongoing studies looking at MPDL3280A in NSCLC patients: one in patients with PD-L1–positive NSCLC, one in combination with bevacizumab and/or chemotherapy, and one randomized phase III trial comparing the agent with docetaxel in patients after platinum failure.

Data on the next agent Dr. Horn discussed, MEDI4736 from MedImmune, are limited. A study of this agent was presented at the 2013 ESMO Congress and included 11 patients who received doses of 0.1, 0.3, and 1.0 mg/kg. The most common treatment-related adverse events were diarrhea, vomiting, and dizziness (18% each), and no grade 3 or 4 adverse events or pneumonitis have been reported to date.

Pharmacokinetic studies of MEDI4736 indicate a dose-dependent increase in target engagement, consistent with binding of the agent to PD-L1. Initial clinical data on eight patients demonstrated response at all different dose levels, ranging from 42% to 80%. "This involves small subsets of patients, so hopefully we’ll see more data on this agent in the next couple of years," Dr. Horn said.

The final anti-PD-L1 in clinical development is MSB0010718C from EMD Serono, but no data are available yet. A three-dose escalation study up to 10 mg/kg is underway. "Hopefully, we’ll see some data on this later this year," Dr. Horn said.

She concluded her remarks by noting that future directions in anti-PD-L1 therapy will involve determining its role in specific molecular cohorts and in patients with PD-L1–negative tumors; combination therapy with chemotherapy, other immune therapy, and targeted therapies; patients with prior radiation therapy to the chest; and patients with early-stage disease.

Dr. Horn disclosed that she is a speaker for Bristol-Myers Squibb, Theradex, and other companies.

[email protected]

SAN DIEGO – Expect an expanded role of immunotherapy in patients with non–small cell lung cancer, Dr. Roy S. Herbst predicted at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Herbst, professor of medical oncology at Yale University, New Haven, Conn., characterized immunotherapy as "probably the most exciting new and specific therapies we have for NSCLC. The extent in its response is impressive, and this is a therapy that has memory. The adaptability of immunotherapy is important as well."

He advised researchers and clinicians to consider using immunotherapy that includes CTLA-4 antibodies, PD-1 antibodies, and PD-L1 antibodies alone or together in patients with earlier stages of lung disease. Clinical studies of immunotherapy in NSCLC patients suggest that some patients don’t get better with immunotherapy, "but a lot of patients do," said Dr. Herbst. "We want to figure out who those patients are. When we see activity like this, we think, can we bring this therapy to earlier disease? These agents might have a role in maintenance therapy and adjuvant/neoadjuvant therapy. Of course, we worry about side effects such as pneumonitis, which occurs rarely, but we still hope these agents will have a benefit in the adjuvant setting. The biology speaks to that. But what about using these agents as maintenance therapy? I think that needs to be explored."

Using immunotherapy as frontline treatment in patients with stage IV lung cancer is also feasible, he said. "I’d feel much better about it if we had a marker, but we should think about some single-agent trials," he said. "Other possibilities in stage IV disease include using immunotherapy with chemotherapy and with tyrosine kinase inhibitors."

Immunotherapy-related adverse events are "not overwhelming, but they’re different than what we see with chemotherapy," Dr. Herbst continued. "For example, some of the endocrine events are not something we often see. We are working on ways to manage this."

Use of biomarkers and immune monitoring can also help clinicians gauge the efficacy of immunotherapy in their NSCLC patients. Dr. Herbst and his associates at Yale Cancer Center follow these patients with biopsies at baseline, during therapy, and at the end of therapy, "because after their therapy at 1 year or more, you wonder: Is this active tumor? Or is this necrotic tissue?" he said. "We now have ways to figure out who is responding and why they’re responding."

Another trend in the future of immunotherapy involves combining with other agents that address key mechanisms in positive and negative regulation of the immune system. Dr. Herbst explained that the biological goal of combinations with a checkpoint inhibitor include the ability to induce antigen-specific T cells, provide more antigen-presenting cells (APCs), activation/modulation of APCs, drive T-cell expansion to expand the pool of antigen-specific cells, and remove other regulatory checkpoints/suppressive factors for T-cell activation/expansion in periphery.

