News from KEYNOTE-671 in early-stage non–small cell lung cancer provides more evidence to support the FDA approval application for perioperative pembrolizumab.
KEYNOTE-671 findings presented at the 2023 ASCO Annual Meeting show that adding pembrolizumab (Keytruda) to neoadjuvant platinum-based chemotherapy followed by resection and adjuvant pembrolizumab alone led to significant improvement in event-free survival (EFS) and pathological response for patients with early-stage non–small cell lung cancer (NSCLC). The data were simultaneously published in the New England Journal of Medicine.1,2
In the double-blind study, the 24-month EFS rate was 62.4% with pembrolizumab plus chemotherapy and adjuvant pembrolizumab compared with 40.6% for placebo plus chemotherapy (HR, 0.58; 95% CI, 0.46-0.72; P < .00001). The major pathologic response (mPR) rate was 30.2% (95% CI, 25.7%-35.0%) with pembrolizumab compared with 11.0% (95% CI, 8.1%-14.5%) with placebo (Δ, 19.2%; 13.9%-24.7%; P < .00001). The pathological complete response (pCR) rate was 18.1% (95% CI, 14.5%-22.3%) with pembrolizumab compared with 4.0% (95% CI, 2.3%-6.4%) for placebo (Δ, 14.2%; 95% CI, 10.1%-18.7%; P < .00001). Overall survival (OS) data were immature at the time of the analysis, with a 24-month OS rate of 80.9% observed in the pembrolizumab arm compared with 77.6% in the placebo arm (HR, 0.73; 95% CI, 0.54-0.99; P = .02124).
“Neoadjuvant pembrolizumab plus chemotherapy followed by surgery and adjuvant pembrolizumab provided statistically significant, clinically meaningful improvement in EFS compared with neoadjuvant chemotherapy and surgery alone,” said lead investigator Heather Wakelee, MD, from Stanford University School of Medicine and the Stanford Cancer Institute. “Data support perioperative pembrolizumab as a promising new treatment option for patients with resectable stage II, IIIA, or IIIB NSCLC.”
In the KEYNOTE-671 trial (NCT03425643), patients were randomly assigned to receive chemotherapy plus pembrolizumab (n = 397) or placebo (n = 399). Pembrolizumab was administered at 200 mg intravenously every 3 weeks in the neoadjuvant setting for 4 cycles and the adjuvant setting for 13 cycles. Chemotherapy was administered every 3 weeks and consisted of cisplatin plus either pemetrexed for nonsquamous histology or gemcitabine for those with squamous histology. Every 3 weeks, cisplatin was administered at 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 arms. In the pembrolizumab group, the median age was 63 years, 70.3% were male, and the ECOG performance status was 0 (63.7%) or 1 (36.3%). Two-thirds of patients were White (63%) and 31.2% were Asian, primarily from non-East Asian countries (69.0%). Histology was balanced at 56.9% nonsquamous and 43.1% squamous. A quarter of patients were current smokers (24.2%) 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%). Nearly half of patients had N2 disease (42.3%), with the remainder having N1 (20.4%) or N0 (37.3%).
PD-L1 status by tumor proportion score was balanced with a 33.2% having PD-L1 expression of 50% or greater and 34.8% having less than 1% expression of PD-L1. 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 approximately two-thirds of patients.
Of the patents who entered the neoadjuvant phase, 87.4% completed 3 or more cycles of treatment in the pembrolizumab arm compared with 87.2% in the placebo group. There were 342 patients in the pembrolizumab arm who proceeded to surgery vs 335 in the placebo group, with 325 actually undergoing surgery in the pembrolizumab arm and 317 in the placebo group. Of those who underwent surgery, 290 received 1 or more doses of adjuvant therapy in the investigational arm compared with 267 in the placebo group. Slightly more than one third completed 13 cycles of adjuvant therapy in the pembrolizumab arm (40.4%) compared with 35.4% in the placebo group. Adjuvant therapy was ongoing for 10.6% and 11.3% of patients, in the investigational and control arms, respectively.
There were more complete R0 resections in the pembrolizumab arm compared with the placebo group, with 92.0% of patients receiving an R0 resection in the PD-1 inhibitor arm compared with 84.2% in the placebo group. Incomplete R1 resections occurred in 5.2% and 9.8% of patients in the pembrolizumab and placebo groups, respectively. The most common type of surgery was a lobectomy, which occurred in 78.8% of patients in the pembrolizumab arm and 75.1% in the placebo group.
