Frontline Lung Cancer Treatment: What's the Best Strategy?


Immunotherapy has drastically changed the treatment landscape for non-small cell lung cancer, but how can practitioners decide who should get frontline chemotherapy, too?

Recent years have brought landmark changes for the treatment of patients with non-small cell lung cancer (NSCLC), though there are still many unanswered questions that remain, especially when it comes to frontline treatment strategies, according to Lecia V. Sequist, MD, MPH.

“One of the big clinical questions when you have a patient who is a candidate for immunotherapy is whether or not to give it alone or with chemotherapy,” Sequist, the Landry Family Associate Professor of Medicine at Harvard Medical School and director of the Center for Innovation in Early Cancer Detection, said.

“For the first couple of years, that this was a frontline paradigm, we had a strict [PD-L1 expression] cutoff of 50%. If expression was greater than 50%, you would do monotherapy with immunotherapy; if the expression was less than that, chemotherapy plus immunotherapy was a better choice.”

However, Sequist mentioned that no large studies have really addressed the question of whether or not it is more beneficial to give patients with PD-L1 expression greater than 50% immunotherapy alone or a chemotherapy/immunotherapy combination.

Multiple frontline regimens combining the 2 types of agents are now FDA approved for nonsquamous NSCLC. For patients with squamous NSCLC, there is carboplatin/pemetrexed and pembrolizumab (Keytruda) or nab-paclitaxel (Abraxane) and pembrolizumab.

Impower150 Trials

More recently, a 4-drug regimen of carboplatin, paclitaxel, bevacizumab (Avastin), and atezolizumab (Tecentriq) was approved based on results from the Impower150 study, which compared chemotherapy to chemotherapy plus immunotherapy, and investigated the importance of VEGF inhibition.

Trial results suggested that there might be some benefit with VEGF and immunotherapy. Also, Impower was the only study that included a subset of patients with ALK and EGFR driver mutations, according to Sequist, who mentioned that there might be a benefit to chemotherapy plus immunotherapy for this small subset of patients.

“There are many interesting leads being generated from that study, but most patients in the community are currently getting one of the pembrolizumab regimens,” she said. “This is just because 4 drugs together are a lot to handle. Nonetheless, many further studies will come out of these Impower150 data.”


The FDA also approved single-agent pembrolizumab for patients with PD-L1 expression TPS ranging from 1% or higher based on results from the KEYNOTE-042 study, which examined pembrolizumab monotherapy versus a chemotherapy doublet. Patients with PD-L1 expression greater than 1% had improved outcomes on pembrolizumab. However, Sequist noted, “the positive signal was really driven by the patients [with PD-L1 expression] greater than 50%.”

“It is an option on my practice for patients who have a PD-L1 expression from 1% to 49%, if they are not great candidates for chemotherapy,” she said. “However, if they are candidates for chemotherapy/immunotherapy combinations, I would prefer that at this time. This is because the survival from KEYNOTE-042trial was driven by patients with higher PD-L1 levels.”

These results were somewhat similar to those in KEYNOTE-189 trial.

“That trial did show a bigger benefit the higher the PD-L1 level, but it was positive for the combination compared with chemotherapy alone in each arm. The overall positive wasn’t driven by the highest expressing group. However, there still did seem to be even more benefit to the higher expressing group,” Sequist said.

The Future of Lung Cancer Treatment

Looking ahead, Sequist said that it is important now more than ever for patients with NSCLC to get genetic testing. Practitioners should remember that chemotherapy/immunotherapy combinations are not standard of care for patients with driver mutations.

Sequist also mentioned that providers are still awaiting much more information about driver mutations such as EGFR and ALK aberrations, and whether or not they will benefit with the addition to immunotherapy.

“There are some studies looking at that questions, and it will be really important to see those results over the next couple of years,” Sequist said.

A version of this article originally appeared on OncLive as, “Unanswered Questions Remain in Frontline NSCLC.”

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