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IO for Squamous NSCLC
Using Immunotherapy to Treat Advanced Squamous NSCLC: Where Are We Now?

Released: February 24, 2020

Expiration: February 22, 2021

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When we consider the treatment options for patients with advanced squamous non‑small-cell lung cancer (NSCLC), we need to start with a benchmark of median OS of approximately 8 months with first-line platinum-based chemotherapy, the standard of care for well over a decade. The presentation of the phase III KEYNOTE-024 trial data at ESMO 2016 introduced monotherapy with pembrolizumab, an immune checkpoint inhibitor (ICI), as a new treatment option for patients with advanced NSCLC including those with squamous histology. In this commentary, I share my thoughts on using ICI as monotherapy or combination therapy for treating our patients with advanced squamous NSCLC today.

ICI Monotherapy
KEYNOTE-024
The phase III KEYNOTE-024 trial compared single-agent pembrolizumab with first-line chemotherapy in 305 patients with advanced NSCLC, either nonsquamous or squamous histology, no actionable EGFR mutation or ALK translocation, and PD-L1 expression ≥ 50%. Patients were randomized 1:1 to an histology‑appropriate platinum doublet chemotherapy regimen for 4‑6 cycles or pembrolizumab every 3 weeks and patients in the chemotherapy arm could cross over to receive pembrolizumab after disease progression.

Pembrolizumab led to profound improvements in the primary endpoint of PFS vs chemotherapy (median: 10.3 vs 6.0 months, respectively; HR: 0.50; P < .001). OS was significantly improved as well (HR: 0.63; P = .002) with updated results presented at WCLC 2019 showing a median OS of 26.3 months in patients receiving pembrolizumab vs 14.2 months in the chemotherapy arm. The survival benefits with pembrolizumab were observed in patients with either nonsquamous or squamous histology. These remarkable findings quickly changed the standard of care in advanced NSCLC and resulted in the FDA approving pembrolizumab monotherapy as frontline treatment for patients with advanced NSCLC and ≥ 50% tumor PD-L1 expression. Based on this evidence, pembrolizumab has been a very appropriate treatment option for that subset of patients regardless of histology since its approval.

KEYNOTE-042
The subsequent phase III KEYNOTE-042 trial with a similar design to KEYNOTE-024 enrolled 1274 patients with advanced NSCLC and no previous systemic treatment or actionable EGFR mutation or ALK translocation. Patients were randomized to histology‑appropriate chemotherapy for up to 6 cycles or pembrolizumab monotherapy every 3 weeks for up to 2 years. Unlike KEYNOTE-024 that limited enrollment to patients with ≥ 50% PD-L1 expression, KEYNOTE-042 enrolled patients with ≥ 1% PD-L1 expression, capturing more than two thirds of the patients with advanced NSCLC.

The results from KEYNOTE-042 confirmed that pembrolizumab is superior to chemotherapy in patients with ≥ 50% PD-L1 expression with an HR for OS of 0.69 (P = .0003). However, the results from an exploratory analysis in patients with tumor PD-L1 expression between 1% and 49% demonstrated no significant OS improvement with pembrolizumab. Based on these results, I would say that pembrolizumab is not a compelling treatment option for patients with PD-L1 expression in the 1% to 49% range. Another reason not to favor pembrolizumab monotherapy in patients with PD-L1 expression < 50% is that a better treatment option, the combination of pembrolizumab and chemotherapy, emerged at the time that the KEYNOTE-042 results became available.

ICI/Chemotherapy Combination
KEYNOTE-407
The phase III KEYNOTE-407 study randomized 559 patients with untreated advanced squamous NSCLC to either chemotherapy (carboplatin plus paclitaxel or nab‑paclitaxel) or pembrolizumab/chemotherapy combination. Patients were limited to 4 cycles of chemotherapy, but those on the combination arm received ongoing pembrolizumab maintenance therapy every 3 weeks up to 31 cycles. Patients on the chemotherapy arm could cross over to receive pembrolizumab after progression.

