1. Eastman, Peggy

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WASHINGTON, D.C.-The 5-year survival rate of a subset of patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab was 16 percent, quadruple the usual 4 percent seen with chemotherapy, according to data presented in a phase I clinical trial by Julie Brahmer, MD, Associate Professor of Oncology at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore. Brahmer presented the data at the annual meeting of the American Association for Cancer Research (AACR), held April 1-5.

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"This is the first report of the long-term survival rate in patients with metastatic NSCLC treated with an immune checkpoint inhibitor," noted Brahmer. "It's an exciting time to have long-term survivors to follow-up. The 5-year overall survival rate reported in this study is much higher than what is reported for this population of patients receiving standard-of-care treatments. Statistics show that most patients with advanced disease die within a year of diagnosis, and the 5-year survival rate for metastatic NSCLC is about 4 percent," stated Brahmer. Most of the study subjects were former or current smokers.


Brahmer noted that now "nivolumab is an established standard-of-care in patients with previously treated advanced NSCLC, based on the results of two pivotal phase III trials." In this trial, Brahmer and her colleagues used data from a cohort of the phase I clinical trial CA209-003, which has the longest survival follow-up for an immune checkpoint inhibitor in advanced NSCLC. Patients with heavily pretreated advanced NSCLC were accepted as subjects regardless of their tumor PD-L1 status and randomized to one of three different dose levels of nivolumab. Data from previous trials had demonstrated that nivolumab had efficacy in this patient population, leading the FDA to approve nivolumab for second-line treatment of patients with advanced NSCLC.


Study Specifics

In this trial, 129 patients treated at more than 11 U.S. hospitals, including Johns Hopkins, were followed for a minimum of about 58 months; the overall survival rate in patients with squamous NSCLC was 16 percent, and the rate for patients with non-squamous NSCLC was 15 percent. Nine of the 16 patients who survived for 5 years or longer were male, and 12 were current smokers when they enrolled in the phase I trial. Twelve patients had a partial response, while two patients had stable disease and two patients had progressive disease as the best response to treatment.


Of the patients in the study cohort, eight completed the 2-year treatment regimen without any side effects, and four stopped treatment due to side effects. None of these 12 patients needed further treatment.


Brahmer presented a case study of one study participant, a 61-year-old heavily pretreated male former smoker. He had squamous NSCLC with unknown PD-L1 status and a high tumor mutation burden-314 total somatic mutations. Six years after beginning nivolumab treatment, the patient remains alive and in response, without evidence of progressive disease.


What is not known at this time is whether the cancerous tumors were completely eliminated in the 5-year survivors by their immune systems, or if the therapy invoked an ongoing immune memory. "I think we can shorten our time of therapy," Brahmer said, but to do that it will be necessary to identify patients who develop immune memory cells. "My personal feeling is that some patients don't need to be treated indefinitely," she added. "Right now there's really no characteristic that stands out" that points to which NSCLC patients will experience long-term survival on nivolumab. "We were unable to see a consistent pattern, a clinical or tumor characteristic, to predict which metastatic lung cancer patients are going to be 5-year survivors," Brahmer explained.


Patients in the study cohort had baseline tumor biopsies as a requirement for enrollment, but several patients did not have adequate tumor samples to determine their PD-L1 status, noted Brahmer. The presence and quantity of the protein PD-L1 are used as biomarkers for patients likely to respond to immune checkpoint inhibitors such as nivolumab that target the PD-1/PDL1 pathway. But PD-L1 status was not clearly associated with 5-year survivors in this patient subset.


Advancing Immunotherapy

"This is a landmark study," said news briefing moderator Suzanne Topalian, MD, Director of the Melanoma Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and Associate Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy. Topalian noted that the quadrupling of 5-year survival of the NSCLC subset that responded to nivolumab is highly statistically significant. "This brought immunotherapy out of the realm of specialized therapy," she said of the study results.


Brahmer said she and her colleagues are doing further studies to learn why the patients who responded did so well for so long; which patients can stop treatment at 2 years; and which need to continue treatment beyond 2 years. "Now, we need to figure out how to make more patients responsive to immunotherapy by exploring combinations of immunotherapy drugs and other treatment agents," she explained.


Some of the first data on this group of 129 patients were published by Brahmer and her colleagues in 2015. At that time, reported side effects from nivolumab included fatigue, thyroid problems, pneumonitis, rashes, and gastrointestinal problems. Patients in the study received nivolumab once every 2 weeks for up to 2 years. Brahmer noted that determining which patients need continuing therapy and which do not would not only get the best treatments to patients earlier, but would present an opportunity for cost savings for patients who do not respond, since nivolumab can cost more than $100,000 a year.


A limitation of the study subset results presented at the AACR meeting, which Brahmer readily pointed out, is that since the study was not a randomized trial, NSCLC patients who received nivolumab were not directly compared with patients who did not receive the drug, but rather with data based on historical survival rates.


Peggy Eastman is a contributing writer.