Pembrolizumab Plus Chemotherapy Continues to Display Survival Advantage Over Chemotherapy in NSCLC

Patients with treatment-naïve metastatic squamous non–small cell lung cancer (NSCLC) experienced a clinically meaningful survival benefit when treated with the PD-1–directed antibody pembrolizumab (Keytruda) in combination with chemotherapy compared with those who received chemotherapy alone, according to long-term follow-up data from the phase 3 KEYNOTE-407 trial (NCT02775435) published in the Journal of Clinical Oncology.¹

Findings from the 5-year KEYNOTE-407 safety and efficacy analysis showed that patients in the intention-to-treat population who were treated with pembrolizumab plus chemotherapy (n = 278) experienced a median overall survival (OS) of 17.2 months (95% CI, 14.4-19.7) compared with 11.6 months (95% CI, 10.1-13.7) among the 281 patients who received placebo plus chemotherapy (HR, 0.71; 95% CI, 0.59-0.85). Additionally, the median progression-free survival (PFS) was 8.0 months (95% CI, 6.3-8.5) vs 5.1 months (95% CI, 4.3-6.0), respectively (HR, 0.62; 95% CI, 0.52-0.74). The median time from randomization to data cutoff was 56.9 months (range, 49.9-66.2).¹

Previously, results from KEYNOTE-407 led to the FDA approval of pembrolizumab in combination with carboplatin and paclitaxel or nab-paclitaxel as a frontline treatment for patients with metastatic squamous NSCLC on October 30, 2018.²

The multicenter, double-blind KEYNOTE-407 trial enrolled patients with stage IV squamous NSCLC who had measurable disease per RECIST 1.1 criteria and provided tumor tissue for investigators to determine PD-L1 status. Eligible patients were randomly assigned 1:1 to receive either pembrolizumab at a dose of 200 mg every 3 weeks in combination with carboplatin area under the curve 6 mg/mL/minute plus paclitaxel 200 mg/m2 or nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 3 weeks for 4 cycles or placebo plus the same chemotherapy regimen. Following completion of chemotherapy, patients received pembrolizumab 200 mg or placebo according to initially assigned treatment until the completion of 35 cycles, disease progression, unacceptable adverse effects (AEs), or withdrawal.

Patients in the placebo arm with disease progression confirmed by blinded independent central review were permitted to crossover to monotherapy with pembrolizumab for up to 35 cycles. Additionally, patients were eligible to receive second-course pembrolizumab monotherapy for 17 cycles in the event of progression following completion of 35 cycles of pembrolizumab if a best response of stable disease or better per investigator assessment was achieve after at least 8 cycles of pembrolizumab.

In the combination arm, 109 patients went on to receive subsequent anticancer treatment, including 33 who were treated with anti–PD-L1 therapy and 12 who received on-study second-course pembrolizumab. In the placebo arm, 172 patients received subsequent anticancer therapy, including 117 who crossed over to pembrolizumab monotherapy on-study and 26 who received anti–PD-L1 therapy. In the combination arm, 55 patients completed 35 cycles of pembrolizumab and 12 started a second course of treatment with the agent.

OS and PFS represented coprimary end points. Key secondary end points included overall response rate (ORR), duration of response (DOR), and safety. Time from randomization to subsequent disease progression following the next line of treatment or death (PFS2) was an exploratory end point.

Baseline patient characteristics were well-balanced between the combination and placebo arms; the median age was 65.0 years (range, 29-87) vs 65.0 years (range, 36-88), respectively. Most patients in both arms were men (79.1% vs 83.6%), were not from East Asia (80.6% vs 81.5%), had an ECOG performance status of 1 (73.7% vs 68.0%), and were former or current smokers (92.1% vs 93.2%).

Most patients in both arms had a PD-L1 tumor performance score (TPS) of at least 1% (63.3% vs 63.0%), including 26.3% and 26.0%, respectively, who had a score of 50% or greater. Patients had a PD-L1 TPS of less than 1% at a rate of 34.2% and 35.2%, respectively. Scores ranging from 1% to 49% were present in 37.1% and 37.0% of patients, respectively.

Additional findings from the long-term analysis showed that the estimated 5-year OS rates were 18.4% in the combination arm compared with 9.7% in the placebo arm. The 5-year PFS rates were 10.8% vs 3.5%, respectively.

