In exploratory analyses of a randomised, open-label, international phase III CheckMate 816 study, numerically improved event-free survival (EFS), overall survival (OS), pathologic complete response (pCR), and major pathologic response (MPR) rates and a greater depth of pathologic response were observed with neoadjuvant nivolumab plus ipilimumab versus chemotherapy in patients with resectable non-small cell lung cancer (NSCLC). Neoadjuvant nivolumab plus ipilimumab had a safety profile that was similar to previous reports.
However, the higher rate of early EFS events preclude use of neoadjuvant nivolumab plus ipilimumab in routine clinical care and nivolumab plus chemotherapy remains the standard neoadjuvant treatment for eligible patients with resectable NSCLC according to Dr. Mark M. Awad of the Dana-Farber Cancer Institute in Boston, MA, US and colleagues, who published the findings on 8 January 2025 in the JCO.
The CheckMate 816 study demonstrated statistically significant improvement with neoadjuvant nivolumab plus chemotherapy versus neoadjuvant chemotherapy in EFS (hazard ratio [HR] 0.63, 97.38% confidence interval [CI] 0.43 to 0.91; p = 0.005) and pCR (24.0% versus 2.2%; odds ratio [OR] 13.94, 99% CI 3.49 to 55.75; p < 0.001). Four-year follow-up results from this study showed durable and clinically relevant improvement in OS (HR 0.71, 98.36% CI 0.47 to 1.07) with neoadjuvant nivolumab plus chemotherapy versus chemotherapy.
Nivolumab plus ipilimumab has shown long-term, durable survival benefit in several phase III studies conducted in patients with advanced cancers, including NSCLC. Furthermore, in the phase II NEOSTAR study, neoadjuvant nivolumab plus ipilimumab with or without concurrent chemotherapy showed promising results in patients with resectable NSCLC.
In the latest article published in the JCO, the investigators report exploratory efficacy, surgical outcomes, and biomarker analyses including circulating tumour DNA (ctDNA) levels and four-gene inflammatory score, as well as the neoadjuvant nivolumab plus ipilimumab versus chemotherapy safety data from the phase III CheckMate 816 study conducted in patients with resectable NSCLC.
Adult patients with stage IB-IIIA (AJCC 7th edition) resectable NSCLC received three cycles of nivolumab once every 2 weeks plus one cycle of ipilimumab or three cycles of chemotherapy (on day 1 or days 1 and 8 of each 3-week cycle) followed by surgery. Analyses included EFS, OS, pathologic response, surgical outcomes, biomarker analyses, and safety.
A total of 113 patients were concurrently randomly assigned to neoadjuvant nivolumab plus ipilimumab and 108 to chemotherapy. At a median follow-up of 49.2 months, the median EFS was 54.8 months (95% CI 24.4 to not reached [NR]) with neoadjuvant nivolumab plus ipilimumab versus 20.9 months (95% CI 14.2 to NR) with chemotherapy (HR 0.77, 95% CI 0.51 to 1.15); 3-year EFS rates were 56% versus 44%.
Higher rates of EFS events were initially seen, with later benefit favouring neoadjuvant nivolumab plus ipilimumab; 3-year OS rates were 73% versus 61% (HR 0.73, 95% CI 0.47 to 1.14); pCR rates were 20.4% versus 4.6%, respectively. In the respective arms, 83 (74%) and 82 patients (76%) underwent definitive surgery. Grade 3-4 treatment-related adverse events occurred in 14% and 36% of patients, respectively.
The efficacy and safety data for nivolumab plus ipilimumab should be weighed against the surgical outcomes observed in this study. Rates of disease progression precluding surgery were numerically higher in the nivolumab plus ipilimumab arm versus the chemotherapy arm and also higher compared with previous reports of anti–PD-(L)1 agents plus chemotherapy although cross-trial comparisons should be performed with caution.
Of note, 18 of 29 (62%) patients with cancelled surgery in the nivolumab plus ipilimumab arm had disease progression compared with 9 of 21 (43%) in the chemotherapy arm; however, surgery cancellations in the chemotherapy arm were mostly due to reasons other than disease progression.
There was a higher R0 resection rate in the nivolumab plus ipilimumab arm (80%) versus the chemotherapy arm (71%) among patients who did undergo surgery, and recurrence rates after surgery were also lower (23% versus 44%), including distant recurrence in the CNS (2% versus 13%).
Therefore, a key consideration for nivolumab plus ipilimumab would be to minimise the risk of disease progression that can potentially preclude surgery for patients with initially resectable disease as surgical resection is necessary to achieve optimal outcomes.
An association of pCR with prolonged EFS was observed with nivolumab plus ipilimumab, consistent with findings reported previously for other immunotherapy-based regimens for patients with resectable NSCLC, supporting pathologic response as an emerging surrogate for survival benefit in patients receiving neoadjuvant treatment.
In CheckMate 816, only 32% of patients in the nivolumab plus ipilimumab arm and 28% in the chemotherapy arm had evaluable ctDNA levels. In both arms, ctDNA levels were reduced after neoadjuvant treatment although the ctDNA clearance rate was surprisingly lower with nivolumab plus ipilimumab versus chemotherapy. By contrast, treatment regimens consisting of anti–PD-(L)1 agents combined with chemotherapy have shown greater ctDNA clearance versus chemotherapy alone across neoadjuvant and perioperative studies.
These findings suggest that chemotherapy may be needed to induce ctDNA clearance in most patients with resectable NSCLC, with anti–PD-(L)1 agents enhancing ctDNA clearance once induced. However, in CheckMate 816, ctDNA levels were only evaluated during the neoadjuvant phase. Long-term clinical research is warranted to fully understand the role of ctDNA levels as a predictor of benefit from neoadjuvant immunotherapy.
In patients treated with nivolumab plus ipilimumab from CheckMate 816 study, a high baseline four-gene inflammatory score (indicative of an inflamed phenotype in the tumour microenvironment) was associated with higher rates of pCR and MPR and improved EFS compared with patients with a low baseline signature; these results are consistent with clinical studies in advanced cancers where a higher baseline four-gene inflammatory signature score appeared to be associated with improved response/survival outcomes compared with a lower baseline score. By contrast, in patients receiving chemotherapy, there was no association between baseline four-gene inflammatory scores and EFS; the number of patients with a pCR or an MPR was too low to allow for interpretation.
The exploratory analyses reported are from the nivolumab plus ipilimumab arm of CheckMate 816, which was not powered for comparison with either the nivolumab plus chemotherapy arm or the chemotherapy arm. Some of the analyses included small sample sizes, and the results should be interpreted with caution.
Despite these limitations, this is the first randomised phase III study evaluating neoadjuvant nivolumab plus ipilimumab versus chemotherapy in a large cohort of patients. This report highlights the complexities of neoadjuvant immune checkpoint blockade with not only higher rates of early tumour progression occurring with neoadjuvant nivolumab plus ipilimumab, but also high pCR rates, low-grade 3-4 treatment-related adverse events, and evidence of long-term clinical benefit.
The study was previously presented in part at the ESMO 2023 Congress.
The study was supported by Bristol Myers Squibb and Ono Pharmaceutical Company, Ltd.
Reference
Awad MM, Forde PM, Girard N, et al. Neoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer. JCO; Published online 8 January 2025. DOI: https://doi.org/10.1200/JCO-24-02