Perioperative Pembrolizumab Regimen Upholds Survival Benefit in Resectable NSCLC

Non–Small Cell Lung cancer |
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Neoadjuvant pembrolizumab (Keytruda) and chemotherapy followed by surgery and adjuvant pembrolizumab showed a continued benefit in event-free and overall survival (OS) compared with neoadjuvant chemotherapy and surgery alone in patients with resectable, early-stage non–small cell lung cancer (NSCLC), according to 4 years of follow-up from the phase 3 KEYNOTE-671 trial (NCT03425643) that was presented at the 2024 ESMO Immuno-Oncology Annual Congress.¹

Results showed that, at a median follow-up of 41.1 months (range, 0.4-75.3), the median OS was not reached (NR) with pembrolizumab (95% CI, NR-NR) nor with placebo (95% CI, 50.3-NR), leading to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.58-0.92) with the pembrolizumab regimen. The 4-year OS rates were 68.0% and 56.7%, respectively.

Additionally, the median event-free survival (EFS) was 57.1 months (95% CI, 38.0-69.1) with pembrolizumab vs 18.4 months (95% CI, 14.8-22.1) with placebo (HR, 0.57; 95% CI, 0.47-0.69). The 4-year EFS rates were 51.9% and 28.1%, respectively.

“These long-term follow-up results continue to support perioperative pembrolizumab as a standard-of-care treatment option for resectable, early-stage non–small cell lung cancer,” lead study author Margarita Majem Tarruella, MD, PhD, of the Department of Medical Oncology in the Hospital de la Santa Creu i Sant Pau, in Barcelona, Spain, said in an oral presentation during the meeting.

In the multicenter, double-blind, placebo-controlled, KEYNOTE-671, investigators compared neoadjuvant pembrolizumab plus chemotherapy followed by surgery and adjuvant pembrolizumab with neoadjuvant placebo and chemotherapy and surgery alone in patients with resectable, early-stage NSCLC.

A total of 797 patients with previously untreated and resectable stage II, IIIA, or IIIB NSCLC by the American Joint Committee on Cancer 8th edition criteria were enrolled, regardless of PD-L1 expression.²

Patients with an active autoimmune disease that required systemic therapy within 2 years of study treatment, a medical condition that required immunosuppressive treatment, or those with a history of interstitial lung disease or pneumonitis that required steroids, were excluded from enrollment.

Patients were randomized 1:1 to the pembrolizumab arm (arm A) or the placebo arm (arm B). Patients received 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. Following 4 to 12 weeks of surgery, patients then received placebo or single-agent pembrolizumab at 200 mg every 3 weeks for up to 13 cycles.

Treatment was continued until all 17 cycles were completed, or patients experienced progressive disease that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not receive surgery or who had incomplete resection and entered the adjuvant phase, or intolerable toxicity.

Stratification factors included disease stage (II vs III), PD-L1 expression (tumor proportion score [TPS] of ≥50% vs <50%), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia).

The primary end points were OS and investigator-assessed EFS, with secondary outcome measures comprising pathologic complete response rate and major pathologic response rate per blinded independent pathology review.

Earlier data from interim analyses showed that the pembrolizumab regimen significantly improved EFS and OS vs the placebo regimen. At the interim analyses, the 3-year EFS rates were 54.3% vs 35.4% (HR, 0.59; 95% CI, 0.48-0.72)² and the 3-year OS rates were 71.3% vs 64.0% (HR, 0.72; 95% CI, 0.56-0.93; P = .0052).

Data from KEYNOTE-671 led to the October 2023 FDA approval of perioperative pembrolizumab in the United States, Europe, and more for this patient population.

At the 2024 ESMO Immuno-Oncology Congress, Tarruella reported on the updated EFS and OS findings of KEYNOTE-671 from approximately 4 years of follow-up, which included a data cutoff date of August 19, 2024.

Baseline characteristics in the intent-to-treat population were similar between the 2 arms. The median age was 63.5 years (range, 26-83), 70.7% of patients were male, and 61.4% were White. Most were not from East Asia (69.4%) and had an ECOG performance status of 0 (62.6%). More than half had nonsquamous histology (56.9%), were former smokers (62.3%), and had clinical stage III disease (70.1%). Patients either had PD-L1 TPS of at least 50% (33.3%), 1% to 49% (30.4%), or less than 1% (36.3%). A total 4.2% and 2.7% of patients had known EGFR and ALK translocations, respectively.

The OS benefit with pembrolizumab was observed across most patient subgroups, except for those who were at least 65 years old (HR, 1.01; 95% CI, 0.73-1.41) and were never smokers (HR, 1.08; 95% CI, 0.47-2.50). The EFS benefit with pembrolizumab was observed across all key subgroups, Tarruella noted.

Regarding safety, no new safety signals were observed with the longer follow-up. Treatment-related AEs (TRAEs) occurred in 96.7% and 95.5% of pembrolizumab- (n = 396) and placebo-treated patients (n = 399), respectively; grade 3 to 5 TRAEs occurred in 45.2% and 37.8%, respectively. Serious TRAEs were reported in 18.4% and 14.8% of patients. In the pembrolizumab arm, 4 patients died due to TRAEs compared with 3 in the placebo arm; treatment discontinuations occurred in 19.4% and 13.3% of patients, respectively.

Furthermore, immune-mediated AEs and infusion reactions occurred in 26.0% and 9.3% of patients on the pembrolizumab and placebo arms, respectively, with grade 3 to 5 events in 6.3% and 1.8% of patients, respectively; these AEs were serious in 6.1% and 1.8% of patients. There was 1 patient death from immune-mediated AEs/infusion reactions on the pembrolizumab arm; 6.1% of patients who experienced these AEs on the pembrolizumab led to treatment discontinuation vs 0.8% on the placebo arm.

Disclosures: Dr Tarruella cited speaker fees from Amgen, AstraZeneca, Casen Recordati, Helsinn, Pfizer, Roche, and Takeda; advisory board fees from Amgen, AstraZeneca, Bristol Myers Squibb, Casen Recordati, Janssen, Pfizer, Roche, Sanofi, and Takeda; and fees to the institution from AstraZeneca, Bristol Myers Squibb, and Roche; research funding support from Merck Sharp & Dohme LLC; and medical writing assistance provided by Young-A Heo, PhD, of ICON plc, which was funded by MSD.

References

1. Tarruella MM, Garassino M, Zhao G, et al. Perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) in early-stage non-small-cell lung cancer (NSCLC): a 4-year update of KEYNOTE-671. Immuno-Oncology and Technology. 2024;24(suppl 101027). doi:10.1016/j.iotech.2024.101027
2. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Eng J Med. 2023;389(6):491-503. doi:10.1056/NEJMoa2302983
3. Spicer JD, Garassino MC, Wakelee H, et al. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;404(10459):1240-1252. doi:10.1016/S0140-6736(24)01756-2
4. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed December 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer