FDA Accepts sBLA for Pembrolizumab in Stage IB, II, or III NSCLC


A new supplemental biologics license application has been accepted by the FDA for pembrolizumab as treatment of patients with 1B (≥4 centimeters), 2, or 3 non-small cell lung cancer after complete surgical resection.

The FDA has accepted a new supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) used to treat patients with stage IB (≥4 cm), II, or III non–small cell lung cancer (NSCLC) following complete surgical resection, according to Merck.1

The basis of the sBLA comes from the phase 3 PEARLS/KEYNOTE-091 trial (NCT02504372), which showed adjuvant pembrolizumab to lead to improved disease-free survival (DFS) compared with placebo in patients with fully resected NSCLC.

“Keytruda is foundational in the treatment of metastatic non-small cell lung cancer. The acceptance of our application demonstrates the progress we are making in earlier lines and earlier stages of certain cancers across our oncology portfolio,” Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer of Merck Research Laboratories, stated in the press release. “If approved, Keytruda would be the first adjuvant immunotherapy-based option in the United States for patients with stage IB (≥4 cm) to IIIA NSCLC following surgical resection regardless of PD-L1 expression.”

KEYNOTE-091 is a global, randomized, phase 3 trial evaluating pembrolizumab vs placebo for the adjuvant treatment of patients with early-stage NSCLC after surgical resection, consisting of lobectomy or pneumonectomy, and with adjuvant chemotherapy when indicated.

Investigators in the trial randomized 1177 patients in a 1:1 ratio to receive pembrolizumab (n = 590) or placebo (n = 587) intravenously at a dose of 200 mg every 3 weeks for up to 18 administrations. The median number of doses of pembrolizumab given to patients was 17 vs 18 for those who received placebo.

Enrollment in the trial was open to patients with an ECOG performance score of 0 or 1, and who were considered to have stage IB disease with a tumor of at least 4 cm, stage II, and stage IIIA disease.

The study had dual primary end points of DFS in the overall population regardless of PD-L1 expression and DFS in patients with a PD-L1 tumor proportion score (TPS) of greater than or equal to 50%. DFS in this trial is determined by whichever occurs first: time from randomization to the date of disease recurrence, occurrence of second primary lung cancer, occurrence of second malignancy, or death from any cause. Secondary end points of the trial included overall survival (OS), lung cancer-specific survival, and safety.

A presentation of the second interim analysis of the KEYNOTE-091 trial presented at the 2022 American Society of Clinical Oncology Annual Meeting, showed the median age of patients enrolled to be 65 years with almost 70% of patients being male. Over half of patients were from western Europe and all others were from eastern Europe, Asia, or other parts of the world. In the pembrolizumab arm, 35.6% patients had an ECOG score of 1, while 41.6% of patients receiving placebo did. Over 80% of patients between both treatment arms received adjuvant chemotherapy.2

A total of 55.8% of patients in the pembrolizumab group presented with stage II disease, 30.0% of patients had stage IIIA, and 14.2% had stage IB. In the placebo group, 57.6% of patients had stage II disease, 27.6% had stage IIIA, and 14.5% had stage IB. The overall majority of patients in both arms had a lobectomy (78.1% given pembrolizumab vs 79.0% given placebo).

In the second interim analysis of KEYNOTE-091, treatment with pembrolizumab resulted in a significant improvement in DFS for patients regardless of PD-L1 expression when compared with placebo. Patients who were given pembrolizumab had a median DFS of 53.6 months (95% CI, 39.2-not reached [NR]) vs a median DFS of 42 months with placebo (95% CI, 31.3-NR; HR, 0.76; P = .0014). In the pembrolizumab arm, the 18-month DFS rate for patients was 73.4% vs 64.3% in patients in the placebo arm. Furthermore, less patients experienced DFS events when receiving pembrolizumab (35.9%) than when receiving placebo (44.3%).

In the patient population with a PD-L1 TPS of 50% or more, DFS was NR in both the pembrolizumab (n = 168) and the placebo (n = 165) population (HR, 0.82; 95% CI, 0.57-1.18; P = .14). Within the experimental arm vs the control arm, the 18-month DFS rates for patients was 71.7% vs 70.1%, respectively. Events from DFS occurred in 32.1% of patients who received pembrolizumab and in 38.2% of patients given the placebo.

The median OS was also NR in both study arms (HR, 0.87; 95% CI, 0.67-1.15; P = .17). With pembrolizumab, the 18-month OS rate was 91.7% vs 91.3% with placebo.

The safety profile of pembrolizumab in this trial remained consistent with prior trials with no new or unexpected safety signals seen. However, grade 3 to 5 adverse events occurred in 34.1% of patients receiving pembrolizumab and in 25.8% of patients receiving placebo.

Along with the KEYNOTE-091 trial are 6 other pivotal trials looking to examine the use of pembrolizumab in patients with early staged cancer, all of which met their primary objectives.1 These trials consist of KEYNOTE-716 (NCT03553836) in stage IIB and IIC melanoma, KEYNOTE-054 (NCT02362594) in stage III melanoma, KEYNOTE-564 (NCT03142334) in renal cell carcinoma, KEYNOTE-522 (NCT03036488) in triple-negative breast cancer, KEYNOTE-629 (NCT03284424) in cutaneous squamous cell carcinoma, and KEYNOTE-057 (NCT02625961) in Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer.

1. FDA accepts application for Merck’s KEYTRUDA® (pembrolizumab) as adjuvant therapy for stage IB (≥4 centimeters)-IIIA non-small cell lung cancer following complete surgical resection. News release. Merck. June 13, 2022. Accessed June 13, 2022. https://bwnews.pr/3tV0lJl
2. O'Brien M, Paz-Ares L, Jha N, et al. EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study of pembrolizumab versus placebo for completely resected early-stage non-small cell lung cancer (NSCLC): outcomes in subgroups related to surgery, disease burden, and adjuvant chemotherapy use. J Clin Oncol. 2022;40(suppl 16):8512. doi:10.1200/JCO.2022.40.16_suppl.8512

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