"The current challenge is to identify the critical deficiencies in individual patients," he said. "We have to continue to investigate the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment."

Dr. Herbst disclosed that he is on the scientific advisory boards of Biothera, Diatech, Kolltan, N of 1, Novarx, and Quintiles. He also has done consulting for Ariad, Astellas, and other companies.

[email protected]

This article was updated March 25, 2014.

SAN DIEGO – Expect an expanded role of immunotherapy in patients with non–small cell lung cancer, Dr. Roy S. Herbst predicted at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Herbst, professor of medical oncology at Yale University, New Haven, Conn., characterized immunotherapy as "probably the most exciting new and specific therapies we have for NSCLC. The extent in its response is impressive, and this is a therapy that has memory. The adaptability of immunotherapy is important as well."

He advised researchers and clinicians to consider using immunotherapy that includes CTLA-4 antibodies, PD-1 antibodies, and PD-L1 antibodies alone or together in patients with earlier stages of lung disease. Clinical studies of immunotherapy in NSCLC patients suggest that some patients don’t get better with immunotherapy, "but a lot of patients do," said Dr. Herbst. "We want to figure out who those patients are. When we see activity like this, we think, can we bring this therapy to earlier disease? These agents might have a role in maintenance therapy and adjuvant/neoadjuvant therapy. Of course, we worry about side effects such as pneumonitis, which occurs rarely, but we still hope these agents will have a benefit in the adjuvant setting. The biology speaks to that. But what about using these agents as maintenance therapy? I think that needs to be explored."

Using immunotherapy as frontline treatment in patients with stage IV lung cancer is also feasible, he said. "I’d feel much better about it if we had a marker, but we should think about some single-agent trials," he said. "Other possibilities in stage IV disease include using immunotherapy with chemotherapy and with tyrosine kinase inhibitors."

Immunotherapy-related adverse events are "not overwhelming, but they’re different than what we see with chemotherapy," Dr. Herbst continued. "For example, some of the endocrine events are not something we often see. We are working on ways to manage this."

Use of biomarkers and immune monitoring can also help clinicians gauge the efficacy of immunotherapy in their NSCLC patients. Dr. Herbst and his associates at Yale Cancer Center follow these patients with biopsies at baseline, during therapy, and at the end of therapy, "because after their therapy at 1 year or more, you wonder: Is this active tumor? Or is this necrotic tissue?" he said. "We now have ways to figure out who is responding and why they’re responding."

Another trend in the future of immunotherapy involves combining with other agents that address key mechanisms in positive and negative regulation of the immune system. Dr. Herbst explained that the biological goal of combinations with a checkpoint inhibitor include the ability to induce antigen-specific T cells, provide more antigen-presenting cells (APCs), activation/modulation of APCs, drive T-cell expansion to expand the pool of antigen-specific cells, and remove other regulatory checkpoints/suppressive factors for T-cell activation/expansion in periphery.

"The current challenge is to identify the critical deficiencies in individual patients," he said. "We have to continue to investigate the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment."

Dr. Herbst disclosed that he is on the scientific advisory boards of Biothera, Diatech, Kolltan, N of 1, Novarx, and Quintiles. He also has done consulting for Ariad, Astellas, and other companies.

[email protected]

This article was updated March 25, 2014.

SAN DIEGO – Expect an expanded role of immunotherapy in patients with non–small cell lung cancer, Dr. Roy S. Herbst predicted at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Herbst, professor of medical oncology at Yale University, New Haven, Conn., characterized immunotherapy as "probably the most exciting new and specific therapies we have for NSCLC. The extent in its response is impressive, and this is a therapy that has memory. The adaptability of immunotherapy is important as well."

He advised researchers and clinicians to consider using immunotherapy that includes CTLA-4 antibodies, PD-1 antibodies, and PD-L1 antibodies alone or together in patients with earlier stages of lung disease. Clinical studies of immunotherapy in NSCLC patients suggest that some patients don’t get better with immunotherapy, "but a lot of patients do," said Dr. Herbst. "We want to figure out who those patients are. When we see activity like this, we think, can we bring this therapy to earlier disease? These agents might have a role in maintenance therapy and adjuvant/neoadjuvant therapy. Of course, we worry about side effects such as pneumonitis, which occurs rarely, but we still hope these agents will have a benefit in the adjuvant setting. The biology speaks to that. But what about using these agents as maintenance therapy? I think that needs to be explored."

