EFS benefit greater with perioperative vs neoadjuvant-only nivolumab in resectable NSCLC

Including adjuvant nivolumab as part of a perioperative regimen for resectable non–small cell lung cancer (NSCLC) further improves the event-free survival (EFS) benefit vs including nivolumab in a neoadjuvant-only setting, as suggested by a patient-level data analysis of the phase III CheckMate 77T and CheckMate 816 trials investigating each modality separately.

Perioperative nivolumab, with ≥1 dose of adjuvant nivolumab, reduced the risk of recurrence or death after surgery by 39 percent vs neoadjuvant-only nivolumab (hazard ratio [HR], 0.61, 95 percent confidence interval [CI], 0.39–0.97), after adjusting for clinically relevant confounders between the active arms of both trials using propensity score weighting with the average treatment effect (ATE).

In another analysis weighted by the ATE for the treated, the magnitude of risk reduction was largely consistent at 44 percent (HR, 0.56, 95 percent CI, 0.35–0.90). [WCLC 2024, abstract PL02.08]

Which patients benefit from adjuvant nivolumab?

“Now that we have these two regimens available to us, a key clinical question that arises is which patients derive benefit from adjuvant nivolumab following neoadjuvant nivolumab plus chemotherapy and surgery,” said Dr Patrick Forde from Johns Hopkins Medicine in Baltimore, Maryland, US, at a plenary session at WCLC 2024, highlighting the rationale behind this exploratory analysis.

Unweighted subgroup analyses were performed to address this question. In both groups of patients with and without a pathologic complete response (pCR), the HRs for EFS trended in favour of perioperative vs neoadjuvant-only nivolumab (HR, 0.58, 95 percent CI, 0.14–2.40 [with pCR] and HR, 0.65, 95 percent CI, 0.40–1.06 [no pCR]). However, “there is an emerging separation” of the Kaplan-Meier curves favouring perioperative nivolumab in patients without a pCR, noted Forde.

For patients with PD-L1 expression <1 percent, perioperative nivolumab reduced the risk of an EFS event by 49 percent vs neoadjuvant-only nivolumab (HR, 0.51, 95 percent CI, 0.28–0.93). For those with PD-L1 expression ≥1 percent, the HR trended in favour of the perioperative approach (HR, 0.86, 95 percent CI, 0.44–1.70).

"A possible explanation for this is that, in the PD-L1–positive group, the effects of neoadjuvant treatment may capture the majority of the true effect, possibly by achieving higher pCR rates," commented discussant Professor Nan Wu from the Peking University Cancer Hospital, Beijing, China. “We also need more validation.”

In lieu of a head-to-head trial

To allow for a simplified reproduction of a randomized trial, the two groups of patients (n=286) receiving nivolumab who underwent definitive surgery in two different trials were adjusted for comparability. [N Engl J Med 2022;386:1973-1985; N Engl J Med 2024;390:1756-1769]

“In the near future, we will not have a randomized controlled trial available to us to guide clinical decisions, and this analysis at present represents the only comparison of perioperative vs neoadjuvant-only immunotherapy treatment for patients with resectable lung cancer,” said Forde.

As one audience member pointed out, the preoperative use of nivolumab plus chemotherapy differed between the two trials (three cycles in CheckMate 816 vs up to four cycles in CheckMate 77T), raising questions about the justification for assessing the EFS by landmarking from the time of surgery instead of using an intention-to-treat analysis.

"The idea here was to try to isolate the effect of the adjuvant therapy,” responded Forde. Given that not all patients could start from baseline and proceed to the adjuvant course uneventfully, Forde and colleagues chose to compare the EFS benefits following surgery between the two approaches.

Nevertheless, based on the overall similar results from two different weighting methodologies, "what it does is provide us with some guidance in the darkness for this population," commented Forde.