FDA Approves Neoadjuvant/Adjuvant Pembrolizumab for Resectable NSCLC

FDA

The FDA has approved pembrolizumab (Keytruda) in combination with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of pembrolizumab monotherapy as post-surgical adjuvant treatment for patients with resectable non–small cell lung cancer.¹

The regulatory decision was supported by data from the phase 3 KEYNOTE-671 trial (NCT03425643). Data indicated that the median overall survival (OS) was not yet reached (95% CI, not estimable [NE]-NE) in the pembrolizumab arm (n = 397) vs 52.4 months (95% CI, 45.7-NE) in the placebo arm (n = 400), translating to a 28% reduction in the risk of death (HR, 0.72; 95% CI, 0.56-0.93; P = .0103).

The median event-free survival (EFS) was also not yet reached in the pembrolizumab arm (95% CI, 34.1-NE) by investigator assessment vs 17 months (95% CI, 14.3-22.0) in the placebo arm (HR, 0.58; 95% CI, 0.46-0.72; P < .0001).

Regarding safety, the most common toxicities experienced by 20% or more of patients included nausea, fatigue, neutropenia, anemia, constipation, reduced appetite, decreased white blood cell count, musculoskeletal pain, rash, cough, vomiting, diarrhea, and dyspnea.

Of the patients who received neoadjuvant treatment in the pembrolizumab arm, 6% were not able to undergo surgery because of adverse reactions vs 4.3% of those in the placebo arm.

About KEYNOTE-671

The multicenter, randomized, double-blind, placebo-controlled trial enrolled 797 patients with previously untreated and resectable stage II, IIIA, or IIIB NSCLC by the American Joint Committee on Cancer 8th edition criteria. Patients could enroll in the trial irrespective of PD-L1 expression.

However, those with an active autoimmune disease that needed systemic therapy within 2 years of study treatment, a medical condition that required immunosuppressive treatment, or who had a history of interstitial lung disease or pneumonitis in need of steroids, were excluded.

Study participants were randomly assigned 1:1 to the pembrolizumab arm (arm A) or the placebo arm (arm B). Patients received neoadjuvant placebo or pembrolizumab at 200 mg on day 1 plus cisplatin at 75 mg/m² plus either pemetrexed at 500 mg/m² on day 1 or gemcitabine at 1000 mg/m² on days 1 and 8 of each 21-day treatment cycle for up to 4 cycles. Patients then underwent surgery. Within 4 to 12 weeks of their procedure, placebo or single-agent pembrolizumab was administered at 200 mg every 3 weeks for up to 13 cycles.

Treatment continued until completed (17 cycles), progressive disease that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not receive surgery or who had incomplete resection and entered the adjuvant phase, or intolerable toxicity.

Key stratification factors included disease stage (II vs III), PD-L1 expression (tumor proportion score [TPS] of ≥50% vs <50%), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia).

OS and investigator-assessed EFS served as the trial's primary efficacy outcome measures. Additional efficacy outcome measures included pathologic complete response (pCR) rate and major pathologic response (mPR) rate per blinded independent pathology review.

The median age in these patients was 64 years (range, 26-83), with 45% aged 65 years or older. Moreover, most patients were White (61%) and had an ECOG performance status of 0 (63%). In terms of disease stage, 70% of patients had stage III disease and the remainder had stage II disease. Regarding PD-L1 expression, 33% had a TPS of 50% or higher and 67% had a TPS that was under 50%. Just under half of patients had squamous histology (43%) and the remaining 57% had nonsquamous disease. Thirty-one percent of patients were from the East Asian region.

Additional findings showed that those in the pembrolizumab arm experienced a significantly higher pCR than those in the placebo arm, at 18.1% vs 4.0%, respectively (P < .0001); this was also true in terms of mPR rate, at 30.2% vs 11.0%, respectively (P < .0001).

The median exposure to the immunotherapy was 10.9 months (range, 1 day to 18.6 months). In the neoadjuvant phase, 396 patients received at least 1 dose of pembrolizumab plus chemotherapy, and 399 patients received at least 1 dose of placebo plus chemotherapy.

In the pembrolizumab arm, 34% of patients experienced serious adverse reactions, the most frequent of which were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal toxicities occurred in 1.3% of patients, and these included death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%).

Eighteen percent of patients in the pembrolizumab arm experienced adverse effects (AEs) that resulted in treatment discontinuation.

In the adjuvant setting, 290 patients received at least 1 dose of pembrolizumab, and 267 patients received at least 1 dose of placebo. In the investigative arm, 14% experienced serious AEs, the most frequent of which was pneumonia (3.4%), and 1 fatal reaction was observed. Twelve percent of patients in the pembrolizumab arm experienced AEs that resulted in treatment discontinuation.

References

1. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed October 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer
2. Pembrolizumab (Keytruda). Prescribing information; Merck. Updated October 2023. Accessed October 16, 2023.https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125514s139lbl.pdf