Perioperative Pembrolizumab Meets Dual Primary End Point of OS in NSCLC

Pembrolizumab (Keytruda) plus chemotherapy prior to surgery, followed by resection and single-agent pembrolizumab in the adjuvant setting, significantly improved overall survival (OS) vs neoadjuvant placebo plus chemotherapy followed by adjuvant placebo in patients with resectable stage II, IIIA, or IIIB (T3-4N2) non–small cell lung cancer (NSCLC), meeting the dual primary end point of the phase 3 KEYNOTE-671 trial (NCT03425643).¹

The toxicity profile of the immunotherapy proved to be in line with what has been previously reported, with no new safety signals observed.

Full findings from the analysis of the trial will be shared at the 2023 ESMO Congress and discussed with regulatory authorities on a global scale, according to Merck.

“This is a significant milestone in the treatment of resectable NSCLC, as it represents the first phase 3 study to show a statistically significant OS benefit for these patients with stage II, IIIA, or IIIB (T3-4N2) NSCLC. These results build upon the previously reported event-free survival data and demonstrate the potential for this [pembrolizumab]-based regimen to help extend the lives of these patients,” Marjorie Green, MD, senior vice president and head of late-stage oncology and global development at Merck Research Laboratories. “We’re excited by the progress we have made to help patients with earlier stages of NSCLC, who are in need of additional treatment options.”

In KEYNOTE-671, participants were randomized to receive chemotherapy plus pembrolizumab (n = 397) or placebo (n = 399). Pembrolizumab was given intravenously at a dose of 200 mg every 3 weeks in the neoadjuvant setting for 4 cycles and the adjuvant setting for 13 cycles.² Chemotherapy was administered every 3 weeks and comprised cisplatin plus pemetrexed for nonsquamous histology or gemcitabine for squamous histology. Every 3 weeks, cisplatin was given at a dose of 75 mg/m², pemetrexed at 500 mg/m², and gemcitabine at 1000 mg/m² on days 1 and 8.

Baseline patient characteristics were balanced between the treatment arms. In the pembrolizumab group, the median age was 63 years, more than half (70.3%) were male, and most had an ECOG performance status of 0 (63.7%). More than half (63%) of patients were White and 31.2% were Asian, primarily from non-East Asian countries (69.0%). Regarding histology, 56.9% had nonsquamous disease and 43.1% had squamous disease. In terms of smoking status, 24.2% of patients were current smokers and 13.6% were never smokers. The disease stage at baseline was most commonly IIIA (54.7%), followed by stage II (29.7%), with the remainder being stage IIIB (15.6%). Moreover, 42.3% of patients had N2 disease, 20.4% had N1 disease, and 37.3% had N0 disease.

PD-L1 status by tumor proportion score was balanced, with a 33.2% having expression of 50% or greater and 34.8% having expression of less than 1%. Those with known driver mutations were included in the trial, with 3.5% of tumors harboring an EGFR mutation and 3.0% with an ALK alteration. Driver mutation status was unknown for about two-thirds of patients.

There were more complete R0 resections in the pembrolizumab arm vs the placebo group, at 92.0% and 84.2%, respectively. Incomplete R1 resections occurred in 5.2% and 9.8% of patients, respectively. The most common type of surgery was a lobectomy, which was done in 78.8% of patients in the pembrolizumab arm vs 75.1% of those in the placebo arm.

Prior data showed that at a median follow-up of 25.2 months, and a data cutoff date of July 29, 2022, the 24-month EFS rate was 62.4% in the pembrolizumab arm vs 40.6% in the placebo arm (HR, 0.58; 95% CI, 0.46-0.72; P < .00001). The median EFS was not yet reached with pembrolizumab (95% CI, 34.1-not reached) vs 17.0 months with placebo (95% CI, 14.3-22.0).

The major pathologic response (mPR) rates were 30.2% (95% CI, 25.7%-35.0%) and 11.0% (95% CI, 8.1%-14.5%), respectively (Δ, 19.2%; 13.9%-24.7%; P < .00001). The pathological complete response (pCR) rates were 18.1% (95% CI, 14.5%-22.3%) and 4.0% (95% CI, 2.3%-6.4%), respectively (Δ, 14.2%; 95% CI, 10.1%-18.7%; P < .00001).

Data from an exploratory analysis, which evaluated EFS by neoadjuvant response, showed that for those with a pCR, the benefit was more pronounced with pembrolizumab vs placebo, with an HR of 0.33 (95% CI, 0.09-1.22). In those without a pCR, the HR was 0.69 (95% CI, 0.55-0.85). For those who experienced an mPR, the HR was 0.54, favoring pembrolizumab (95% CI, 0.24-1.22). For those without an mPR, the HR was 0.73; 95% CI, 0.58-0.92).

Treatment-related adverse effects (AEs) were comparable between the arms, with grade 3 to 5 events reported in 44.9% of those in the pembrolizumab arm and 37.3% of those in the placebo arm. Serious AEs were reported in 17.7% and 14.3% of patients, respectively. Immune-mediate AEs occurred in 25.3% of those who received pembrolizumab vs 10.5% of those given placebo. There was 1 death related to an immune-mediate AE in the pembrolizumab arm. Immune-mediated AEs led to pembrolizumab discontinuation in 5.1% of patients.

The most common AEs were those frequently associated with platinum-based chemotherapy, and included nausea, neutropenia, anemia, leukopenia, and fatigue. The most common all-grade, immune-mediate AEs reported with pembrolizumab and placebo, respectively, were hypothyroidism (11.1% vs 1.8%), hyperthyroidism (5.6% vs 3.3%), and pneumonitis (5.6% vs 1.8%).

In March 2023, the FDA accepted a supplemental biologics license application seeking the approval of neoadjuvant pembrolizumab in combination with platinum-containing chemotherapy, followed by adjuvant pembrolizumab monotherapy, for the treatment of patients with resectable stage II, IIIA, or IIIB (T3-4N2) non–small cell lung cancer.³ The application is supported by data from KEYNOTE-671 and has a target action date of October 16, 2023.

References

1. Merck announces pivotal KEYNOTE-671 trial meets dual primary endpoint of overall survival (OS) in resectable stage II, IIIA or IIIB non-small cell lung cancer (NSCLC). News release. Merck. October 10, 2023. Accessed October 10, 2023. https://www.merck.com/news/merck-announces-pivotal-keynote-671-trial-meets-dual-primary-endpoint-of-overall-survival-os-in-resectable-stage-ii-iiia-or-iiib-non-small-cell-lung-cancer-nsclc/
2. Wakelee H, Liberman M, Kato T, et al; KEYNOTE-671 Investigators. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Engl J Med. Published online June 3, 2023. doi:10.1056/NEJMoa2302983
3. Merck announces phase 3 KEYNOTE-671 trial met primary endpoint of event-free survival (EFS) in patients with resectable stage II, IIIA or IIIB non-small cell lung cancer. News release. Merck. March 1, 2023. Accessed October 10, 2023. https://www.merck.com/news/merck-announces-phase-3-keynote-671-trial-met-primary-endpoint-of-event-free-survival-efs-in-patients-with-resectable-stage-ii-iiia-or-iiib-non-small-cell-lung-cancer/