FDA Approval Sought for Adjuvant Pembrolizumab in Stage IB to IIIA NSCLC Following Surgical Resection

The FDA has accepted for review a new supplemental biologics license application (sBLA) seeking approval of pembrolizumab (Keytruda) in the adjuvant treatment of patients with stage IB to IIIA non–small cell lung cancer (NSCLC) after complete surgical resection.¹

The sBLA is supported by data from the phase 3 KEYNOTE-091 trial (EORTC-1416-LCG/ETOP-8-15-PEARLS), in which the immunotherapy (n = 590) was found to result in a median disease-free survival (DFS) of 53.6 months (95% CI, 39.2–not reached ;HR]) vs 42.0 months (95% CI, 31.3-NR) with placebo (n = 587) in the overall patient population, irrespective of PD-L1 expression; this translated to an improvement of almost 1 year (HR, 0.76; 95% CI, 0.63-0.91; P = .0014).²

Prior to the data that read out during the March 2022 ESMO Virtual Plenary, an improvement in DFS with pembrolizumab over placebo was also reported in the subgroup of patients with a PD-L1 tumor proportion score (TPS) of 50% or higher, although the benefit was not determined to be of statistical significance (HR, 0.82; 95% CI, 0.57-1.18; P = .14). The median DFS had not been reached in either treatment arm for this subset.

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the application by January 29, 2023. However, additional findings may be provided during the review process that could delay this decision date, according to Merck.

“[Pembrolizumab] is foundational in the treatment of metastatic NSCLC. 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 at Merck Research Laboratories, stated in a press release. “If approved, [pembrolizumab] would be the first adjuvant immunotherapy-based option in the United States for patients with stage IB to IIIA NSCLC following surgical resection regardless of PD-L1 expression.”

Patients with confirmed stage IB, II, or IIIA NSCLC who underwent complete surgical resection with negative margins were enrolled to the triple-blind phase 3 trial. Patients were required to have an ECOG performance of 0 or 1, and who had tumor tissue available for PD-L1 testing.

Those with stage IB disease could be considered for adjuvant chemotherapy; this treatment was strong recommended for those with stage II and IIIA disease but was limited to 4 treatment cycles. Notably, patients could not have evidence of disease.

Patients were randomized 1:1 to receive 200 mg of pembrolizumab or placebo every 3 weeks for up to 18 administrations or about 1 year. They were stratified based on disease stage (stage IB vs stage II vs stage IIIA), PD-L1 TPS score (<1% vs 1%-49% vs ≥50%), receipt of adjuvant chemotherapy (yes vs no), and geographic region (Asia vs Eastern Europe vs rest of the world).

The trial had dual primary end points, which were DFS in the overall population, as well as in the subgroup of patients with a PD-L1 TPS of 50% or higher. Secondary end points comprised DFS in the subset of patients with a PD-L1 TPS of 1% or higher, overall survival (OS) in the overall population and in the subsets of patients with a PD-L1 TPS of 50% or higher and 1% or higher, disease-specific survival in the overall population, and safety.

The median age across the arms was 65 years and most patients in the pembrolizumab and placebo arms, respectively, were male (68.0% vs 68.7%), from Western Europe (51.4% vs 51.3%), had nonsquamous histology (67.5% vs 61.8%), and stage II disease (55.8% vs 57.6%). Moreover, 85.8% of those in the investigative arm and 85.9% of those in the control arm received adjuvant chemotherapy.

In the pembrolizumab arm, 39.5% of patients had a PD-L1 TPS of less than 1%, 32.0% had a TPS between 1% and 49%, and 28.5% had a TPS of 50% or higher. In the placebo arm, 39.5% of patients had a PD-L1 TPS of less than 1%, 32.4% had a TPS between 1% and 49%, and 28.1% had a TPS of 50% or higher.

Additional data revealed an OS trend that favored pembrolizumab over placebo, irrespective of PD-L1 expression (HR, 0.87; 95% CI, 0.67-1.15; P = .07), although these data remain immature and had not reached statistical significance at the time of the trial’s interim analysis.

The safety profile of adjuvant pembrolizumab was found to be consistent with what has previously been reported with the immunotherapy in prior trials.

Investigators of KEYNOTE-091 will continue to evaluate DFS in patients with tumors that have high levels of PD-L1 expression, as well as other secondary end points of interest.

References

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://bit.ly/3xMJCKm
2. Paz-Ares L, O’Brien MER, Mauer M, et al. Pembrolizumab (pembro) versus placebo for early-stage non-small cell lung cancer (NSCLC) following complete resection and adjuvant chemotherapy (chemo) when indicated: randomized, triple-blind, phase III EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study. Ann Oncol. Published online March 17, 2022. doi:10.1016/j.annonc.2022.02.224