“There are several possible ways to move first-line immunotherapy for non–small cell lung cancer (NSCLC) forward, according to invited discussant Edward B. Garon, MD, Director of Thoracic Oncology at the David Geffen School of Medicine at the University of California, Los Angeles. “We could expand the group of patients who stand to benefit from front-line immunotherapy. We could also enhance the selectivity of the biomarkers. And, of course, anything that would improve toxicity or enhance efficacy would be a welcome addition,” Dr. Garon elaborated.
The CheckMate 012 data look “quite good,” showing a marked gain in efficacy by combining nivolumab (Opdivo) with ipilimumab (Yervoy), with little increase in overall toxicity, Dr. Garon commented.
Until we see randomized data…, I will remain hopeful—but not yet entirely confident—that this combination will be the new standard for front-line therapy for metastatic NSCLC.— Edward B. Garon, MD
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“Is there any doubt that this will become the standard front-line approach for patients with NSCLC? I would argue that perhaps there is reason to be at least cautious,” he admitted. Specifically, the better efficacy outcomes with the combination may be due in part to biases, such as patient selection bias. He noted that the presented combination therapy cohorts were enrolled after earlier cohorts with more frequent ipilimumab were poorly tolerated.
“Referring to the patients selected for enrollment in the presented cohorts, if the only problem were that they were selecting out patients who would have toxicity prior to the potential for efficacy, that’s probably okay because if these drugs are approved, we certainly will be doing that in our clinics,” Dr. Garon commented. “On the other hand, if this (favorable data) is all related to patient selection for a more robust patient population, there is some risk that our enthusiasm will not be sufficiently rewarded.”
“So does this expand the group of patients who benefit? It certainly may,” he said. “But from my perspective, until we see randomized data that can control for some of the biases mentioned, I will remain hopeful—but not yet entirely confident—that this combination will be the new standard for front-line therapy for metastatic NSCLC.”
Turning to the BIRCH trial, Dr. Garon noted that the response rate with atezolizumab (Tecentriq) in patients with programmed cell death ligand 1 (PD-L1) positivity of tumor cell (TC) 3 or immune cell (IC) 3 was not better than that of pembrolizumab (Keytruda) in the KEYNOTE-024 trial. And previous research suggests such patients make up about 15% of all patients, a lesser percentage of patients than for whom pembrolizumab is currently approved.
“So it does not appear that this biomarker at this point is expanding the population of the patients who are eligible, and at least numerically, the response rate is a little bit less,” he remarked. “But that is in contrast to what I would say is fairly impressive overall survival data, and the TC3/IC3 group has of course the most impressive survival data.”
The BIRCH results do not suggest substantial gain with respect to expanding the group of patients who would benefit, enhancing selectivity of the biomarker, or improving efficacy or toxicity, according to Dr. Garon. “It should be noted, however, that atezolizumab was recently approved by the U.S. Food and Drug Administration [for use after chemotherapy], and that in the recently presented OAK study, it looked to be at least as good as the numbers we have seen for the programmed cell death protein 1 (PD-1) inhibitors.”
The antibody used to assess PD-L1 status for atezolizumab, SP 142, has been shown to be less sensitive than other antibodies in use, he noted.1 Additionally, staining is assessed in two cell populations: tumor cells and tumor-infiltrating immune cells.
Dr. Garon asked, does that matter? “My feeling is that you actually are not looking at a single biomarker, despite that this is how that is reported, but in fact you are looking at two biomarkers…. And I would argue that at this point, we have enough data that we should be able to see the data presented” in stratified fashion (eg, assessing outcome in patients whose tumors are IC3/TC1), which could help parse out the importance of each TC and IC individually. “Hopefully, data like this will be forthcoming.”
JAVELIN Solid Tumor Trial
Finally, in the JAVELIN Solid Tumor trial, with the exception of somewhat higher rates of infusion-related reactions and chills, treatment-related adverse events with avelumab were generally similar to what has been seen with other PD-1 and PD-L1 inhibitors, according to Dr. Garon.
“The 22.4% response rate that was reported is certainly quite respectable,” he said. However, “although the follow-up data are fairly immature at this point, there is nothing in the efficacy to necessarily indicate either superiority or inferiority over other agents.” And results thus far do not suggest gains with respect to expanding the eligible population or improving biomarker selectivity.
“So is there a place for avelumab in this treatment paradigm? My sense would be, potentially. The way I look at it is if I were developing a new cola drink with Coke and Pepsi already on the market, one thing I might do is try to price my new cola drink less than the others,” Dr. Garon proposed. “That is not typically what we have done in oncology. But were that to be done, it would be possible that we would be able to increase the availability of this exciting class of medicines to people to whom it is not currently available.” ■
Disclosure: Edward B. Garon, MD, has received research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mirati, Genentech, Pfizer, and Novartis.
1. Hirsch F, Philip R, Averbuch SD, et al: The Blueprint Project. 2016 American Association for Cancer Research. Presented April 19, 2016.
In 2016, the KEYNOTE-024 trial set the bar for first-line immunotherapy in non–small cell lung cancer (NSCLC). Trial results showed that pembrolizumab (Keytruda), an antibody to programmed cell death protein 1 (PD-1), reduced the risk of disease progression or death by 50% and the risk of death by...