Analysis Further Shows Perioperative Pembrolizumab Efficacy in Early-Stage NSCLC

David R. Jones, MD

The neoadjuvant combination of pembrolizumab (Keytruda) plus chemotherapy led to greater pathologic regression based on percent residual volume tumor (%RVT) vs placebo plus chemotherapy in patients with early-stage non–small cell lung cancer (NSCLC), according to a post hoc analysis of the phase 3 KEYNOTE-671 trial [NCT03425643] presented at the IASLC 2024 World Conference on Lung Cancer.¹

In the overall KEYNOTE-671 trial, 797 patients with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were randomized in a 1:1 ratio to receive neoadjuvant chemotherapy plus either pembrolizumab (n = 397) or placebo (n = 400), followed by adjuvant pembrolizumab in the treatment arm or placebo in the control arm. Data from the overall study population showed statistically significant improvements in overall survival (OS) and event-free survival (EFS) in the pembrolizumab vs the placebo arm. Pathological complete response (pCR) and major pathologic response (mPR) were also improved with pembrolizumab.

An exploratory analysis from KEYNOTE-671 found that there was an EFS benefit with pembrolizumab vs placebo among patients who reached a pCR or mPR. However, David R. Jones, MD, Memorial Sloan Kettering Cancer Center, explained at the IASLC conference that “stratification using only pCR or mPR does not address the pathologic response and its relationship to EFS in a more granular manner and may, in fact, be oversimplified.”

Accordingly, Jones et al sought to close this knowledge gap by assessing the “efficacy of perioperative pembrolizumab across different RVT cutpoints, beyond pCR and mPR.” To categorize pathological regression, the researchers in the KEYNOTE-671 study evaluated data from 620 patients who had received neoadjuvant treatment and surgery and had evaluable tissue to be reviewed by blinded independent pathology.

Baseline patient characteristics for these 620 patients were balanced between the pembrolizumab (n = 320) and placebo (n = 300) arms. In the pembrolizumab group, the median age was 63 years (range 26-83), 67.8% were male, and the majority were White (62.2%) or Asian (31.3%). The ECOG performance status was 0 (65.6%) or 1 (34.4%). Regarding histology, 59.1% were nonsquamous and 40.9% were squamous. Tumor (T) status was T1 (15.3%), T2 (29.4%), T3 (29.4%), and T4 (25.9%). Nodal status was pN0 (36.6%), pN1 (20.9%), and pN2 (42.5%). Regarding PD-L1 tumor proportion score, about one-third of patients fell into each of the categories: ≥50%, 1%-49%, and <1%. Most patients were either current (23.1%) or former (63.4%) smokers.

Among this population of patients with pathologically evaluable tumors, the median %RVT was 29.5% (interquartile range [IQR], 1.0-56.0) in the pembrolizumab arm) vs 52.0% (IQR, 29.0-68.0) in the placebo arm. Jones et al also stratified patients into 4 categories based on %RVT in the primary lung tumor and sampled lymph nodes. Among the 4 stratified RVT groups, the %RVT for the pembrolizumab vs control groups was 31.9% vs 12.3% (0%-≤5% RVT); 19.1% vs 14.7% (>5%-≤30% RVT); 31.6% vs 38.0% (>30%-≤60% RVT); and 17.5% vs 35.0% (>60% RVT). Jones said that as expected, lower %RVT was associated with more favorable EFS, regardless of treatment arm.

When assessing the relationship within the %RVT categories, the EFS was higher in the pembrolizumab arm vs the placebo arm across all groups: 0%-≤5% RVT (HR, 0.58); >5%-≤30% RVT (HR, 0.73); >30%-≤60% RVT (HR, 0.65); and >60% RVT (HR, 0.90).

“Perioperative pembrolizumab demonstrated clinically significant EFS benefits that extend to patients with residual viable tumors after neoadjuvant treatment; this supports the benefit of a perioperative regimen of neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab for early-stage NSCLC,” said Jones, adding that, “Further studies are needed to validate %RVT for evaluation of outcomes in this patient population.”

Overall KEYNOTE-671 trial

In the double-blind, multicenter KEYNOTE-671 trial, patients with early-stage NSCLC received neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks.^2,3 Patients in both arms also received 4 cycles of chemotherapy, which consisted of cisplatin plus either pemetrexed (nonsquamous histology) or gemcitabine (squamous histology) and was administered every 3 weeks. All patients then underwent surgery, which was followed by adjuvant pembrolizumab (200 mg) in the treatment arm or placebo in the control arm once very 3 weeks for a maximum of 13 cycles.

At the first interim analysis, the 24-month EFS rate was 62.4% vs 40.6% in the pembrolizumab vs control arms, respectively (HR, 0.58; 95% CI, 0.46-0.72; P <.00001).^2,3 The mPR and pCR rates were 30.2% vs 11.0% (P <.00001) and 18.1% vs 4.0% (P <.00001), respectively.^2,3

The second interim analysis showed that at 36 months, the EFS rates were 54.3% vs 35.4%, respectively (HR, 0.59; 95% CI, 0.48-0.72).⁴ It was also shown at this analysis that the pembrolizumab regimen led to a statistically significant improvement in OS. The median OS was not yet reached (95% CI, not estimable [NE]-NE) in the pembrolizumab arm vs 52.4 months (95% CI, 45.7-NE) in the placebo arm (HR, 0.72; 95% CI, 0.56-0.93; P = .00517).⁴ The 36-month OS rates were 71.3% in the pembrolizumab arm vs 64.0% in the control arm.⁴

Based on data from KEYNOTE-671 trial, the FDA approved pembrolizumab in October 2023 for use in combination with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of pembrolizumab monotherapy as post-surgical adjuvant treatment for patients with resectable NSCLC.⁵ The regimen also has a category 1 recommendation in this setting in the NCCN guidelines.

References

1. Jones DR, Wakelee H, Spicer JD, et al. Association of Pathologic Regression With Event-Free Survival in the KEYNOTE-671 Study of Perioperative Pembrolizumab for Early-Stage NSCLC. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-11, 2024; San Diego, CA. Abstract OA01.03
2. 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
3. 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. June 3, 2023. doi:10.1056/NEJMoa2302983
4. Spicer JD, Gao S, Liberman M, et al. Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC). Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA56
5. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. September 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer