The Anticipated Next Season of EGFR Inhibitors

Over the past decade, the story of EGFR inhibitors in lung cancer has unfolded much like a top cable TV drama with an iconic cast of characters (drugs, in this case) that we have gotten to know better and better with each passing season. We have come to recognize each “character’s” attributes and flaws and watched the players strategically position themselves among the others through episodes filled with unexpected plot twists and suspenseful cliff-hangers. And although the resulting advances have been significant and impactful, if given the chance to go back and shoot it all over again, I suspect we might edit some of the details. In particular, we might rewrite the script for the early pivotal trials of gefitinib and erlotinib, which were initiated prior to the discovery of EGFR mutations and hence were not designed with this target population in mind. The results of this key misstep in the U.S. included the market removal of gefitinib by the U.S. Food and Drug Administration in 2005 and the widespread use of erlotinib in EGFR wild-type patients for many years, although we now know this yields no benefit compared with chemotherapy in unselected patients [1–3]. In this issue of The Oncologist, Burotto and colleagues concisely recap the highlights of this narrative and offer new analyses that they performed to compare and contrast available EGFR inhibitors [4]. They dissected 31 large prospective phase II and III studies of gefitinib, erlotinib, and afatinib that included a total of >12,000 lung cancer patients. They modeled aggregate data comparisons of both the toxicity and the efficacy of the drugs, taking care to attempt to match study populations by also examining the performance of the control groups across randomized trials if possible. They concluded that gefitinib and erlotinib were overall extremely similar in both toxicity and efficacy. With the caveat of having much less data available currently, afatinib also seemed similarly efficacious, although it may be too early to accurately state whether there is a difference in the toxicity profile for afatinib. Other meta-analyses of EGFR tyrosine kinase inhibitors (TKIs) have come to similar conclusions, with some authors noting that rash and diarrhea with both erlotinib and afatinib are more common than with either gefitinib or the EGFR TKI used in China, icotinib [5, 6]. How are we to use this information in our daily practice? Despite the power of eloquent meta-analyses, we still lack gold standard trials doing straight head-to-head comparisons of these agents. The Lux-Lung 7 trial, which is expected to yield results within the next year, is a front-line direct comparison of gefitinib and afatinib in EGFR-mutant patients and will be helpful for our decision making regardless of the results observed, although its primary outcome is progression-free rather than overall survival. Until this study is completed, we remain with the status quo, namely, plentiful data suggesting that all of the drugs are roughly equivalent, and with our own personal experiences. My approach to patients who are newly diagnosed with EGFR mutation-positive disease is to assess their ability to withstand the predicted side effects and to examine the specific type of EGFR mutation found in their cancer. For patients with an exon 19 deletion mutation, data from two randomized trials with afatinib suggest an overall survival benefit for afatinib compared to chemotherapy among this particular mutation cohort, and thus I favor afatinib in del19 patients [7]. For all other mutation types, no clear data currently show that efficacy is different between erlotinib and afatinib, so my practice is to hold a discussion with the patient about the two options, and I frequently prescribe both drugs. I often recommend starting reduced-dose erlotinib for patients who are elderly, frail, or very wary of rash or diarrhea. How will this saga wrap up? Well, unlike a TV show, no series finale is scheduled. Thankfully for our patients, EGFR-directed therapy is here to stay, with new drugs targeting T790M-mediated resistance coming quickly and the field continuing to advance by leaps and bounds [8, 9]. With greater access to sophisticated tools for interrogating both the somatic and germline genome at our disposal, and with widespread acceptance of the scientific and clinical value of obtaining serial repeated biopsies from patients with oncogene-addicted tumors, we are now poised to answer more nuanced questions. I expect the next few years will bring increasing information about the evolution of tumor subclones through treatment courses and about how the different drugs in this class interact distinctly with the EGFR mutation subtypes and according to patient-specific factors. For example, although gefitinib was removed from the U.S. market in 2005, ∼200 EGFR-mutant patients in the U.S. today have remained on the drug for ≥10 years via a compassionate access program, and inquiry into these exceptional responders is in progress to understand how they have done so well for so long (P. Bunn, personal communication). It is an undoubtedly exciting era. I can’t wait to see what happens next!