FDA Approves Pembrolizumab Resectable Non–Small Cell Lung Cancer

The FDA has approved pembrolizumab (Keytruda) combined with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a monotherapy for the post-surgical adjuvant treatment of patients with resectable non–small cell lung cancer (NSCLC).

This marks the sixth approval of pembrolizumab in the treatment of NSCLC, across the metastatic and earlier stages of the disease.

“Keytruda continues to change the way non-small cell lung cancer is treated across earlier and metastatic disease regardless of PD-L1 expression,” said Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories, in a press release. “This approval marks a pivotal moment for the lung cancer community by providing certain patients with earlier stages of non-small cell lung cancer and health care providers with an important new treatment option.”

The approval was based on findings from the multicenter, randomized, double-blind, placebo-controlled, phase 3 KEYNOTE-671 trial (NCT03425643). Investigators enrolled 797 patients irrespective of PD-L1 expression with previously untreated and resectable stage II, IIIA, or IIIB NSCLC by the American Joint Committee on Cancer 8th edition criteria.

Patients were excluded if they had an active autoimmune disease requiring systemic therapy within 2 years of study treatment, a medical condition requiring immunosuppressive treatment, or a history of interstitial lung disease or pneumonitis requiring steroids.

Patients were randomized 1:1 to receive 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 before undergoing surgery. Within 4 to 12 weeks of surgery, patients received either placebo or pembrolizumab monotherapy at 200 mg every 3 weeks for up to 13 cycles.

Treatment was continued until either completion of 17 cycles, progressive disease that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for patients who did not undergo surgery or who had incomplete resection and began the adjuvant phase, or intolerable toxicity.

Median exposure to pembrolizumab was 10.9 months (range, 1 day to 18.6 months). In the neoadjuvant phase of the trial, 396 patients were administered at least 1 dose of pembrolizumab plus chemotherapy, whereas 399 patients received at least 1 dose of placebo plus chemotherapy.

The trial’s primary outcomes were overall survival (OS) and investigator-assessed event-free survival (EFS), with secondary outcome measures that included pathologic complete response (pCR) rate and major pathologic response (mPR) rate per blinded independent pathology review. The median age of patients enrolled in the trial was 64 years of age (range, 26-83), with 45% being 65 years of age or older. Further, 61% of patients were White, 63% had an ECOG performance status of 0, 70% of patients had stage III disease, and the rest had stage II disease.

Results from the trial showed that the median OS was not yet reached (95% CI, not estimable [NE]-NE) in the pembrolizumab cohort (n = 397) compared with 52.4 months (95% CI, 45.7-NE) in the placebo cohort (n = 400), which translated to a 28% decrease in the risk of death (HR, 0.72; 95% CI, 0.56-0.93; P = .0103). The data also show that 18.1% patients in the pembrolizumab cohort had a pCR compared with 4.0% of patients in the placebo cohort (P < .0001). Patients in the treatment cohort had a 30.2% mPR rate compared with 11.0% in the placebo cohort (P < .0001).

Median EFS was also not reached in the pembrolizumab cohort (95% CI, 34.1-NE) by investigator assessment compared with 17 months (95% CI, 14.3-22.0) in the placebo cohort (HR, 0.58; 95% CI, 0.46-0.72; P < .0001).

The most common adverse events (AEs) 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. Six percent of patients administered neoadjuvant treatment in the pembrolizumab cohort were unable to undergo surgery because of AEs compared with 4.3% of patients in the placebo cohort.

In the pembrolizumab cohort, 34% of patients experienced serious AEs, with the most common being pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal toxicities were reported in 1.3% of patients, including death from an unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Further, 18% of patients in the pembrolizumab cohort experienced AEs that led to treatment discontinuation.

“There remains a need for treatment options to improve outcomes for patients with earlier stages of non-small cell lung cancer,” KEYNOTE-671 principal investigator Heather Wakelee, MD, thoracic medical oncologist and professor of medicine at Stanford University and past president of the International Association for the Study of Lung Cancer, said in a press release. “This important milestone has the potential to change the current treatment paradigm for resectable non-small cell lung cancer that is greater than 4 centimeters or has lymph node involvement, by offering an immunotherapy-based regimen that has demonstrated statistically significant improvements in overall survival and event-free survival compared to a placebo and chemotherapy regimen.”

Reference

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