Immunotherapy Shakes Up Stage IV Squamous NSCLC Treatment

Christine Bestvina, MD, discusses immunotherapy options in squamous non–small cell lung cancer, unanswered questions regarding patient selection, and directions for future research.

Christine Bestvina, MD

The emergence of immunotherapy in the treatment paradigm for stage IV squamous non—small cell lung cancer (NSCLC) has led to prolonged survival benefit in select patients, said Christine Bestvina, MD, and PD-L1 expression can be used to determine whether these agents should be given alone or in combination with chemotherapy. However, questions remain.

“For patients who have squamous cell carcinoma of the lung, the standard of care would be immunotherapy alone in those with high PD-L1 expression, or a combination of chemotherapy plus immunotherapy for those with PD-L1 expression between 0% and 49%,” explained Bestvina.

The effectiveness of chemoimmunotherapy was demonstrated in the phase III KEYNOTE-407 trial, in which the combination of pembrolizumab (Keytruda) plus carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) was compared with chemotherapy alone. Results showed a median overall survival (OS) was 15.9 months with chemoimmunotherapy compared with 11.3 months with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P <.001). This benefit was observed regardless of PD-L1 status.1

However, not all chemoimmunotherapy trials have shown the same impressive benefit. The final results of the phase III IMpower131 trial showed a significant OS benefit with atezolizumab (Tecentriq) in combination with chemotherapy in a subset of patients with treatment-naïve, stage IV squamous disease and high PD-L1 status versus chemotherapy alone (23.4 months vs 10.2 months; HR, 0.48; 95% CI, 0.29-0.81). However, a statistically significant OS benefit was not observed in the intent-to-treat population with the combination, leaving more questions to be answered with future research.2

“For instance, why are we seeing such different results between this trial and KEYNOTE-407? Is it a difference in the immunotherapy [agent] that we're using? Is it something else?” questioned Bestvina. “How that will all play out remains unclear, but what this tells us is that right now, pembrolizumab is the only immunotherapy given in combination with chemotherapy that's a [beneficial] option for patients with squamous cell disease.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Lung Cancer, Bestvina, a thoracic oncologist at the University of Chicago, discussed immunotherapy options in squamous NSCLC, unanswered questions regarding patient selection, and directions for future research.

OncLive: Could you discuss the pivotal KEYNOTE-407 trial combining immunotherapy with chemotherapy?

Bestvina: In KEYNOTE-407, patients were treated with a combination of carboplatin plus paclitaxel versus nab-paclitaxel with or without pembrolizumab. Essentially, patients with squamous cell carcinoma received a frontline regimen that they would [normally receive], with or without immunotherapy. What we saw, which was so exciting, was that patients experienced longer progression-free survival (PFS), and most importantly OS; this benefit was seen in all subgroups of PD-L1 expression, including patients with PD-L1 [expression of] 0%. Basically, we saw that this combination of chemotherapy plus immunotherapy was able to synergistically help patients live longer with a reasonable safety profile.

In light of these data, do you still believe that testing for PD-L1 expression is necessary in this patient population?

I have heard some argue that based off of these results, it's no longer necessary to perform PD-L1 testing. I would certainly not support that. Having that information available, particularly to determine if patients are PD-L1—high, is very important; these patients may also be eligible to receive pembrolizumab monotherapy, which has an improved toxicity profile and allows us to delay chemotherapy until later in their treatment when we may need it.

The IMpower131 trial, although similarly designed to KEYNOTE-407, was not as positive. Could you discuss the data that came out of that study?

IMpower131 was a trial similarly looking at a combination of chemotherapy plus immunotherapy, but in this case, atezolizumab (Tecentriq). However, here, we did not see the same improvement of OS for these patients. In particular, the patients who were moderate expressors [of PD-L1], or PD-L1 1% to 49%, even seemed to do worse with the addition of immunotherapy. As such, this trial raises as many questions as it does provide answers.

What other key trials are worth mentioning in this space?

An additional trial, CheckMate-227, examined the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) in patients with NSCLC; this group included both adenocarcinomas as well as squamous cell carcinomas. It was a positive trial, meaning that patients fared better and had improved OS with the combination immunotherapy over chemotherapy alone. It's just a little tough for us to interpret [the data from] this trial in the context of others, as it was in a head-to-head trial with chemotherapy plus immunotherapy.

Taking into consideration all of the data coming out of these pivotal trials, how are you taking this information and applying it to practice when making treatment decisions?

For patients who are high¬—PD-L1, PD-L1 50% or greater, my initial instinct is to go with pembrolizumab monotherapy. We don't have data comparing immunotherapy monotherapy in this group versus chemoimmunotherapy, but I know that these patients tolerate the single agent much better. However, in those who have lower expression, a PD-L1 of 0%-49%, I have a great deal of comfort in giving combination chemotherapy and immunotherapy, knowing that these patients are still going to derive benefit with the addition of immunotherapy.

Where will future research efforts be focused in this field?

Additional research is going to be focused in narrowing down what specific patients benefit from what therapies, particularly patients who are high PD-L1 expressors. Are there certain patients who would really benefit from the addition of chemotherapy? Can patients be treated with immunotherapy alone? Also, at the time of progression on immunotherapy, should the immunotherapy be continued, or should the immunotherapy be stopped and chemotherapy alone be started? [Those questions are] big areas of exploration.


  1. 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 15; abstr 105). doi: 10.1200/JCO.2018.36.15_suppl.105.
  2. R. Jotte, F. Cappuzzo, I. Vynnychenko, et al. IMPOWER131: Final OS results of carboplatin + nab-paclitaxel ± atezolizumab in advanced squamous NSCLC. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA14.02.