Using immunotherapy as frontline treatment in patients with stage IV lung cancer is also feasible, he said. "I’d feel much better about it if we had a marker, but we should think about some single-agent trials," he said. "Other possibilities in stage IV disease include using immunotherapy with chemotherapy and with tyrosine kinase inhibitors."

Immunotherapy-related adverse events are "not overwhelming, but they’re different than what we see with chemotherapy," Dr. Herbst continued. "For example, some of the endocrine events are not something we often see. We are working on ways to manage this."

Use of biomarkers and immune monitoring can also help clinicians gauge the efficacy of immunotherapy in their NSCLC patients. Dr. Herbst and his associates at Yale Cancer Center follow these patients with biopsies at baseline, during therapy, and at the end of therapy, "because after their therapy at 1 year or more, you wonder: Is this active tumor? Or is this necrotic tissue?" he said. "We now have ways to figure out who is responding and why they’re responding."

Another trend in the future of immunotherapy involves combining with other agents that address key mechanisms in positive and negative regulation of the immune system. Dr. Herbst explained that the biological goal of combinations with a checkpoint inhibitor include the ability to induce antigen-specific T cells, provide more antigen-presenting cells (APCs), activation/modulation of APCs, drive T-cell expansion to expand the pool of antigen-specific cells, and remove other regulatory checkpoints/suppressive factors for T-cell activation/expansion in periphery.

"The current challenge is to identify the critical deficiencies in individual patients," he said. "We have to continue to investigate the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment."

Dr. Herbst disclosed that he is on the scientific advisory boards of Biothera, Diatech, Kolltan, N of 1, Novarx, and Quintiles. He also has done consulting for Ariad, Astellas, and other companies.

[email protected]

This article was updated March 25, 2014.

SAN DIEGO – About 30% of nodules detected by CT screening fit the criteria for an indeterminate pulmonary nodule. Very few of those nodules represent cancer, and the question is, what do you recommend for those patients in terms of follow-up?

"We’re encountering more and more patients with lung nodules in the clinic, and with the advance of screening, it will become even more of a problem. The numbers are tremendous," Dr. Pierre P. Massion stated at the Joint Conference on the Molecular Origins of Lung Cancer, sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Massion, the Ingram Professor of Cancer Research at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said it’s important to differentiate – early, accurately, and noninvasively – benign lesions from cancer. "There is a race for early diagnosis, because surgery is the best chance for cure ... but we also need to decrease the number of thoracotomies performed for benign disease."

Data from eight large trials of lung cancer screening examined the relationship between lesion size and the probability of lung cancer (Chest 2007;132[3 Suppl]:94S-107S). The probability of cancer was 0-1% for lesions less than 5 mm in diameter; 6%-28% for those 5-10 mm, 33%-60% for those 11-20 mm, and 64%-82% for those 21-30 mm.

"The bigger the nodule, the greater the probability of cancer. In fact, however, the number of large nodules is very small," Dr. Massion said. "The indeterminate ones are between 5 and 15 mm in diameter, and these are the ones we struggle with how best to handle." The probability of cancer from indeterminate pulmonary nodules ranges from 6% to 60%, which is a large range.

The shape of the nodule provides additional information, Dr. Massion said. Triangular shape abutting a fissure and central calcification are generally indicators of benign disease and typically do not require follow-up. Alternatively, solid, noncalcified spiculated nodules have a high likelihood of being cancer. Part solid nodules are "very worrisome," he said. "These are most likely to contain malignancy. Nonsolid lesions, also called ground-glass opacities, are troublesome and difficult to assess. They represent about a 20% probability of disease."

The rate of growth of small nodules over time "is probably one of the best imaging markers, [but] for small nodules such as those 5 mm in diameter, the volumetric analysis has a large coefficient of variance," he said.