The median follow-up at the July 29, 2022, data cutoff was 25.2 months. At this point, 35.0% of patients in the pembrolizumab arm had experienced an event, defined as local progression, progression, recurrence, or death. In the placebo arm, 51.3% of patients had experienced an event. The median EFS was not yet reached with pembrolizumab (95% CI, 34.1-not reached) compared with 17.0 months for the placebo arm (95% CI, 14.3-22.0).
EFS was consistently improved across subgroups, Wakelee noted, including those with driver mutations. She drew attention to a few key groups, noting that outcomes were similar by histology, PD-L1 expression level, and stage. For histology, the HRs were 0.58 for nonsquamous and 0.57 for squamous, both favoring pembrolizumab. By PD-L1 expression, there was an HR of 0.77 for those with PD-L1 expression less than 1%. The HRs were 0.51 and 0.42 for those with 1% to 49% expression and 50% expression or more, respectively. The HRs were 0.65, 0.54, and 0.52 for those with stage II, IIIA, and IIIB disease, respectively.
At the time of the data cutoff, 19.1% and 25.3% of patients had died from any cause in the pembrolizumab and placebo arms, respectively. The median OS was not yet reached for those in the pembrolizumab group compared with 45.5 months for the placebo arm (95% CI, 42.0-not reached).
“The KEYNOTE-671 trial and other perioperative immunotherapy studies represent a major advance as new standards of care for the treatment of resectable lung cancer,” said ASCO discussant Mark M. Awad, MD, PhD, from Harvard Medical School and the Dana-Farber Cancer Institute. “Although data are immature, there appears to be an encouraging signal for OS benefit favoring the neoadjuvant with or with adjuvant immunotherapy approach.”
In an exploratory analysis, EFS was examined by neoadjuvant response. For those with a pCR, the benefit for pembrolizumab was more pronounced 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). Similar findings were found with mPR, although less pronounced. 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).
“Neoadjuvant immunotherapy leads to high rates of mPR and pCR in a variety of solid tumors, and mPR and pCR after neoadjuvant immunotherapy are associated with excellent outcome,” said commenter Myriam Chalabi, MD, PhD, from the Netherlands Cancer Institute. “De-escalation of systemic therapy, less extensive surgery, and omission of surgery are realistic options to consider.”
Treatment-related adverse events (AEs) were similar between treatment groups, with grade 3 to 5 events experienced by 44.9% of patients in the pembrolizumab arm and 37.3% of those in the placebo group. Serious AEs were experienced by 17.7% and 14.3%, respectively. The most pronounced AE differences were observed for immune-mediate AEs, including infusion reactions, Wakelee noted. Immune-mediate AEs occurred in 25.3% of patients treated with pembrolizumab compared with 10.5% in the placebo group. There was 1 death related to an immune-mediate AE in the pembrolizumab arm. Immune-mediate AEs led to pembrolizumab discontinuation for 5.1% of patients.
The most common AEs were those frequently associated with platinum-based chemotherapy, Wakelee said. These include nausea, neutropenia, anemia, leukopenia, and fatigue. The most common all-grade, immune-mediate AEs for pembrolizumab and placebo, respectively, were hypothyroidism (11.1% vs 1.8%), hyperthyroidism (5.6% vs 3.3%), and pneumonitis (5.6% vs 1.8%). “The AE profile was as expected, based on the known profiles of the individual treatment components,” Wakelee said.
Merck, the developer of pembrolizumab, has already submitted a supplemental new drug application to the FDA, based on findings from the KEYNOTE-671 study. The proposed indication is for the treatment of patients with resectable stage II, IIIA, or IIIB NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment. The FDA is expected to make a decision on the application by October 16, 2023.3
1. Wakelee HA, Liberman M, Kato T, et al. KEYNOTE-671: randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. J Clin Oncol. 2023;41 (suppl 17):LBA100. doi:10.1200/JCO.2023.41.17_suppl.LBA100
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’s Keytruda (pembrolizumab) plus chemotherapy before surgery and continued as a single agent after surgery reduced the risk of event-free survival events by 42% versus pre-operative chemotherapy in resectable stage II, IIIA or IIIB NSCLC. News release. Merck. June 3, 2023. Accessed June 3, 2023. https://www.merck.com