In recent years immunotherapy with PD-1 inhibitors has become the standard of care for first-line treatment of patients with nonsquamous non-small cell lung cancer (nonsq NSCLC) in the absence of targetable driver mutations. For patients with PD-L1 expression >50%, pembrolizumab monotherapy is an approved treatment option for both nonsq and squamous (sq) NSCLC. Based on survival improvement in KEYNOTE 21 cohort G and the confirmatory KEYNOTE 189 trial, pembrolizumab plus carboplatin/pemetrexed chemotherapy recently became the new standard in first-line treatment for nonsq NSCLC, regardless of PD-L1 expression status. In contrast, treatment options for sq NSCLC with PD-L1 expression ≤50% remain limited to chemotherapy doublets (± necitumumab).
At the 2018 American Society of Clinical Oncology (ASCO) annual meeting, Luis Paz-Ares, MD, PhD (Hospital Universitario 12 de Octubre, Madrid, Spain), presented practice-changing results from the phase III KEYNOTE-407 trial, which evaluated the addition of pembrolizumab to standard platinum-doublet chemotherapy in 559 newly diagnosed patients with metastatic sq NSCLC. Patients in the treatment group received pembrolizumab (200 mg every 3 weeks) plus standard carboplatin and paclitaxel or nab-paclitaxel for four cycles, followed by pembrolizumab maintenance for up to 31 cycles. The control group received placebo plus carboplatin/paclitaxel or nab-paclitaxel followed by placebo, with the option for crossover to pembrolizumab following progressive disease.
At a median follow-up of 7.8 months, the addition of pembrolizumab to chemotherapy significantly improved overall survival (OS), from 11.3 months with chemotherapy alone to 15.9 months with pembrolizumab plus chemotherapy (HR 0.64, P = .0008). The OS benefit of pembrolizumab was seen across all prespecified patient subgroups, including patients with low or no PD-L1 expression. The median progression-free survival (PFS) was 6.4 months for patients receiving pembrolizumab plus chemotherapy, compared to 4.8 months for chemotherapy alone (HR 0.56, P<.0001).
There were similar rates of adverse events (AEs) between the two treatment groups, though patients receiving pembrolizumab had higher rates of immune-mediated AEs, including hypothyroidism (7.9% vs 1.8%), hyperthyroidism (7.2% vs 0.7%), and pneumonitis (6.5% vs 2.1%). Dr Paz-Ares concluded that pembrolizumab in combination with carboplatin and paclitaxel or nab-paclitaxel should be considered the new standard of care for previously untreated patients with metastatic sq NSCLC, irrespective of PD-L1 expression.
In another first-line, phase III, tri-arm trial in sq NSCLC (IMpower131) that involved 1021 patients, atezolizumab plus carboplatin/paclitaxel was compared to atezolizumab plus carboplatin/nab-paclitaxel and to the carboplatin/nab-paclitaxel doublet. Patients in both atezolizumab containing arms also received atezolizumab maintenance after 4-6 cycles of immunotherapy and chemotherapy combination. This trial, presented by Robert Jotte, MD, PhD (Rocky Mountain Cancer Centers, Denver, Colorado, United States), demonstrated that the addition of atezolizumab to first-line carboplatin/nab-paclitaxel significantly improves PFS (6.3 months vs 5.6 months; HR 0.71, P = .0001) in all patients, regardless of PD-L1 expression, though PFS benefit was enriched in subgroups with higher PD-L1 expression. However, there was no OS benefit at the interim analysis.
Both these large, randomized, phase III trials demonstrate that the addition of PD-1 and PD-L1 inhibitors to first-line chemotherapy improves outcomes for patients with sq NSCLC. In his discussion, Tom Stinchcombe, MD (Duke University, Durham, North Carolina, United States), indicated that based on these results, pembrolizumab will likely become a standard of care for sq NSCLC, but that an OS benefit will be necessary for atezolizumab plus chemotherapy to be adopted as a new treatment option in this setting.
For more information on these data and other immunotherapy first-line trials presented at 2018 ASCO annual meeting, their critical analysis, and practice application, see prIME Oncology’s Clinical Update from Chicago.