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Despite Treatment Advances, Chemotherapy Retains Role in Metastatic NSCLC

Caroline Seymour
Published: Friday, Aug 24, 2018

Ryan D. Gentzler, MD

Ryan D. Gentzler, MD

Although immunotherapy and targeted agents are revolutionizing the treatment paradigm in metastatic non–small cell lung cancer (NSCLC), chemotherapy retains a vital role for the majority of patients, according to Ryan D. Gentzler, MD.

“The data that we have now suggest that chemotherapy plus immunotherapy is the only combination strategy we have that has shown an overall survival (OS) improvement. The chemotherapy backbone is still an important one for patients,” said Gentzler.

As reported in the New England Journal of Medicine and presented at the 2018 AACR Annual Meeting, the first-line combination of pembrolizumab (Keytruda) with standard chemotherapy reduced the risk of death by more than 50% in patients with nonsquamous NSCLC without EGFR or ALK mutations in the phase III KEYNOTE-189 trial.

In the study, patients were randomized to frontline pembrolizumab or placebo in combination with pemetrexed and either cisplatin or carboplatin. The estimated 12-month OS rate at a median follow-up of 10.5 months was 69.2% (95% CI, 64.1%-73.8%) in the pembrolizumab arm versus 49.4% (95% CI, 42.1%-56.2%) in the control arm (HR, 0.49; 95% CI, 0.38-0.64; P <.001). Notably, an OS benefit was seen regardless of PD-L1 status. The median PFS was 8.8 months (95% CI, 7.6-9.2) versus 4.9 months (95% CI, 4.7-5.5) in the pembrolizumab and placebo arms, respectively (HR, 0.52; 95% CI, 0.43-0.64; P <.001).1,2

In August 2018, the FDA granted a full approval to the combination based on these phase III data. However, Gentzler explained that there are patients with NSCLC who may benefit from combination immunotherapy, such as nivolumab (Opdivo) and ipilimumab (Yervoy) as seen in the CheckMate-227 trial. Until physicians see greater standardization of biomarkers such as tumor mutational burden (TMB), the decision of which combination to use should be individualized to each patient, he added.

In an interview during the 2018 OncLive® State of the Science Summit on Advanced Non–Small Cell Lung Cancer, Gentzler, assistant professor, Division of Hematology/Oncology, University of Virginia Health System, highlighted how chemotherapy remains a critical component of the metastatic NSCLC treatment paradigm.

OncLive: Does chemotherapy have a role in the frontline treatment of metastatic NSCLC?

Gentzler: This has been an evolving field, particularly in the last several years—maybe even just the last 6 to 12 months. The theme of my talk was what role chemotherapy has in our treatment of this disease. There has been a lot of progress in the last decade or so of moving away from chemotherapy. We've now identified multiple oncogenic driver mutations that exist in lung adenocarcinoma [that we’re] able to successfully pair a targeted therapy to. We have been able to delay the need for chemotherapy in a large portion of patients.

More recently, we have identified that immunotherapy can be quite effective in the rest of the population. This includes those who were smokers and those who don't have these oncogenic driver mutations. Our hope has always been that we can get away from cytotoxic chemotherapy and the side effects that come along with those treatments and replace it with a single-agent tyrosine kinase inhibitor or an immunotherapy drug.

What we found in the data that have been released over the last year or so is that chemotherapy still seems to have an important role. When we add chemotherapy to an immunotherapy regimen it seems as though there may be a better chance of response or a longer duration of response. Several studies have looked at chemotherapy as a backbone with immunotherapy. Now, trials are showing OS improvement by adding PD-1/PD-L1 drugs to standard chemotherapy.

What chemoimmunotherapy combinations are we looking at?

There are several immunotherapy/chemotherapy combinations that have been looked at. The KEYNOTE-189 trial looked at pembrolizumab plus chemotherapy. There was a similar trial that was for patients with squamous cell lung cancer that looked at platinum-doublet chemotherapy plus pembrolizumab; that was the KEYNOTE-407 trial. That study also showed a survival improvement in that group. There has been a combination of chemotherapy plus atezolizumab (Tecentriq) plus bevacizumab (Avastin) that has also resulted in an OS improvement compared with chemotherapy alone.

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Online CME Activities
TitleExpiration DateCME Credits
Online Medical Crossfire®: 5th Annual Miami Lung Cancer ConferenceMay 30, 20196.5
Community Practice Connections™: Working Group for Changing Standards in EGFR-Mutated Lung Cancers: Real-World Applications of the Evidence for NursesJun 29, 20191.5
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