Halmos Highlights Advances in Squamous NSCLC

Balazs Halmos, MD, MS

The addition of pembrolizumab (Keytruda) to chemotherapy should define the frontline standard of care for patients with metastatic squamous non—small cell lung cancer (NSCLC), following the results of the phase III KEYNOTE-407 trial, said Balazs Halmos, MD.

Based on KEYNOTE-407, the FDA approved pembrolizumab for use in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for the treatment of patients with metastatic squamous NSCLC.

In the study, combining pembrolizumab with chemotherapy reduced the risk of death by 36% compared with chemotherapy alone. The median overall survival (OS) was 15.9 months (95% CI, 13.2 — not evaluable) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0017). The OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.

OncLive: How have recent clinical trials altered the management of squamous NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Halmos discussed the latest developments in the treatment paradigm for patients with squamous cell NSCLC.Halmos: At the meeting, I covered major advances in the management of advanced squamous cell lung cancer. This certainly has been a breakthrough year in progress for this particular subset of patients. Up until a few years ago, the standard of care had remained doublet chemotherapy for frontline management of squamous cell lung cancer. The major thing that we learned was what not to use, such as bevacizumab (Avastin) or pemetrexed.

Later on, we saw a series of positive randomized studies, such as LUX-Lung 8 and SQUIRE. These were important studies leading to FDA approvals of compounds, such as afatinib (Gilotrif), necitumumab (Portrazza), as well as ramucirumab (Cyramza). The benefit with each of those studies seemed to be small enough that enthusiasm has remained low in terms of market share for these compounds.

It's been welcoming news to see the very positive results of CheckMate-017. The trial showed a very substantial survival benefit, and not just a progression-free survival (PFS) benefit with second-line nivolumab (Opdivo) versus docetaxel. Of course, the hope was that immunotherapy could be moved into the frontline management, similar to what we've seen with nonsquamous NSCLC, especially with the KEYNOTE-189 trial.

For immunotherapy studies of both squamous and nonsquamous subsets, we've seen significant benefits in the squamous subset, such as KEYNOTE-024, which demonstrated benefit for frontline pembrolizumab versus doublet chemotherapy. Additionally, in CheckMate-227, the combination [of nivolumab and ipilimumab (Yervoy) demonstrated benefit in patients with high] tumor mutational burden. Of course, these are still preliminary data with CheckMate-227. There is no OS benefit and no FDA approval, but it’s certainly something to watch out for.

Within the last year, we've seen results from 2 pivotal studies looking at the combination of doublet chemotherapy and immunotherapy in the frontline setting. The first study, IMpower131, looked at the combination of taxane-based doublet chemotherapy plus atezolizumab (Tecentriq). Though the study had shown significant PFS benefits for the combination, it didn't translate into an OS benefit, disappointingly.

More encouragingly was the KEYNOTE-407 study, which looked at the combination of taxane-based chemotherapy with investigator’s choice of paclitaxel or nab-paclitaxel, with or without pembrolizumab. This was followed by maintenance pembrolizumab versus placebo. [The addition of pembrolizumab] showed not just a PFS benefit, but a very substantial OS benefit, as well, with an HR just around 0.6. This benefit was seen in every single PD-L1 subset.

Was the PFS benefit in IMpower131 not significant enough to be applied in practice?

What does the tolerability of this regimen look like?

Can second-line immunotherapy continue to be administered?

The benefit was independent of which particular chemotherapy doublet was used. This translated to an approximately 20% improvement in response rates. These pivotal data were presented at the 2018 ASCO Annual Meeting. The follow-up data were presented at the 2018 World Conference on Lung Cancer, which was then published in the New England Journal of Medicine. This was a practice-changing study. Single-agent pembrolizumab or the combination are both appropriate standards of care for patients with a tumor proportion score of more than 50%.The PFS benefit is important, but in reality, we need to see an OS benefit. If you look at the survival curves in the KEYNOTE-407, they separate extremely early within the first few cycles of combination therapy. This demonstrates how robust the data are and how important it is to translate into clinical practice right away.Fortunately, as in all studies with the combination of chemotherapy and immunotherapy, the toxicity tends to be manageable. Of course, there are added side effects. There are more immune-related adverse events as you might anticipate in the combination arm, but there didn't seem to be any safety signals from the study outside of what could be expected from doublet chemotherapy as well as single-agent immunotherapy.The second-line setting is certainly wide open in terms of our treatment strategies. As of today, for the management of metastatic nonsquamous NSCLC, metastatic squamous NSCLC, and also as of 2 weeks ago, extensive-stage small cell lung cancer, the standard of care should be a combination of chemotherapy and immunotherapy. That leaves no realistic options for the second-line setting outside of standard second-line chemotherapy for patients who had received the triplet combination.

Where would you like the research to focus in squamous NSCLC?

While second-line chemotherapy certainly has benefits, and while these benefits can be enhanced in the right patients with the addition of ramucirumab, we still have to work harder to achieve more than what second-line chemotherapy can do. That's an open area for research. We need to understand reasons for resistance to immunotherapy. We need to focus on individualized strategies in terms of chimer antigen receptor T cells and other types of therapies. There is a lot of research that we still need to do, though a lot has been accomplished.We have to move this into earlier-stage settings. Of course, we've seen the dramatic benefits with adjuvant durvalumab (Imfinzi) in stage III unresectable patients. In resectable patients, the adjuvant treatment is still chemotherapy. Though it provides benefit, the benefit is small and comes at a significant cost of toxicities.

[We have to investigate immunotherapy and biomarkers] in adjuvant studies to be able to predict patients who will benefit from these agents, [using] risk-stratifying biomarkers, have early use of circulating tumor DNA testing, and things of that nature.

Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36(suppl; abstr 105).