Prediction models are important to the evaluation of lung nodules, yet even with existing tools "we’re wrong about 30% of the time," he said. The best three prediction models come from studies of patients at the Mayo Clinic (Arch. Intern. Med. 1997;157:849-55) and the Veterans Affairs department (Chest 2007;131:383-88), and from patients enrolled in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial (N. Engl. J. Med. 2013;368:728-36). These prediction models are now recommended for use on nodules greater than 8 mm in diameter in the ACCP 2013 guidelines for evaluation of lung nodules (Chest 2013;143[5 Suppl]:e93S-120S).

"We have no models for never-smokers, which is a huge problem in the community at the moment."

Dr. Massion predicted that serum biomarkers might "come to the rescue" for deciding which patients with indeterminate pulmonary nodules might need to go for a biopsy or resection and which can be carefully watched over time.

In a separate study of 62 lung nodules that integrated clinical, imaging, and protein biomarker findings, clinical information alone resulted in about 50% sensitivity for predicting disease, "which is not great," said Dr. Massion, who was the principal investigator (Cancer Epidemiol. Biomarkers Prev. 2012;21:786-92). The addition of CT imaging increased the area under the curve to about 61%. Adding biomarkers in the blood raised the bar to about 69%.

"It’s not a panacea, but we show a trend toward improvement of classification of these nodules, which is where I think this field is going – integrating information from the clinic, imaging, and the discriminatory power of biomarkers."

Dr. Massion said that he had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – About 30% of nodules detected by CT screening fit the criteria for an indeterminate pulmonary nodule. Very few of those nodules represent cancer, and the question is, what do you recommend for those patients in terms of follow-up?

"We’re encountering more and more patients with lung nodules in the clinic, and with the advance of screening, it will become even more of a problem. The numbers are tremendous," Dr. Pierre P. Massion stated at the Joint Conference on the Molecular Origins of Lung Cancer, sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Massion, the Ingram Professor of Cancer Research at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said it’s important to differentiate – early, accurately, and noninvasively – benign lesions from cancer. "There is a race for early diagnosis, because surgery is the best chance for cure ... but we also need to decrease the number of thoracotomies performed for benign disease."

Data from eight large trials of lung cancer screening examined the relationship between lesion size and the probability of lung cancer (Chest 2007;132[3 Suppl]:94S-107S). The probability of cancer was 0-1% for lesions less than 5 mm in diameter; 6%-28% for those 5-10 mm, 33%-60% for those 11-20 mm, and 64%-82% for those 21-30 mm.

"The bigger the nodule, the greater the probability of cancer. In fact, however, the number of large nodules is very small," Dr. Massion said. "The indeterminate ones are between 5 and 15 mm in diameter, and these are the ones we struggle with how best to handle." The probability of cancer from indeterminate pulmonary nodules ranges from 6% to 60%, which is a large range.

The shape of the nodule provides additional information, Dr. Massion said. Triangular shape abutting a fissure and central calcification are generally indicators of benign disease and typically do not require follow-up. Alternatively, solid, noncalcified spiculated nodules have a high likelihood of being cancer. Part solid nodules are "very worrisome," he said. "These are most likely to contain malignancy. Nonsolid lesions, also called ground-glass opacities, are troublesome and difficult to assess. They represent about a 20% probability of disease."

The rate of growth of small nodules over time "is probably one of the best imaging markers, [but] for small nodules such as those 5 mm in diameter, the volumetric analysis has a large coefficient of variance," he said.

Prediction models are important to the evaluation of lung nodules, yet even with existing tools "we’re wrong about 30% of the time," he said. The best three prediction models come from studies of patients at the Mayo Clinic (Arch. Intern. Med. 1997;157:849-55) and the Veterans Affairs department (Chest 2007;131:383-88), and from patients enrolled in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial (N. Engl. J. Med. 2013;368:728-36). These prediction models are now recommended for use on nodules greater than 8 mm in diameter in the ACCP 2013 guidelines for evaluation of lung nodules (Chest 2013;143[5 Suppl]:e93S-120S).

"We have no models for never-smokers, which is a huge problem in the community at the moment."

Dr. Massion predicted that serum biomarkers might "come to the rescue" for deciding which patients with indeterminate pulmonary nodules might need to go for a biopsy or resection and which can be carefully watched over time.

