Perioperative Pembrolizumab Regimen Receives Positive CHMP Opinion in NSCLC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of neoadjuvant pembrolizumab (Keytruda) plus platinum-based chemotherapy, followed by adjuvant pembrolizumab alone for the treatment of adult patients with high-risk, resectable non–small cell lung cancer (NSCLC).¹

The positive opinion was supported by data from the phase 3 KEYNOTE-671 trial (NCT03425643), in which this investigational approach led to a statistically significant and clinically meaningful improvement in the trial’s dual primary end points of overall survival (OS) and event-free survival (EFS) when compared with placebo in this patient population. The median OS was not yet reached (95% CI, not estimable [NE]-NE) in the pembrolizumab combination arm (n = 397) compared with an OS of 52.4 months (95% CI, 45.7-NE) in the placebo arm (n = 400). This translated to a 28% decrease in the risk of death (HR, 0.72; 95% CI, 0.56-0.93; P = .0103).^2,3 

Furthermore, the median EFS was 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).

In October 2023, the FDA approved the use of neoadjuvant pembrolizumab with platinum-containing chemotherapy followed by adjuvant pembrolizumab monotherapy treatment for this same patient population based on results from KEYNOTE-671.²

“The CHMP’s positive opinion puts us another step closer to helping certain patients in Europe with earlier stages of NSCLC, regardless of PD-L1 expression,” Marjorie Green, MD, senior vice president and head of Oncology, Global, and Clinical Development at Merck Research Laboratories, said in a news release. “We look forward to the European Commission’s decision, as we continue to build on the legacy of pembrolizumab in certain types of lung cancer and pursue meaningful advances that may help extend the lives of patients.”

KEYNOTE-671 was a randomized, double-blind, placebo-controlled clinical trial of patients with previously untreated and resectable stage II, IIIA, or IIIB NSCLC, according to criteria from the 8th edition of the American Joint Committee on Cancer Staging Manual. Patients were eligible for enrollment regardless of their PD-L1 expression status. However, individuals with an active autoimmune disease requiring systemic therapy within 2 years of study commencement, a medical condition necessitating immunosuppressive treatment, or a history of interstitial lung disease or pneumonitis requiring steroids were excluded from participation.³

Eligible patients with resectable disease were randomly assigned 1:1 to receive either 200 mg of neoadjuvant pembrolizumab or placebo every 3 weeks. Both groups also received cisplatin-based chemotherapy for 4 cycles before undergoing surgery. After surgery, participants received either adjuvant pembrolizumab at 200 mg or placebo every 3 weeks for a maximum of 13 cycles. Treatment continued for patients until completion of the regimen, progressive disease that prevented surgery, disease recurrence in the adjuvant phase, disease progression in patients who did not undergo surgery, incomplete resection of disease, or intolerable toxicity.³

The trial’s dual primary end points were OS and EFS; key secondary end points included major pathological response, pathological complete response, and safety.^1,3

Adverse effects (AEs) reported in 20% or more of patients on the trial included nausea, fatigue, neutropenia, anemia, constipation, decreased appetite, decreased white blood cell count, musculoskeletal pain, rash, cough, vomiting, diarrhea, and dyspnea. Among patients who received neoadjuvant treatment with pembrolizumab, 6% were unable to undergo surgery due to AEs compared with 4.3% in the placebo group. Additionally, 3.1% of patients in the pembrolizumab group experienced delays in surgery due to AEs compared with 2.5% in the placebo group.²

The CHMP’s recommendation undergo a review by the European Commission for marketing authorization in the European Union, with a final decision anticipated in the first half of 2024.¹

References

1. Merck receives positive EU CHMP opinion for Keytruda® (pembrolizumab) in combination with chemotherapy as neoadjuvant treatment, then continued as monotherapy as adjuvant treatment, for the treatment of resectable NSCLC at high risk of recurrence. News release. Merck. February 23, 2024. Accessed February 23, 2024. https://www.merck.com/news/merck-receives-positive-eu-chmp-opinion-for-keytruda-pembrolizumab-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued-as-monotherapy-as-adjuvant-treatment-for-the-treat/
2. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed February 23, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer
3. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Engl J Med. Published online August 10, 2023. doi:10.1056/NEJMoa2302983