The CheckMate- 816 Study

Prof Nicolas Girard, Director of Medical Oncology at Institut Curie in Paris, presented an overview of the CheckMate 816 trial’s findings during the ESMO 2023 meeting. This randomised study focused on the neoadjuvant treatment of patients with resectable NSCLC, specifically those in stages 2 to 3. The trial included 358 patients who were randomised into two groups: one received chemotherapy for three cycles, and the other received a combination of chemotherapy and nivolumab. Following these interventions, the patients underwent surgery, and the investigator conducted a comprehensive follow-up.

The primary endpoints of the trial were particularly encouraging, with a focus on the achievement of a complete pathological response. Notably, in the group receiving nivolumab in addition to chemotherapy, 24% of patients achieved a PCR, while in the chemotherapy-only group, the rate was a mere 2%. Furthermore, the trial demonstrated a remarkable 40% reduction in the risk of disease progression or death, signifying a significant benefit in EFS when nivolumab was added to chemotherapy.

While the results from this trial were published in the New England Journal of Medicine the previous year, there are still key insights to be gained from the study. Of particular note is the information regarding the PD-L1 status, along with a three-year update on EFS.  In Europe, the utilisation and labelling of nivolumab in the neoadjuvant setting are restricted to patients with a PD-L1-positive tumour. This restriction is primarily due to the observation that patients with a PD-L1 negative tumour, constituting about one-third of the study population, exhibit a lower signal for EFS benefit compared to those with PD-L1 positive tumours. Consequently, the European Medicines Agency has limited the indication to PD-L1-positive tumours. Nevertheless, it’s worth highlighting that there is still a benefit in PD-L1 negative tumours, particularly concerning the complete pathological response rate, which remains at 17%—a substantial improvement compared to the 2% achieved with chemotherapy alone. Patients who achieve a pathological complete response experience extended EFS, marked by a nearly flat EFS curve and minimal risk of disease recurrence.

The study also provided valuable insights into the third arm, which was discontinued towards the end of the trial. This arm explored the combination of nivolumab and ipilimumab, a combination that was believed to be highly effective in the metastatic setting. The data from this study align with previous phase II studies, demonstrating a higher PCR of approximately 25% and an EFS benefit when compared to chemotherapy. As expected and in line with findings in the metastatic setting, an early crossover of the survival curves was observed, suggesting that some patients might experience a detrimental effect from nivolumab plus ipilimumab, albeit within a small subset. Therefore, patient selection is crucial, and chemotherapy appears necessary to safeguard patients from early progression. These findings are exploratory but nonetheless compelling.

These findings may open the door to potential escalations in the neoadjuvant space, involving combinations of chemotherapy with immune checkpoint inhibitors targeting PD-1 or PD-L1, potentially combined with other agents. The objective is to increase the PCR rate, ultimately reducing the risk of disease recurrence. The trial presents intriguing data, and the medical community eagerly awaits the long-term follow-up to formally assess the benefits in terms of OS. While the hazard ratio for OS in CheckMate 816 already stands at 0.6, statistical significance has not yet been reached.

References:

Mark Awad –  Neoadjuvant nivolumab (N) + ipilimumab (I) vs chemotherapy (C) in the phase 3 CheckMate 816 trial – ESMO 2023 – #1261O

Mariano Provencio Pulla – Neoadjuvant nivolumab (N) + chemotherapy (C) in the phase 3 CheckMate 816 study: 3-y results by tumor PD-L1 expression – ESMO 2023 – #LBA57