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Therapeutic Options Developing for Non-Driver NSCLC, But Challenges Remain

Jonathan Alicea
Published: Thursday, Jul 27, 2017

Corey Langer, MD
Corey Langer, MD
While challenges remain for patients with non-driver non-small lung cancer (NSCLC), there continues to be ongoing trials that are evaluating and testing various immunotherapy and chemotherapy combinations in the frontline setting, according to Corey Langer, MD.

In the ongoing phase III KEYNOTE-189 trial, the efficacy of the PD-1 inhibitor pembrolizumab (Keytruda) combined with platinum/pemetrexed chemotherapy versus chemotherapy alone is being studied in the frontline setting for patients with nonsquamous NSCLC (NCT02578680).

This is a follow-up study to cohort G of the KEYNOTE-021 trial, in which the pembrolizumab triplet elicited an objective response rate of 55% compared with 29% with the chemotherapy agents alone (= .0032). The FDA approved the regimen in May 2017 based on these findings.

Moreover, practicing clinicians have the standard therapeutic option of the angiogenesis inhibitor bevacizumab (Avastin) in this patient population. In 2006, the FDA granted approval for a labeling extension for bevacizumab administered in combination with carboplatin/paclitaxel as frontline treatment of patients with unresectable, locally advanced, recurrent, or metastatic, nonsquamous disease.

In an interview with OncLive, Langer, who is director of thoracic oncology at the University of Pennsylvania, provided further detail of the goals and implications of this clinical trial. Moreover, he discussed the current arena in NSCLC treatment and the obstacles that remain in effectively treating patients with non-driver mutations.

OncLive: What is the prevalence of patients with non-driver NSCLC?

Langer: The incidence of patients with non-driver mutations in NSCLC, specifically adenocarcinoma, is close to 70%. In squamous cell carcinoma, it’s 95% or higher. The vast majority of individuals we treat with advanced NSCLC, either metastatic at diagnosis or recurrent, do not have driver mutations or translocations. For those individuals, specifically with nonsquamous disease, the standard options generally include pemetrexed with carboplatin or a taxane with carboplatin. Now, [we have] the option of pembrolizumab combined with a platinum-based combination and, of course, bevacizumab combined with a platinum-based combination. 

What are the current treatment strategies for nonsquamous NSCLC? Also, what are the considering factors for bevacizumab?

The standard approach for nonsquamous NSCLC, at least in 2017, involves a platinum combination in individuals who do not have an oncogenic driver. Usually that platinum combination in the United States is carboplatin and pemetrexed. In individuals who are not candidates for pemetrexed, it is carboplatin plus a taxane either every 3 weeks or weekly. 

Up until recently, in individuals who not have a history of hemoptysis or untreated brain metastases, I would generally add bevacizumab onto the platinum combination of either carboplatin and paclitaxel or carboplatin and pemetrexed. With the recent approval of pembrolizumab in this setting—specifically pembrolizumab in combination with pemetrexed and carboplatin—our therapeutic options have expanded. However, they have also gotten a bit more confusing. 

Pembrolizumab was approved based on a randomized phase II trial that compared the combination of pembrolizumab with chemotherapy to just chemotherapy alone. Bevacizumab was not included in the control arm. We have no direct head-to-head comparisons of pemetrexed/carboplatin plus bevacizumab versus pemetrexed-carboplatin plus pembrolizumab.

That is really the root of one of my dilemmas.  There are some patients who have an autoimmune disease or other contraindications to pembrolizumab where I will certainly and preferentially use bevacizumab.

The other interesting population are those with oncogenic drivers—be it an EGFR mutation or ALK translocation. Here, immunotherapy does not work that well. If you look at the randomized phase III trials in the second-line setting that compared single agents with docetaxel, the 1 group that consistently failed to derive any benefit were those with oncogenic drivers. The response rates were quite low: they were 3% or 4%. Survival advantages were not seen in that group. In fact, in some of these studies, there was a survival advantage for chemotherapy. Inevitably, those individuals will develop disease progression on the original tyrosine kinase inhibitor (TKI).

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