Preoperative pembrolizumab regimen sets a new standard of care for resectable early-stage non-small cell lung cancer

Previously, several phase 3 studies have failed to demonstrate a survival benefit of PD-1 and PD-L1 inhibitor-based therapies in the treatment of resectable early-stage non-small cell lung cancer (NSCLC) patients. Results from KEYNOTE-671 presented at ESMO 2023 now demonstrate a substantial overall survival benefit with neoadjuvant pembrolizumab combined with chemotherapy, followed by surgery and adjuvant pembrolizumab, compared to neoadjuvant chemotherapy and surgery alone, establishing this regimen as a novel standard of care for patient with resectable, early-stage NSCLC.

PD-1 and PD-L1 inhibitor-based therapies have become the established standard of care for patients with  advanced or metastatic non-small cell lung cancer (NSCLC) in the absence of targetable genetic abnormalities. In recent years, several phase 3 studies have also explored regimens involving PD-1 and PD-L1 inhibitors in the treatment of early-stage NSCLC. However, none of these regimens was able to demonstrate a statistically significant improvement in overall survival (OS). At the protocol-specified first interim analysis of the phase 3 KEYNOTE-671 study, neoadjuvant pembrolizumab combined with chemotherapy followed by surgical resection and adjuvant pembrolizumab was shown to significantly improve the event-free survival (EFS), the major pathological response (mPR), and pathologic complete response (pCR) compared to neoadjuvant chemotherapy and surgery alone in patients with resectable, early-stage NSCLC. The results from the protocol-specified second interim analysis of this trial were presented at ESMO 2023.

Methods

The phase 3 KEYNOTE-671 trial enrolled patients with resectable, stage II, IIIA, or IIIB (N2) NSCLC who had not received prior therapy. In total, 795 patients were assigned (1:1) to receive neoadjuvant chemotherapy (cisplatin and gemcitabine or cisplatin and pemetrexed) for up to four cycles with or without pembrolizumab 200 mg IV Q3W. Subsequently, patients underwent surgery followed by adjuvant pembrolizumab 200 mg IV Q3W or placebo for up to 13 cycles. Dual primary endpoints were EFS and OS), with the rate of mPR and pCR as key secondary objectives

Results

After a median follow-up of 36.6 months, the use of pembrolizumab in the preoperative setting was associated with a significant improvement in OS in patients with resectable NSCLC (HR[95%CI]: 0.72[0.56-0.93]; p=0.00517). The median OS was not reached in the pembrolizumab arm, while it was 52.4 months in the control arm. At 3 years, 71.3% of patients receiving pembrolizumab were still alive as compared to 64.0% in the control group. Interestingly, this benefit continued to increase over time, with estimated 4-year OS rates of 67.1% vs. 51.5%, respectively. PD-L1 expression was associated with a greater OS benefit, while histological subtype or nodal status did not significantly impact outcomes. In terms of EFS, there was a notable benefit with pembrolizumab at 36 months, with a rate of 54.3% as compared to 35.4% in the control arm. The median EFS was reported at 47.2 months with perioperative pembrolizumab as compared to 18.3 months with the control regimen, translating into a an HR of 0.59 (95%CI: 0.48-0.72).

Treatment-related AEs of grade ≥3 occurred in 45.2% of patients in the pembrolizumab arm vs. 37.8% in the control arm. These events led to treatment discontinuation in 20.2% vs. 9.3% of patients, and resulted in death in 1.0% and. 0.8%, respectively. No new treatment-related deaths were observed since the first interim analysis. While treatment-related AEs with an incidence ≥10% were similar between the groups, immune-mediated AEs were more common among patients receiving pembrolizumab, with hypothyroidism (10.9% vs. 1.5% in the pembrolizumab and placebo groups, respectively) and pneumonitis (6.1% vs. 1.8%) being the most frequent. The incidence of grade 3-5 immune-mediated AEs remained low.

Conclusions

The phase 3 KEYNOTE-671 demonstrated a significant OS improvement with neoadjuvant pembrolizumab plus chemotherapy followed by surgery and adjuvant pembrolizumab compared to neoadjuvant chemotherapy and surgery alone. The observed OS benefit in KEYNOTE-671, without the emergence of new safety concerns, establishes the perioperative pembrolizumab regimen as a new standard of care for patients with resectable, early-stage NSCLC.

Reference

Spicer JD. Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC). Presented at ESMO 2023; Abstract LBA56.