In a separate study of 62 lung nodules that integrated clinical, imaging, and protein biomarker findings, clinical information alone resulted in about 50% sensitivity for predicting disease, "which is not great," said Dr. Massion, who was the principal investigator (Cancer Epidemiol. Biomarkers Prev. 2012;21:786-92). The addition of CT imaging increased the area under the curve to about 61%. Adding biomarkers in the blood raised the bar to about 69%.

"It’s not a panacea, but we show a trend toward improvement of classification of these nodules, which is where I think this field is going – integrating information from the clinic, imaging, and the discriminatory power of biomarkers."

Dr. Massion said that he had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – About 30% of nodules detected by CT screening fit the criteria for an indeterminate pulmonary nodule. Very few of those nodules represent cancer, and the question is, what do you recommend for those patients in terms of follow-up?

"We’re encountering more and more patients with lung nodules in the clinic, and with the advance of screening, it will become even more of a problem. The numbers are tremendous," Dr. Pierre P. Massion stated at the Joint Conference on the Molecular Origins of Lung Cancer, sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

Dr. Massion, the Ingram Professor of Cancer Research at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said it’s important to differentiate – early, accurately, and noninvasively – benign lesions from cancer. "There is a race for early diagnosis, because surgery is the best chance for cure ... but we also need to decrease the number of thoracotomies performed for benign disease."

Data from eight large trials of lung cancer screening examined the relationship between lesion size and the probability of lung cancer (Chest 2007;132[3 Suppl]:94S-107S). The probability of cancer was 0-1% for lesions less than 5 mm in diameter; 6%-28% for those 5-10 mm, 33%-60% for those 11-20 mm, and 64%-82% for those 21-30 mm.

"The bigger the nodule, the greater the probability of cancer. In fact, however, the number of large nodules is very small," Dr. Massion said. "The indeterminate ones are between 5 and 15 mm in diameter, and these are the ones we struggle with how best to handle." The probability of cancer from indeterminate pulmonary nodules ranges from 6% to 60%, which is a large range.

The shape of the nodule provides additional information, Dr. Massion said. Triangular shape abutting a fissure and central calcification are generally indicators of benign disease and typically do not require follow-up. Alternatively, solid, noncalcified spiculated nodules have a high likelihood of being cancer. Part solid nodules are "very worrisome," he said. "These are most likely to contain malignancy. Nonsolid lesions, also called ground-glass opacities, are troublesome and difficult to assess. They represent about a 20% probability of disease."

The rate of growth of small nodules over time "is probably one of the best imaging markers, [but] for small nodules such as those 5 mm in diameter, the volumetric analysis has a large coefficient of variance," he said.

Prediction models are important to the evaluation of lung nodules, yet even with existing tools "we’re wrong about 30% of the time," he said. The best three prediction models come from studies of patients at the Mayo Clinic (Arch. Intern. Med. 1997;157:849-55) and the Veterans Affairs department (Chest 2007;131:383-88), and from patients enrolled in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial (N. Engl. J. Med. 2013;368:728-36). These prediction models are now recommended for use on nodules greater than 8 mm in diameter in the ACCP 2013 guidelines for evaluation of lung nodules (Chest 2013;143[5 Suppl]:e93S-120S).

"We have no models for never-smokers, which is a huge problem in the community at the moment."

Dr. Massion predicted that serum biomarkers might "come to the rescue" for deciding which patients with indeterminate pulmonary nodules might need to go for a biopsy or resection and which can be carefully watched over time.

In a separate study of 62 lung nodules that integrated clinical, imaging, and protein biomarker findings, clinical information alone resulted in about 50% sensitivity for predicting disease, "which is not great," said Dr. Massion, who was the principal investigator (Cancer Epidemiol. Biomarkers Prev. 2012;21:786-92). The addition of CT imaging increased the area under the curve to about 61%. Adding biomarkers in the blood raised the bar to about 69%.

"It’s not a panacea, but we show a trend toward improvement of classification of these nodules, which is where I think this field is going – integrating information from the clinic, imaging, and the discriminatory power of biomarkers."

Dr. Massion said that he had no relevant financial conflicts to disclose.

[email protected]