Treating Squamous Non-Small Cell Lung Cancer With EGFR TKI Therapy

H. Jack West, MD


July 15, 2016

In March 2015, nivolumab was approved by the US Food and Drug Administration (FDA)[1] for patients with chemotherapy-pretreated squamous non-small cell lung cancer (NSCLC), based on a highly significant improvement in median overall survival (OS) of 3 months, relegating docetaxel and any subsequent treatment to third line or later for the vast majority of these patients.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib had been approved more than a decade ago, based on the modest survival benefit seen for this agent compared with placebo in the BR.21 trial that enrolled a molecularly and clinically unselected population that included patients with squamous NSCLC.[2] Enthusiasm for erlotinib in this setting has been tepid, however, in part because of the infrequency of significant responses among patients with squamous NSCLC[3] and partly because of the emerging sentiment articulated by the American Society of Clinical Oncology (ASCO) that targeted therapies should be administered to molecularly targeted populations.[4]

Where should treatments providing very limited benefits fit in?

Just over a year after the approval of nivolumab in this setting, the FDA approved the second-generation EGFR TKI afatinib for chemotherapy-pretreated advanced NSCLC, based on a modestly superior efficacy compared with erlotinib in the LUX-Lung 8 trial.[5] But in a world of high response rates and durable responses for molecularly selected patients receiving some targeted therapies—and, in some cases, immune checkpoint inhibitors—where should treatments providing very limited benefits fit in?

LUX-Lung 8 was a global trial that enrolled 795 previously treated patients with advanced squamous NSCLC to receive either the FDA-approved standard salvage therapy of erlotinib or afatinib, with a primary endpoint of progression-free survival (PFS) and a key secondary endpoint of OS. While afatinib recipients demonstrated a statistically significant increase in both PFS and OS, with hazard ratios (HR) of 0.82 (P = .0427) and 0.81 (P = .0077), respectively, the absolute differences in median OS were very modest: Median PFS was only 2.4 versus. 1.9 months, while median OS was 7.9 versus 6.8 months, both in favor of afatinib. With an objective response rate (ORR) of 6% and 3%, respectively, for afatinib and erlotinib (P = .0551), are we just damning with faint praise? Can a superior arm be declared the "winner" with such underwhelming results?

Can a superior arm be declared the "winner" with such underwhelming results?

At the same time, tolerability of therapy is a critical consideration in any noncurative setting, and especially so when the anticipated benefits of therapy are comparably modest. Perhaps surprisingly for an agent often associated with particularly challenging toxicity, the data showed quite comparable tolerability, with 57% of patients on each arm reporting grade 3 or higher adverse events. Though afatinib was associated with higher reported grade > 3 diarrhea (10% vs 2%) and stomatitis (4% vs 0%), grade > 3 rash or acne was less commonly reported with afatinib than with erlotinib (6% vs 10%).

The recent FDA approval of afatinib now begs the question of whether patients with advanced squamous NSCLC should receive afatinib, erlotinib, or neither. Although the balance of a very limited anticipated survival benefit with potentially challenging side effects and considerable cost leave room for skeptical patients and/or treating oncologists to balk at any EGFR TKI, the efficacy benefits of afatinib are not in comparison with placebo but to an active therapy with an established survival benefit that also demonstrates a comparable toxicity profile and similar cost. This is in marked contrast to a situation in which a new agent of great cost must be added to an existing regimen. Taken together, these considerations lead me to conclude that if a patient with advanced NSCLC has progressed through chemotherapy and immunotherapy and still has the motivation and performance status to pursue additional therapy, afatinib should be the preferred EGFR TKI.

A separate question, however, is whether either afatinib or erlotinib provides sufficient benefit to recommend either. Notably, unlike a relatively modest survival benefit in an earlier line of therapy, the survival benefit conferred by third- or fourth-line EGFR TKI therapy is very unlikely to be diluted by subsequent effective treatment. Moreover, we have a limited arsenal of therapies in advanced NSCLC that confer a significant survival benefit.

Can we rationalize commonly recommending treatments based on speculation while discarding those with a proven benefit?

Meanwhile, the reality I see every day is that most oncologists, whether general oncologists practicing in community-based practices or subspecialists working in academic centers, do not limit the treatments they offer to patients with advanced lung or other cancers to only those that have a proven survival benefit. Can we rationalize commonly recommending treatments based on speculation while discarding those with a proven benefit? With afatinib's new indication, based on a survival benefit not just over placebo but over an FDA-approved alternative with established efficacy, along with comparable toxicity and cost/value, I feel that the weight of the evidence should lead us to recommend it to appropriate patients rather than minimizing the benefit that it confers.


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