FDA Approves Perioperative Pembrolizumab Plus Chemotherapy in Early NSCLC

• The approval of pembrolizumab (Keytruda) in the perioperative setting for resectable stage II, IIIA, or IIIB non–small cell lung cancer (NSCLC) marks the 6th indication for the drug in NSCLC.

• Moving treatment into earlier stages of NSCLC could significantly reduce the risk of disease recurrence, according to Merck.¹

• Other important studies of pembrolizumab in earlier stages of NSCLC include KEYNOTE-091 (NCT02504372), KEYNOTE-867 (NCT03924869), KEYLYNK-012 (NCT04380636) and KEYVIBE-006 (NCT05298423).

The FDA has approved perioperative pembrolizumab (Keytruda) in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent in the adjuvant setting for the treatment of patients with resectable stage II, IIIA, or IIIB (T3-4N2) non–small cell lung cancer (NSCLC).²

Findings from the double-blind, phase 3 KEYNOTE-671 clinical trial (NCT03425643) support this approval as it met its primary end point by showing a statistically significant and clinically meaningful improvement in event-free survival (EFS).^3,4 

At 24 months, the EFS rate was 62.4% with pembrolizumab plus chemotherapy and adjuvant pembrolizumab vs 40.6% for placebo plus chemotherapy (HR, 0.58; 95% CI, 0.46-0.72; P < .00001). With pembrolizumab, the major pathologic response (mPR) rate was 30.2% (95% CI, 25.7%-35.0%) with pembrolizumab compared with 11.0% (95% CI, 8.1%-14.5%) with placebo (Δ, 19.2%; 13.9%-24.7%; P < .00001). The pathological complete response (pCR) rate was 18.1% (95% CI, 14.5%-22.3%) with pembrolizumab vs 4.0% (95% CI, 2.3%-6.4%) for placebo (Δ, 14.2%; 95% CI, 10.1%-18.7%; P < .00001). Moreover, the overall survival (OS) data were immature at the time of the analysis, however, the 24-month OS rate was 80.9% in the pembrolizumab arm compared with 77.6% in the placebo arm (HR, 0.73; 95% CI, 0.54-0.99; P = .02124).

"The use of perioperative checkpoint inhibitors is an exciting area. When we think about what we're able to offer patients with early-stage lung cancer, we are trying to cure and are hoping to have an impact on what's going on with the disease to hopefully make sure that it is at bay as much as possible,” Heather Wakelee, MD, FASCO, professor of medicine and chief of the division of oncology, Stanford University School of Medicine, deputy director, Stanford Cancer Institute,president, International Association for the Study of Lung Cancer (IASLC), told Targeted Oncology^TM.

In the randomized, double-blind KEYNOTE-671 study, 786 patients were randomly assigned to receive chemotherapy plus pembrolizumab (n = 397) or placebo (n = 399). In the perioperative pembrolizumab arm, patients were given pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 4 cycles plus cisplatin 75 mg/m², IV on day 1 of each cycle, and either gemcitabine 1000 mg/m², IV on days 1 and 8 of each cycle, or pemetrexed 500 mg/m², IV on day 1 of each cycle. In this arm, treatment was given as neoadjuvant therapy prior to surgery, followed by pembrolizumab 200 mg IV Q3W for up to 13 cycles as adjuvant therapy post-surgery. Patients in the control arm were given matching placebo plus chemotherapy.⁵

Between arms, baseline patient characteristics were balanced with a median age of 63 years. A total of 70.3% of patients were male and had an ECOG performance status of 0 (63.7%) or 1 (36.3%). Two-thirds of patients were White (63%) and 31.2% were Asian, primarily from non-East Asian countries (69.0%). Histology was balanced at 56.9% nonsquamous and 43.1% squamous. Current smokers made up 24.2% of patients while 13.6% were never smokers, and for disease stage, patients most commonly were stage IIIA (54.7%), then stage II (29.7%), with the remainder of patients being stage IIIB (15.6%). Further, 42.3% of patients had N2 disease, 20.4% had N1, and 37.3% had N0.

At a median follow-up of 25.2 months, 35.0% of patients given pembrolizumab had experienced an event, defined as local progression, progression, recurrence, or death vs 51.3% of patients in the placebo arm. In the pembrolizumab arm, the median EFS was not yet reached (95% CI, 34.1-not reached) compared with 17.0 months in the placebo arm (95% CI, 14.3-22.0).

Regarding safety, treatment-related adverse events (AEs) were similar between treatment groups, with grade 3 to 5 events experienced by 44.9% of patients treated with pembrolizumab vs 37.3% treated with placebo, and serious AEs were experienced by 17.7% and 14.3%, respectively. Immune-mediated AEs occurred in 25.3% of patients in the pembrolizumab arm vs 10.5% in the placebo group. One death was related to an immune-mediate AE in the pembrolizumab arm, and immune-mediated AEs led to discontinuation of pembrolizumab among 5.1% of patients.

The most common AEs were those frequently associated with platinum-based chemotherapy, including nausea, neutropenia, anemia, leukopenia, and fatigue. The most common all-grade, immune-mediated AEs for pembrolizumab and placebo, respectively, were hypothyroidism (11.1% vs 1.8%), hyperthyroidism (5.6% vs 3.3%), and pneumonitis (5.6% vs 1.8%).

REFERENCES:

1. Merck announces phase 3 KEYNOTE-671 trial met primary endpoint of event-free survival (efs) in patients with resectable stage II, IIIA or IIIB non-small cell lung cancer. News release. March 1, 2023. Accessed October 16, 2023. https://tinyurl.com/47xatbps 

2. FDA Approves KEYTRUDA® (pembrolizumab) for treatment of patients with resectable (T≥4 cm or N+) NSCLC in combination with chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment after surgery. News release. Merck. October 16, 2023. Accessed October 16, 2023. https://tinyurl.com/55sbyxxj

3. Wakelee HA, Liberman M, Kato T, et al. KEYNOTE-671: randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. J Clin Oncol. 2023;41 (suppl 17):LBA100. doi:10.1200/JCO.2023.41.17_suppl.LBA100

4. Wakelee H, Liberma M, Kato T, et al. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. New Engl J Med. Published June 3, 2023. doi: 10.1056/NEJMoa2302983

5. Efficacy and safety of pembrolizumab (MK-3475) with platinum doublet chemotherapy as neoadjuvant/adjuvant therapy for participants with resectable stage II, IIIA, and resectable IIIB (T3-4N2) non-small cell lung cancer (MK-3475-671/KEYNOTE-671). ClinicalTrials.gov. Updated August 19, 2022. Accessed June 22, 2023. https://tinyurl.com/4wakzadr