FIRST LINE IMMUNOTHERAPY NOT YET READY FOR NSCLC

Immune checkpoint inhibitors have dramatically changed the treatment landscape of advanced non-small cell lung cancer (NSCLC), says Justin F. Gainor, MD, from Massachusetts General Hospital Cancer Center in Boston, in an editorial published online July 5 in the Journal of Clinical Oncology.

Both nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) have improved overall survival compared with docetaxel in the second-line setting of advanced disease. This new standard of care has been much publicized and applauded, as reported by Medscape Medical News.

Dr Gainor observes that the success of the drugs, as well as new favorable information about tolerability, have prompted the question: Are these drugs ready for a role in first-line treatment?

"Outside of a clinical trial, the simple answer is no," he answers.

Dr Gainor explains that more than 10 randomized clinical trials are underway that "will be crucial" in determining the role of various programmed cell death protein (PD)-1 inhibitors in the frontline setting.

But, currently, the data do not exist to support initial use of either drug.

There are, however, two new sets of results from a nonrandomized trial of nivolumab in patients with treatment-naive NSCLC.

These early-phase studies, which prompted Dr Gainor's editorial, are from separate cohorts of the multiarm, phase 1B CheckMate 012 trial. Each patient cohort is exposed to a different approach to PD-1 inhibition as a first-line therapy.

The first study looked at first-line nivolumab monotherapy in patients with advanced NSCLC; the results were published online June 27 in the Journal of Clinical Oncology.

The researchers, led by Scott Gettinger, MD, from Yale University Cancer Center in New Haven, Connecticut, report a confirmed objective response rate (ORR) of 23% (12 of 52 patients), including 4 ongoing complete responses.

Median progression-free survival (PFS) with nivolumab was 3.6 months, but the median duration of response was not reached. Median overall survival (OS) was 19.4 months, which the editorialist Dr Gainor calls "noteworthy."

But Dr Gainor is not thoroughly impressed.

He observes that nivolumab's first-line ORR is similar to that seen in clinical trials of second-line nivolumab. More important, he also observes that the first-line response rate is not better than the current first-line standard of care, platinum-based chemotherapy (ORR, 25% to 30%). Nivolumab will somehow have to trump the current standard chemotherapy in order to be approved in this setting, Dr Gainor suggests.

The second study, also published online June 27, in the same journal, looks at first-line nivolumab in combination with three different platinum-based chemotherapy doublets in 56 patients with advanced NSCLC.

This study represents a second major strategy for nivolumab in the first-line setting: namely, in combination with platinum-based chemotherapy

These researchers, led by Naiyer A. Rizvi, MD, from Columbia University Medical Center in New York, New York, report confirmed response rates of 33% to 47% of patients across all chemotherapy groups.

But Dr Gainor again highlights the fact that the results are not exceptional.

"Notably, these response rates [in the first-line setting] were not substantially different from those expected with platinum-based doublet chemotherapy alone," he writes, adding that 2-year OS rates "offered a hint of additional activity, particularly in the nivolumab (5 mg/kg) plus carboplatin-paclitaxel arm."

But two other small studies previously have explored separate PD-1/PD-L1 inhibitors (pembrolizumab and atezolizumab) in combination with chemotherapy in treatment-naive NSCLC and have produced more encouraging preliminary results (ORRs of 58% to 67%).

Finally, editorialist Dr Gainor returns to discussing the phase 3 trials currently investigating use of PD-1/PD-L1 inhibitors in the first-line treatment of advanced NSCLC.

Some challenges herein are unique to these drugs, he says.

Most of these phase 3 trials rely on PFS as a primary endpoint because overall survival outcomes will be muted by crossover. But these PFS results may not be what oncologists are used to seeing, Dr Gainor also suggests.

"The shape of the PFS Kaplan-Meier curves may be atypical, and medians may fail to adequately capture the degree of benefit with immune checkpoint inhibitors," he writes.

In an email to Medscape Medical News, Dr Gainor explained the issue with PFS results: "Unlike targeted therapies (where the vast majority of patients respond, but resistance develops), only a subset of patients respond to immunotherapy, but those responses can be durable. This places an emphasis on the tail of the curve."

Identifying the subset of patients who optimally respond to PD-1 pathway blockade is needed. And for that, better predictive biomarkers would be helpful, Dr Gainor said.

Currently, PD-L1 expression is the biomarker of choice. Earlier research has shown that patients who test positive for the PD-L1 biomarker are more responsive to checkpoint inhibition.

But PD-L1 is also "imperfect," he said.

"The problem is that not everyone who is PD-L1 positive will respond, while PD-L1–negative patients can respond. This is very different than other biomarkers in lung cancer. For example, EGFR mutations are highly predictive of response (and patients without EGFR mutations generally don't respond)," Dr Gainor said.