Pembrolizumab plus Chemotherapy Doubled Response Rate Over Chemotherapy Alone in NSCLC

ESMO 2016

With the success of programmed death-1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors in non–small cell lung cancer (NSCLC), attention has focused on how best to combine these immunotherapies, and one question has been whether they can be safely and effectively combined with standard chemotherapy. Combining pembrolizumab with a standard chemotherapy doublet doubled response rates in advanced NSCLC compared with chemotherapy alone in a phase 2 study presented at the European Society for Medical Oncology 2016 Congress and published in Lancet Oncology to coincide with this presentation. The combination appears to be safe. Further confirmatory phase 3 data are needed to bring this combination into clinical practice.

Overall response rate with pembrolizumab plus pemetrexed/carboplatin was 55% versus 29% with the chemotherapy doublet alone (P = .0016). Although not the primary end point, the pembrolizumab/chemotherapy arm extended progression-free survival (PFS) compared with chemotherapy.

“To the best of our knowledge, these data constitute the first published report of a randomized controlled clinical trial in NSCLC to prospectively evaluate the benefit of combining a PD-1 inhibitor and chemotherapy in the first-line setting. These data suggest that the addition of pembrolizumab to platinum-doublet chemotherapy could help a greater number of patients experience durable response more rapidly compared with standard platinum-based chemotherapy alone and may be an effective option for patients with chemotherapy-naive, advanced nonsquamous NSCLC,” stated lead author Corey J. Langer, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

Dr Langer presented findings from cohort G (NSCLC patients) enrolled in the KEYNOTE-021 phase 2 prospective, randomized, open-label study. The study enrolled 123 patients with chemotherapy-naive stage IIIB or IV nonsquamous NSCLC without targetable EGFR or ALK mutations. Although patients were stratified for PD-L1 expression, PD-L1 expression was not required for enrollment in the trial.

Patients were randomized 1:1 to receive 4 cycles of pembrolizumab 200 mg plus carboplatin/pemetrexed every 3 weeks followed by pembrolizumab for 24 months and pemetrexed maintenance therapy versus 4 cycles of carboplatin/pemetrexed followed by pemetrexed maintenance therapy. Patients in the control arm (chemotherapy) were allowed to cross over to pembrolizumab monotherapy at disease progression, and 51% crossed over or received subsequent immunotherapy.

Median PFS was 13 months for the pembrolizumab/chemotherapy arm versus 8.9 months for chemotherapy alone. At data cutoff, the rate of PFS was 77% versus 63%, respectively.

“This makes KEYNOTE-021 one of the first randomized, controlled trials of first-line therapy for advanced NSCLC in which median PFS exceeded 1 year,” Dr Langer said.

Response rates were similar in patients with PD-L1 expression <1% and those with higher levels of PD-L1 expression. Using a cutoff score of PD-L1 expression of 50% or higher, a larger proportion of responders were observed, Dr Langer said. However, the small sample sizes of the individual PD-L1 subgroups in this study preclude determining the relationship between PD-L1 expression and responses to pembrolizumab plus chemotherapy.

There was no difference in overall survival between the treatment arms; 92% were alive at data cutoff.

The most common treatment-related adverse events of any grade were fatigue (59% in the investigational arm vs 15% in the control arm) and alopecia (14% vs 2%, respectively).

Rates of grade 3/4 toxicity (anemia, decreased neutrophil count, thrombocytopenia, and decreased lymphocyte count) were higher at 39% in the pembrolizumab/chemotherapy arm versus 26% for chemotherapy alone. The most common immune-mediated events of any grade in the pembrolizumab-containing arm were hypothyroidism (15%), hyperthyroidism (8%), and pneumonitis (5%).

Phase 3 studies in the KEYNOTE development program are evaluating pembrolizumab with or without chemotherapy in chemotherapy-naive patients with NSCLC.

Dr Langer noted that PD-L1 assessment should be part of the standard workup of patients prior to treatment with pembrolizumab.

Pembrolizumab is approved by the FDA for PD-L1–expressing NSCLC that has progressed on 1 or more prior therapies.

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