Frontline Therapy Options for EGFR-Mutated Lung Cancer

There are now several targeted therapy options for the treatment of advanced lung cancer that harbor an activating epidermal growth factor receptor (EGFR) mutation-the first driver mutation identified and the most common among patients with non-small cell lung cancer (NSCLC).

Speaking at the 11^th Annual New York Lung Cancer Symposium, held on November 12, 2016, in New York City, Howard (Jack) West, MD, medical director of the thoracic oncology program at the Swedish Cancer Institute in Seattle, laid out the available treatment options for patients with treatment-naïve, EGFR-positive NCSLC cancer. “There is a strong argument to be made for individual recommendations based on a patient preference and tolerability and [physician’s] judgment and experiences,” he said.

Initially, two Japan-based trials compared gefitinib (Iressa) to platinum-based chemotherapy, demonstrating that the EGFR-mutation targeted oral therapy resulted in better response rates and progression-free survival (PFS)compared to chemotherapy.^{1, 2} These trials were followed by additional trials with other EGFR mutation-targeted agents (erlotinib [Tarceva] and afatinib [Gilotrif])such as the First-Signal, OPTIMAL, and EURTAC which confirmed the PFS benefit of these oral agents, even though the studies did not show an overall survival benefit. Subsequently, results of the pooled LUX-Lung 3 and Lux-Lung 6  phase III trials of afatinib demonstrated a “clear survival benefit for patients with an exon 19 deletion, but not for patients with the L858R activating mutation,” said West. 

Trials comparing the EGFR-targeting tyrosine kinase inhibitors (TKIs) with chemotherapy were followed by head-to-head trials of EGFR oral agents including the LUX-Lung 7 trial first-line trial which showed that afatinib significantly improved outcomes for patients compared to gefitinib. Updated results from the trial at the 2016 European Society of Medical Oncology (ESMO) meeting showed that both agents extended survival by more than 2 years with afatinib extending survival by an additional 3.4 months, consistently across all common EGFR mutation types (LBA#43 ESMO 2016).

“Important factors to consider in choosing among these agents are the adverse events,” said West. In clinical trials, the most common drug related adverse events with afatinib are diarrhea, rash, stomatitis, and paronychia. “This corroborates our experience. Afatinib is a somewhat more challenging agent to deliver and dose reductions are commonly used,” West noted.

“We need to individualize treatment decisions for our patients based on our experience and recognize that while efficacy may be marginally greater with afatinib, tolerability issues may favor erlotinib or gefitinib, and in the US, we see that erlotinib is the most commonly prescribed followed by afatinib,” said West.

Frontline data with the third-generation EGFR TKI osimertinib (Tagrisso) is still immature, but is so far indicating, based on the AURA trial subgroup analysis, that the drug is effective (#LBA1, ESMO 2016). An ongoing phase III clinical trial, FLAURA, is currently investigating the efficacy of osimertinib in treatment-naïve EGFR-mutated NSCLC patients. “The drug is well-tolerated and is likely beneficial to all patients, not just those with the T790M resistance mutation. According to West, there is still disagreement of whether osimertinib, which is active against the T790M resistance mutation, should be an upfront option for these patients or whether it should be reserved for those patients who progress on a first- or second-generation EGFR TKI.

For patients with a rare EGFR mutation, there is still a dearth of data, yet West noted that by some analyses, response rates to EGFR TKIS for patients with rare mutations may be as high as 70%.

Lastly, West outlined the data from second-line NSCLC trials with anti-PD1 and anti-PD-L1 antibodies. Thus far, these later-line trials suggest that these immunotherapy antibodies are not the optimal option for EGFR mutation-positive patients as patients in this setting appear not to have robust responses to these agents.^{3, 4}

As combining the anti-PD-L1 antibody durvalumab with osimertinib has resulted in higher levels of pulmonary toxicities that caused the drug manufacturer to suspend their trials of this combination in lung cancer, “[this] should give us pause on being cavalier about doing ad hoc combinations without data to speak to. This is a setting where we don't have evidence that patients are benefiting from immunotherapy yet,” said West.

References:

Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010 Feb;11(2):121-8.

Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380-8.

Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39.

Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28.