Upfront Immunotherapy Pivotal in Squamous NSCLC Paradigm

Liza C. Villaruz, MD

Pivotal clinical trials, such as KEYNOTE-024 and KEYNOTE-407, have shown a crucial role for upfront immunotherapy in patients with advanced squamous non—small cell lung cancer (NSCLC), whether alone or in combination, said Liza C. Villaruz, MD.

"Early immunotherapy is absolutely critical in these patients,” said Villaruz, an assistant professor of medicine at the University of Pittsburg Medical Center Hillman Cancer Center. "Upfront immunotherapy has a positive impact on subsequent lines of therapy. The survival benefit [with immunotherapy] is preserved in spite of a high crossover rate in the chemotherapy-alone control arms." 

In a subset analysis of the KEYNOTE-024 trial, for example, results showed that patients with squamous NSCLC who were treated upfront with single-agent pembrolizumab had an improvement in overall survival (OS) versus standard chemotherapy (HR, 0.78; 95% CI, 0.63-0.95).¹

Similarly, the KEYNOTE-407 trial reported a significant OS benefit with pembrolizumab in combination with platinum-based chemotherapy for patients with squamous NSCLC. At a follow-up of 7.8 months, the median OS was 15.9 with the pembrolizumab plus chemotherapy compared with 11.3 months with placebo plus chemotherapy (HR, 0.64; 95% CI, 0.49-0.85;&#8239; P &#8239;<.001).^2&#8239;

Based on these data, in October 2018, the FDA approved frontline pembrolizumab for use in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for the treatment of patients with metastatic squamous NSCLC.

In an interview during the 2019 OncLive State of the Science Summit on Non—Small Cell Lung Cancer, Villaruz discussed the data with immunotherapy in squamous NSCLC.

OncLive: What data have demonstrated the benefit of immunotherapy in squamous NSCLC?

Villaruz: In KEYNOTE-024, the progression-free survival (PFS) for patients was equivalent to the OS associated with platinum-doublet therapies in patients with squamous cell carcinoma [of the lung].&#8239;

This trial was specifically for patients with high PD-L1—expressing tumors, and the results established PD-L1 as a biomarker for single-agent immunotherapy in patients with advanced NSCLC.&#8239;

KEYNOTE-407 showed a significant survival benefit with the addition of pembrolizumab to chemotherapy in patients with squamous NSCLC and that benefit was preserved, regardless of PD-L1 expression.&#8239;

How are you determining which patients receive chemoimmunotherapy versus single-agent immunotherapy?

PD-L1 is the most important determinant. If a patient has a high level of PD-L1 expression, they could be candidates&#8239;for immunotherapy by itself.

Typically, I factor in the patient's age, performance status, tumor burden, and essentially, how quickly I need a response. If a patient has high tumor burden and is symptomatic on the basis of tumor burden, it might be more beneficial to add chemotherapy to immunotherapy because it can induce a true tumor response quickly. Single-agent immunotherapy always has the potential of early progression, in which a patient may deteriorate&#8239;very quickly.&#8239;

Could you discuss the IMpower131 trial and what effect the data have had?

The IMpower131 clinical trial looked at platinum-based chemotherapy with either paclitaxel or nab-paclitaxel (Abraxane) with or without the PD-L1 inhibitor atezolizumab (Tecentriq). It was similar to the KEYNOTE-407 clinical trial because there was a clear PFS benefit when you add atezolizumab to platinum-based chemotherapy [in squamous NSCLC].

Unfortunately, there was not a statistically significant survival benefit in adding atezolizumab to platinum-based chemotherapy, which is a bit discouraging.&#8239;It is notable that patients with high levels of PD-L1 expression, either on tumor cells or immune cells, did have a survival benefit. Therefore, it is may remain an option for those patients, though it is yet to be determined how we incorporate that into clinical practice.&#8239;

What are the next steps for studying immunotherapy in this patient population?

[We should] look at additional biomarkers that may select which patients can be spared chemotherapy. Tumor mutational burden (TMB) is an interesting biomarker in patients with advanced nonsquamous and squamous NSCLC, especially as it pertains to immunotherapy and immunotherapy combinations. PD-1/PD-L1 plus a CTLA-4 inhibitor may identify a subset of patients with have the greatest levels of benefit if they have high TMB.

What are some challenges with squamous histology? What research efforts should be done in this area?

The greatest challenges with squamous histology as opposed to nonsquamous disease is that we don't have targetable oncogenic drivers. In adenocarcinoma, there is a good proportion of patients where you can find a genomic driver that can be targeted with a drug. Unfortunately, we don't have that in squamous [NSCLC].&#8239;

A number of genomic subsets have been looked at, such as patients with FGFR alterations. Unfortunately, nothing practice changing has panned out. The good news is that many of these cancers are smoking-related and tend to do very well with immunotherapy.

With that said, we could definitely do better. Identifying genomic subsets that could be treated with targeted therapies would be a great advance.&#8239;

What are your thoughts on combining immunotherapy with targeted agents?

That's a great question. A number of studies have looked at combining immunotherapy with targeted agents, specifically in patients with genomic alterations of EGFR and ALK. Unfortunately, many of those trials seemed to identify a toxicity signal like pneumonitis when you add the targeted agents to immunotherapy. This, unfortunately, precluded further study of TKIs with immunotherapy.&#8239;

What biomarkers are emerging in nonsquamous NSCLC?

Emerging biomarkers are intriguing because if you look at a pie chart of genomic drivers in nonsquamous NSCLC, each genomic driver only comprises 1% to 2% of patients. When you add up mutations in RET, MET, NTRK, HER2, and BRAF for example, it comprises up to 15% of patients with nonsquamous NSCLC.

It is important to identify these patients because targeted therapies for this population are better than chemotherapy. These patients could be spared the toxicity of chemotherapy with significant durable response rates.

What are your recommendations for testing for these alterations?

I am a big advocate of comprehensive genomic profiling. Even though many of these emerging oncogenic drivers are considered rare, when you identify a patient and are able to give them effective therapy, it can be incredibly impactful in their quality of life and their survival. It's better than chemotherapy in those settings.&#8239;

References

1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. &#8239;N Eng J Med. 2016;375:1823-1833.doi: 10.1056/NEJMoa1606774.
2. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small cell lung cancer. N Eng J Med. 2018;379:2040-2051. doi: 10.1056/NEJMoa1810865.