The trial demonstrated a significant improvement in PFS (HR: 0.56; P < .001) and OS (HR: 0.64; P < .001) with the addition of pembrolizumab to chemotherapy. The OS benefits were seen across all patients regardless of whether they received paclitaxel or nab-paclitaxel. In particular, a comparable benefit in OS was seen across the spectrum of tumor PD-L1 expression, from < 1% to ≥ 50%. Based on the KEYNOTE-407 results, the combination of chemotherapy and pembrolizumab was approved by the FDA and has become a very compelling standard of care for patients with advanced squamous NSCLC. Those patients who have high PD-L1 expression (≥ 50%) are also candidates for pembrolizumab monotherapy based on the KEYNOTE-024 data.

IMpower131
The phase III IMpower131 study examined carboplatin plus nab-paclitaxel with or without atezolizumab in 1021 patients with previously untreated advanced squamous NSCLC. This study showed a significant improvement in PFS with the addition of atezolizumab to chemotherapy (median: 6.3 vs 5.6 months, respectively; HR: 0.71; P = .0001), but it failed to demonstrate any improvement in OS with early follow-up (median: 14.0 vs 13.9 months, respectively; HR:0.96; P = .6931). While we are waiting for the long‑term follow-up OS data, I think that it is quite unlikely that this trial will ultimately demonstrate an OS benefit. Therefore, the combination of chemotherapy and pembrolizumab from KEYNOTE-407 is clearly a better treatment option for patients with advanced squamous NSCLC compared with atezolizumab plus chemotherapy that is not yet approved by the FDA.

ICI/ICI Combination
Besides ICI/chemotherapy combinations, another emerging immunotherapy combination regimen for NSCLC is nivolumab plus low-dose ipilimumab. The phase III CheckMate-227 trial enrolled 1739 patients with previously untreated advanced NSCLC and no known sensitizing EGFR/ALK alterations. Patients with either nonsquamous or squamous histology were allowed on the trial. This large and complex study was analyzed in multiple different ways over the last several years, with recent results showing a significant OS benefit with nivolumab plus ipilimumab compared with chemotherapy in patients with ≥ 1% PD-L1 expression (median: 17.1 vs 14.9 months, respectively; HR: 0.79; P = .007). Notably, a significant OS benefit with nivolumab plus ipilimumab vs chemotherapy was also shown in patients with < 1% PD-L1 expression in an exploratory subset analysis.

The FDA is currently evaluating the combination of nivolumab plus ipilimumab as first-line therapy for advanced NSCLC, and I anticipate that it will become an approved treatment option for patients with either nonsquamous or squamous histology. We need to consider which patients should receive this dual immunotherapy regimen over other options in advanced squamous NSCLC. Pembrolizumab monotherapy is an established standard of care in patients with high PD-L1 expression and the combination of chemotherapy and pembrolizumab has also emerged as a valuable treatment choice for all patients with advanced squamous NSCLC, particularly those with low or no PD-L1 expression. Nivolumab plus ipilimumab is certainly an appealing option for those patients who refuse chemotherapy or want to defer it. However, it is worth noting that nivolumab plus ipilimumab is not less toxic than a chemotherapy‑based approach, although it has a different safety profile from chemotherapy. Overall, nivolumab plus ipilimumab should be considered a new treatment option for many patients with advanced squamous NSCLC and may be an optimal one for selected patients, alongside pembrolizumab monotherapy and pembrolizumab combination regimens that are already FDA-approved.

In the future, we may have a better idea about which patients require chemotherapy and which do not, and which patients are likely to do better with ICI monotherapy vs an ICI/chemotherapy combination or ICI/ICI combination. For now, we have several treatments that have demonstrated significant OS improvements over chemotherapy for advanced squamous NSCLC, which is great news for our patients who previously lacked more effective therapeutic options.

Your Thoughts?
How are you using ICI monotherapy and combination regimens for your patients with advanced squamous NSCLC and what challenges have you had? I encourage you to answer the polling question and post your questions and thoughts in the discussion box below.