Long-Term Data Back Anti-PD-1 in Advanced Non-Squamous NSCLC

Long-term data from an early first-line trial of pembrolizumab (Keytruda) plus chemotherapy showed that more than half of patients with advanced non-squamous non-small cell lung cancer (NSCLC) remained alive at 3 years.

In cohort G of KEYNOTE-021, the 3-year overall survival (OS) rates were 53% in the group receiving pembrolizumab plus carboplatin and pemetrexed (Alimta), as compared to 30% with chemotherapy alone. Median OS was 34.5 months versus 21.1 months, respectively (HR 0.71, 95% CI 0.45-1.12), reported Mark Awad, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“With more than 4 years of follow-up, pembrolizumab plus carboplatin and pemetrexed continued to provide durable responses and long-term overall survival benefit compared to chemotherapy alone,” Awad said during his poster presentation at the virtual North America Conference on Lung Cancer. “Pembrolizumab plus chemotherapy reduced the risk of death by 30% compared to chemotherapy alone, despite an effective crossover rate of 70% to subsequent PD-1 or PD-L1 therapy.”

Previously reported in the study’s primary analysis, median progression-free survival (PFS) improved from 9.9 months with chemotherapy alone to 24.5 months with the addition of pembrolizumab. PFS rates at 36-month were 37% in the pembrolizumab arm versus 16% in the chemotherapy-alone arm, according to the new findings, which were published simultaneously in the Journal of Thoracic Oncology.

Cohort G of KEYNOTE-021 was a phase II study that randomized 123 patients with previously untreated stage IIIB/IV non-squamous NSCLC without sensitizing EGFR mutations or ALK alterations to either pemetrexed and carboplatin alone or with pembrolizumab. Among the 63 patients in the control arm, 28 subsequently crossed over to receive anti-PD-1/L1 following disease progression.

The primary analysis showed that adding pembrolizumab improved overall response rates (58% vs 33%) regardless of PD-L1 status. The new findings from Awad showed a median duration of response (DOR) of 36.3 months in the immunotherapy group, as compared to 22.8 months with chemotherapy alone.

The updated analysis (median 49.4 months follow-up) also looked at the 12 patients who either completed 35 cycles or 2 years of pembrolizumab, with 92% still alive at data cutoff (11 patients). Four of these patients had achieved complete responses to treatment, while the remaining eight had partial responses; median DOR in this group was not reached (range: 11.7+ to 49.3+ months). Among evaluable patients, all had DORs beyond 36 months and seven remained on therapy.

“These data provide the longest follow-up with any anti-PD-1 or PD-L1 antibody in combination with chemotherapy in patients with non-squamous advanced non-small cell lung cancer lacking EGFR and ALK alterations,” Awad concluded. “Together with results from the phase III KEYNOTE-189 study, these results support first-line treatment with pembrolizumab plus pemetrexed-carboplatin in this population.”

Findings from KEYNOTE-021 led to the accelerated approval of pembrolizumab as a first-line therapy in combination with chemotherapy for patients with advanced non-squamous NSCLC. The combination received full approval following results of KEYNOTE-189.

Treatment-related adverse events (AEs) of any grade were similar between the pembrolizumab and control arms (93% vs 94%) in cohort G of KEYNOTE-021. Grade ≥3 AEs occurred in 39% versus 31%, respectively. A similar proportion of patients discontinued treatment due to toxicity, 17% in the pembrolizumab arm and 16% in the control arm. One patient died due to a treatment-related AE in the investigational arm versus two in the control arm.