Pembrolizumab (anti–PD-1 therapy) plus chemotherapy continued to demonstrate a survival benefit and durable responses as first-line treatment of metastatic non–small cell lung cancer (NSCLC), according to the results of two phase III trials.^1,2 Five-year overall survival was improved in both nonsquamous and squamous NSCLC in the two trials, respectively.

Landmark Studies

In metastatic nonsquamous NSCLC, KEYNOTE-189 demonstrated that patients who received treatment with pembrolizumab plus pemetrexed and platinum chemotherapy (cisplatin or carboplatin) had a 5-year overall survival rate of 19.4% vs 11.3% with chemotherapy alone.¹ Median overall survival was more than double with the combination compared with chemotherapy alone: 22.0 months vs 10.6 months.

For patients with metastatic squamous NSCLC, KEYNOTE-407 demonstrated similar results.² The 5-year rate of overall survival was 18.4% with pembrolizumab/chemotherapy vs 9.7% with chemotherapy alone. Median overall survival was 17.2 months with pembrolizumab/chemotherapy vs 11.6 months with chemotherapy alone.

Marina C. Garassino, MD

In both studies, of the approximately 55 patients who completed 2 years of treatment, about 70% were alive at 5 years.

“Prior to these landmark studies, the 5-year survival for lung cancer was one of the lowest of any cancer,” said presenting author and principal investigator of KEYNOTE-189, Marina C. Garassino, MD, Professor of Medicine, University of Chicago. “These results show meaningful improvements in 5-year survival for patients receiving pembrolizumab plus chemotherapy and reinforce the important role of these pembrolizumab-based regimens as standards of care for metastatic non–small cell lung cancer.”

“Long-term data continue to support pembrolizumab plus chemotherapy as standard-of-care front-line treatment of metastatic NSCLC,” stated lead author of KEYNOTE-407, Silvia Novello, MD, PhD, of the Department of Oncology, San Luigi Hospital, University of Turin, Italy.

Long-term data continue to support pembrolizumab plus chemotherapy as standard-of-care front-line treatment of metastatic NSCLC.

— Silvia Novello, MD, PhD

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KEYNOTE-189: Key Findings

KEYNOTE-189 is a pivotal phase III, randomized trial evaluating pembrolizumab plus chemotherapy (pemetrexed and cisplatin or carboplatin) as first-line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations vs chemotherapy alone. At the ESMO Congress, Dr. Garassino presented an exploratory analysis of the efficacy and safety outcomes at 5 years of follow-up, as well as additional analyses in patients who completed 35 cycles (approximately 2 years) of treatment with pembrolizumab.

At a median follow-up of 64.6 months, pembrolizumab plus chemotherapy continued to sustain improvement in overall and progression-free survival. The overall survival benefit was observed despite a 57.3% crossover rate from chemotherapy to subsequent anti–PD-1/PD-L1 therapy. The pembrolizumab/pemetrexed/platinum combination reduced the risk of disease progression or death vs chemotherapy alone, with an almost double median progression-free survival of 9.0 months vs 4.9 months and a 5-year progression-free survival rate of 7.5% vs 0.6%. The objective response rate was 48.3% with the immunotherapy/pemetrexed/chemotherapy arm vs 19.9% with chemotherapy alone, with a median duration of response of 12.7 months vs 7.1 months, respectively.

A separate exploratory analysis of 57 patients who completed approximately 2 years of treatment (35 cycles) with pembrolizumab plus chemotherapy showed that 71.9% were alive at 5 years post randomization, with an objective response rate of 86.0% (with 8 complete responses and 41 partial responses). Among these patients, 40.4% were alive without progressive disease or subsequent therapy.

No new safety signals were identified with long-term follow-up. Among all patients treated, 72.8% of those who received the three-drug regimen and 67.3% of those who received chemotherapy alone experienced grade 3 to 5 adverse events. Among patients who completed 2 years of treatment with the pembrolizumab combination, grade 3 to 5 adverse events were reported in 66.7%. 

KEYNOTE-407: Long-Term Outcomes 

KEYNOTE-407 was a pivotal phase III, randomized, double-blind, placebo-controlled trial with a similar design to that of KEYNOTE-189. Patients were randomly assigned to receive pembrolizumab plus carboplatin/paclitaxel or nab-paclitaxel for the first-line treatment of metastatic squamous NSCLC vs carboplatin/paclitaxel or nab-paclitaxel alone. The study included an exploratory analysis of the efficacy and safety outcomes at 5 years of follow-up and additional analyses in patients who completed 35 cycles (approximately 2 years) of treatment with ­pembrolizumab.

At a median follow-up of 56.9 months, pembrolizumab plus chemotherapy demonstrated sustained improvement in overall and progression-free survival compared with chemotherapy alone. The significant overall survival benefit (median overall survival = 17.2 vs 11.6 months) was achieved despite a 50.9% crossover rate from chemotherapy to subsequent anti–PD-1/PD-L1 therapy. Pembrolizumab plus chemotherapy reduced the risk of disease progression or death vs chemotherapy alone, with a median progression-free survival of 8 months vs 5.1 months and a 5-year progression-free survival rate of 10.8% vs 3.5%. The objective response rate was 62.2% with pembrolizumab/chemotherapy vs 38.8% with chemotherapy.

In an exploratory analysis of 55 patients who completed 2 years (35 cycles) of pembrolizumab/chemotherapy treatment, 69.5% were alive at 5 years. The objective response rate in these patients was 90.9% (with 9 complete responses and 41 partial responses). Among these patients, 43.6% were alive without progressive disease or subsequent therapy.

No new safety signals for pembrolizumab emerged with longer-term follow-up. Among all patients treated, grade 3 to 5 adverse events were reported in 74.8% of the combination arm and 70.0% of those who received chemotherapy alone. Among patients who completed 2 years of treatment with pembrolizu­mab, grade 3 to 5 adverse events were reported in 63.6%. 

DISCLOSURE: Dr. Garassino reported financial relationships with AstraZeneca, Merck, Roche, Bristol Myers Squibb, Celgene, Boehringer Ingelheim, Novartis, GlaxoSmithKline, Pfizer, Eli Lilly, and Takeda. Dr. Novello reported financial relationships with Amgen, AstraZeneca, BeiGene, Eli Lilly, Merck Sharpe and Dohme, Novartis, Takeda, Pfizer, Roche, ThermoFisher, Sanofi, Janssen, GlaxoSmithKline, and Boehringer Ingelheim.

REFERENCES

1. Garassino MC, Gadgeel SM, Felip E, et al: KEYNOTE-189: 5-year update: First-line pembrolizumab + pemetrexed and platinum vs placebo + pembrolizumab and platinum for metastatic nonsquamous NSCLC. ESMO Congress 2022. Abstract 973MO. Presented September 9, 2022.

2. Novello S, Kowalski DM, Baz DV, et al: 5-year update from KEYNOTE-407: Pembrolizumab plus chemotherapy in squamous non-small cell lung cancer. ESMO Congress 2022. Abstract 974MO. Presented September 9, 2022.