Patrick M. Forde, MBBCh, PhD
An examination of patient-level data from the phase III CheckMate 816 and CheckMate 77T trials supports the perioperative use of the PD-1 inhibitor nivolumab plus chemotherapy, as compared with the neoadjuvant use of nivolumab plus chemotherapy without adjuvant therapy, in resectable non–small cell lung cancer (NSCLC). The findings were presented at the International Association for the Study of Lung Cancer 2024 World Conference on Lung Cancer by Patrick M. Forde, MBBCh, PhD, Co-Director of the Division of Upper Aerodigestive Malignancies and Director of the Thoracic Oncology Clinical Research Program at Johns Hopkins Medicine.1
Patients who received at least one dose of adjuvant nivolumab following neoadjuvant nivolumab plus chemotherapy and surgery experienced a 39% reduction in the risk of disease recurrence or death, as compared with patients who were treated with nivolumab plus chemotherapy solely in the neoadjuvant setting.
“In the absence of a randomized controlled trial, this analysis represents the only comparison of perioperative vs neoadjuvant-alone immunotherapy for patients with resectable NSCLC, using individual patient-level data from two randomized phase III trials…. It further supports perioperative use of nivolumab as a treatment option for eligible patients,” Dr. Forde said.
About the Study
In CheckMate 77T, patients received neoadjuvant nivolumab plus chemotherapy followed by definitive surgery and at least one dose of adjuvant nivolumab (N = 139). In CheckMate 816, patients received neoadjuvant nivolumab plus chemotherapy followed by definitive surgery (N = 147). Patients had stage IB to stage III N2 disease; about half the patients had squamous histology, and about half had PD-L1 expression ≥ 1%
Exploratory propensity score–weighting analyses were performed to allow simplified reproduction of a randomized trial; this analysis adjusts for and reduces the confounding effects of baseline demographics and disease characteristics between the study populations. The primary endpoint was event-free survival by blinded independent central review, landmarked from the time of surgery.
Benefit Shown With Perioperative Use of Nivolumab
At a median follow-up of about 30 months, the analysis showed added benefit in the weighted average treatment effect for patients who received nivolumab perioperatively compared with patients who received nivolumab plus chemotherapy in the neoadjuvant setting (hazard ratio [HR] = 0.61; 95% confidence interval [CI] = 0.39–0.97). Additionally, Dr. Forde added these comments: “When we performed an unweighted analysis of all patients who had surgery, and irrespective of whether they received adjuvant nivolumab in the CheckMate 77T trial (HR = 0.59; 95% CI = 0.38–0.92), it also trended in favor of perioperative therapy.”
When the landmark event-free survival analysis was stratified based on pathologic complete response, PD-L1 expression, or stage, the outcomes again favored perioperative use of nivolumab compared with neoadjuvant use of nivolumab plus chemotherapy. “Similar benefit was seen regardless of baseline stage, with a greater magnitude of benefit seen in patients with tumor PD-L1 expression < 1% (HR = 0.51; 95% CI = 0.28–0.93). Perioperative use of nivolumab also improved event-free survival benefit for patients without a pathologic complete response (HR = 0.65; 95% CI = 0.40–1.06),” Dr. Forde stated. He explained that patients achieving a pathologic complete response “are already doing very well from neoadjuvant therapy.”
Perioperative use of nivolumab had a generally manageable safety profile. Treatment-related adverse events of any grade leading to discontinuation of therapy occurred in 16% of the perioperative treatment group, compared with 11% of those not receiving adjuvant nivolumab; surgery-related adverse events were noted in 38% vs 42%, respectively.
Implications for Clinical Practice
In a press briefing, Dr. Forde was asked whether all patients with resectable NSCLC should receive perioperative immunotherapy. “This study shows there are patients who benefit from further immunotherapy after neoadjuvant chemoimmunotherapy. Now, whether all patients benefit, that’s less likely…. There are likely some subgroups who derive benefit, and some who do not,” he responded.
The analysis suggests, he explained, that patients not deriving as much benefit from neoadjuvant-alone treatment are those most likely to benefit from more treatment. This includes patients with PD-L1–negative tumors and those not achieving a pathologic complete response. “Those are two groups at higher risk of relapse,” stated Dr. Forde. “You’re not trying to push their relapse-free survival from 95% to 96%, but you might be trying to improve it from 55% to 70%, which is a bigger increment.”
EXPERT POINT OF VIEW
Nan Wu, MD
The invited discussant of the patient-level data analysis of CheckMate 8162 CheckMate 77T3 was Nan Wu, MD, of Peking University Cancer Hospital in Beijing. He commented that the direct comparison of perioperative nivolumab to neoadjuvant-alone nivolumab, based on this analysis, “support perioperative nivolumab as a treatment option for eligible patients with resectable non–small cell lung cancer.”
Previous studies comparing neoadjuvant-alone vs perioperative use of immunotherapy have yielded conflicting results, Dr. Wu noted, with some showing a lack of survival benefit with continued treatment. Dr. Forde’s study, however, which represents the first direct comparison of these approaches, “indicated superiority” of perioperative as compared with neoadjuvant-alone treatment. “After [propensity score] weighting, we saw about a 40% reduction in the risk of recurrence or death with perioperative nivolumab, with a safety profile that was comparable between two approaches. Of course, a randomized controlled trial is needed for a solid conclusion,” he said.
Aligning with prior findings, the study showed particular benefit for adding adjuvant nivolumab in patients not achieving a pathologic complete response. The same goes for patients with PD-L1–negative tumors, where a 49% reduction in risk was observed, Dr. Wu added. “However, these data were not weighted, the sample sizes are small, and we need validation…. And in the future, we need to answer which of these prognostic markers might be better for both treatment approaches.”
DISCLOSURE: Dr. Forde has served as a consultant to Amgen, Ascendis, AstraZeneca, Bristol Myers Squibb, Curevac, F Star, Foresight, Fosun, G1, Genelux, Genentech, Gritstone, Iteos, Janssen, Merck, Novocure, Regeneron, Sanofi, Synthekine, Tavotek, Teva, and Veracyte. Dr. Wu reported no conflicts of interest.
REFERENCE
1. Forde PM, Peters S, Donington J, et al: Perioperative vs neoadjuvant nivolumab for resectable NSCLC: Patient-level data analysis of CheckMate 77T vs CheckMate 816. 2024 World Conference on Lung Cancer. Abstract PL02.08. Presented September 8, 2024.
2. Forde PM, Spicer J, Lu S, et al: Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 386:1973-1985, 2022.
3. Cascone T, Awad MM, Spicer JD, et al: Perioperative nivolumab in resectable lung cancer. N Engl J Med 390:1756-1769, 2024.