Notably, patients treated with the combination experienced a benefit in terms of OS compared with those who received placebo regardless of PD-L1 status. The median OS was 19.9 months (95% CI, 12.2-25.2) vs 11.5 months (95% CI, 7.5-17.1), 18.0 months (95% CI, 13.6-22.8) vs 13.1 (95% CI, 9.1-13.8), 15.0 months (95% CI, 13.2-19.4) vs 11.0 months (95% CI, 8.7-13.8), among patients with a PD-L1 TPS of 50% or greater, a PD-L1 TPS of 1% to 49%, and a PD-L1 TPS of less than 1%, respectively. These improvements led to respective HRs of 0.68 (95% CI, 0.47-0.97), 0.61 (95% CI, 0.45-0.83), and 0.83 (95% CI, 0.61-1.13).

Similarly, patients who received pembrolizumab plus chemotherapy experienced a PFS benefit compared with those who were treated with placebo plus chemotherapy irrespective of PD-L1 status. The median PFS was 8.3 months (95% CI, 6.2-10.7) vs 4.2 months (95% CI, 2.9-4.8), 8.2 months (95% CI, 6.2-11.4) vs 6.0 months (95% CI, 4.2-6.2), and 6.3 months (95% CI, 6.1-8.5) vs 5.9 months (95% CI, 4.4-6.2), respectively. The HRs were 0.48 (95% CI, 0.33-0.69), 0.60 (95% CI, 0.45-0.81), and 0.70 (95% CI, 0.52-0.95), respectively.

In terms of response, the ORR in the overall population was 62.2% (95% CI, 56.2%-68.0%) and 38.8% (95% CI, 33.1%-44.8%) in the combination and placebo arms, respectively. The CR rates were 3.6% and 3.9%, respectively, and 23.7% vs 36.3% of respective patients achieved stable disease. The median DOR was 9.0 months (95% CI, 1.3+ to 61.5+) vs 4.9 months (95% CI, 1.3+ to 58.6+), respectively.

Safety findings showed that most patients in both the combination and placebo arms experienced an AE (98.6% vs 98.2%). Grade 3 to 5 AEs occurred at a rate of 74.8% vs 70.0%, respectively. Immune-mediated AEs occurred in 35.6% and 9.3% of patients, respectively. Grade 3 to 5 immune-mediated AEs were present in 13.3% vs 3.2% of patients, respectively.

In the combination arm, patients were forced to discontinue any treated meant due to an AE at a rate of 28.8%. AEs led to death in 11.5% of patients; treatment-related AEs led to treatment discontinuation and death in 20.9% vs 4.3% of patients, respectively.

In the placebo arm, patients were forced to discontinue any treated meant due to an AE at a rate of 13.2%. AEs led to death in 7.1% of patients; treatment-related AEs led to treatment discontinuation and death in 7.5% vs 1.8% of patients, respectively.

Common AEs of any grade in the combination arm included anemia (54.7%), alopecia (46.0%), and neutropenia (37.8%). Grade 3 to 5 AEs included neutropenia (23.0%), anemia (15.8%), and thrombocytopenia (8.3%).

Comparatively, among patients treated with placebo, any grade AEs consisted of anemia (51.8%), alopecia (37.5%), neutropenia (32.5%), and nausea (32.5%). Grade 3 to 5 AEs included neutropenia (24.6%), anemia (20.7%), and thrombocytopenia (6.8%).

In their conclusion, study authors noted that sustained improvements in OS were observed despite an effective crossover rate of 50.9% of patients in the combination arm to subsequent anti–PD-L1 therapy. The findings from KEYNOTE-407 supported the combination of pembrolizumab and chemotherapy as astandard-of-care first-line treatment option for metastatic squamous NSCLC, irrespective of their PD-L1 status, they wrote.

References

1. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab plus chemotherapy in squamous non–small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study. J Clin Oncol. Published online February 3, 2023. doi:10.1200/JCO.22.01990
2. FDA approves pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC. FDA. October 30, 2018. Accessed March 17, 2023. https://www.fda.gov/drugs/fda-approves-pembrolizumab-combination-chemotherapy-first-line-treatment-metastatic-squamous-nsclc