In the CheckMate 77T study, the addition of perioperative nivolumab to neoadjuvant chemotherapy resulted in significantly longer event-free survival (EFS) than perioperative placebo added to neoadjuvant chemotherapy in patients with resectable stage IIA to IIIB non-small cell lung cancer (NSCLC). The study team also observed that a higher percentage of patients in the nivolumab group than in the chemotherapy group had a pathological complete response (pCR) and a major pathological response (MPR).
Furthermore, the perioperative use of nivolumab resulted in a lower risk of definitive deterioration of disease-related symptoms than chemotherapy. No new safety signals were reported with perioperative nivolumab; surgical outcomes were similar in the two treatment groups according to Dr. Tina Cascone of the University of Texas M.D. Anderson Cancer Center in Houston, TX, US and colleagues who published the findings on 15 May 2024 in The New England Journal of Medicine.
The clinical benefit of nivolumab in combination with platinum-doublet chemotherapy in patients with resectable NSCLC was initially observed in several phase II studies and subsequently confirmed in the landmark phase III CheckMate 816 study, which showed significant improvements in EFS and in pCR with neoadjuvant nivolumab plus chemotherapy as compared with chemotherapy alone. Furthermore, at an interim analysis from the CheckMate 816 study, overall survival (OS) appeared to favour neoadjuvant nivolumab plus chemotherapy over chemotherapy alone with data continuing to mature. Adjuvant immunotherapy has also shown benefit with respect to disease-free survival as compared with best supportive care or placebo in patients with resectable NSCLC.
A perioperative approach (which involves treatment with neoadjuvant therapy followed by surgery and adjuvant therapy) with immunotherapy-based treatments may further reduce the risk of disease relapse, which is typically observed in 30 to 55% of patients who undergo surgery with curative intent. This approach may also improve clinical outcomes by enhancing antitumour immunity and promoting the elimination of micrometastasis and residual tumour cells.
Recently, perioperative durvalumab and pembrolizumab in combination with neoadjuvant chemotherapy resulted in significant improvements in EFS and pathological response, with perioperative pembrolizumab also showing significant OS benefit as compared with perioperative placebo added to neoadjuvant chemotherapy in patients with resectable stage IIA to IIIB (N2 node stage) NSCLC in the phase III AEGEAN and KEYNOTE-671 studies. In the phase II NADIM II study, perioperative nivolumab also resulted in significant improvements in pCR, as well as in substantial improvements in progression-free survival and OS, as compared with chemotherapy alone, in patients with stage IIIA or IIIB resectable NSCLC.
In the article published in The New England Journal of Medicine, the investigators report efficacy and safety results from the prespecified interim analysis of the phase III, randomised, double-blind, international CheckMate study that evaluated neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab (perioperative nivolumab group) as compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo (chemotherapy group) in patients with resectable NSCLC.
Adult patients with resectable stage IIA to IIIB NSCLC were assigned to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was EFS according to blinded independent review. Secondary outcomes were pCR and MPR according to blinded independent review, OS, and safety.
At this prespecified interim analysis with a median follow-up of 25.4 months, the percentage of patients with 18-month EFS was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio [HR] for disease progression or recurrence, abandoned surgery, or death 0.58; 97.36% confidence interval [CI] 0.42 to 0.81; p < 0.001). pCR occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio [OR] 6.64; 95% CI 3.40 to 12.97); MPR occurred in 35.4% and 12.1% of the patients (OR 4.01; 95% CI 2.48 to 6.49).
The overall safety profile and surgical outcomes in CheckMate 77T were similar in the two treatment groups and correspond to the findings in previous studies. Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. Of patients who underwent surgery, surgery-related adverse events occurred in 41.0% of those in the nivolumab group and in 38.8% of those in the chemotherapy group; 11.8% in each group had grade 3 or 4 events.
In an accompanied editorial article, Dr. Marina Chiara Garassino of the Department of Medicine, Section of Hematology/Oncology, University of Chicago in Chicago, IL, US and Dr. Valter Torri of the Department of Oncology, Institute of Pharmacological Research Mario Negri, Istituto di Ricovero e Cura a Carattere Scientifico in Milan, Italy wrote that during the past few years, five phase III studies have used similar methods to explore a perioperative approach.
Heterogeneity among studies was modest, as indicated by the mean I2 statistic (the percentage of variation across studies that is due to heterogeneity rather than chance) of 42%, which is mostly explained by case-mix factors. By answering whether we can substitute one drug for another among the five that have been evaluated, the editorialists stated that physicians who are faced with these options should consider the interchangeability of regimens on the basis of factors such as drug availability, cost, and individual preference.
In each of the trials, investigators found that approximately 20% of surgeries were cancelled, mainly because of tumour progression. In light of the borderline benefit observed in Checkmate 77T, the editorialists questioned should we treat all patients who have resectable stage II disease with a neoadjuvant therapy first. If we pool the data from the five trials, the overall benefit for stage II NSCLC corresponds to HR for death or progression of 0.64 (95% CI 0.49 to 0.82), with an I2 of 0. The observed benefits support the use of neoadjuvant treatment for all patients with resectable stage II and stage III disease. The progress in this area emphasises the importance of a multidisciplinary collaboration among surgeons and medical oncologists to define the best strategy for each patient.
In CheckMate 77T, a smaller benefit was found for patients with less than 1% expression of PD-L1. All the trials showed that most of the benefit is driven by the population of patients with tumour PD-L1 expression of more than 50%. Such patients are more likely to have a pCR or MPR and to have a long-term benefit from the treatment. However, patients with PD-L1 expression of less than 1% can also derive benefit from a perioperative regimen. In pooled data from the five trials, the HR for progression or death is 0.73 (95% CI 0.60 to 0.89) with an I2 of 0.
The question of whether to continue immunotherapy for 1 year after a complete resection following three to four cycles of chemoimmunotherapy remains unanswered. In the absence of definitive trials to address this issue, leveraging the results of CheckMate 816 and CheckMate 77T, which share a neoadjuvant backbone, can inform decision making. CheckMate 77T investigators present multiple landmark analyses in an attempt to evaluate the superiority of a perioperative approach over a neoadjuvant-only approach. However, a carryover effect of the initial neoadjuvant component cannot be excluded. Although perioperative approaches, including the strategy that was used in CheckMate 77T, have shown a benefit, they may not be superior to neoadjuvant-only strategies. Until clearer evidence emerges, personalised decision making on the basis of patient preference is recommended according to the editorialists.
CheckMate 77T study was supported by Bristol Myers Squibb. Dako, an Agilent Technologies company, was acknowledged for collaborative development of the PD-L1 IHC 28-8 pharmDx assay.
References
- Cascone T, Awad MM, Spicer JD, et al. for the CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med 2024;390:1756-1769.
- Garassino MC, Torri V. Neoadjuvant or Perioperative Approach in Lung Cancer. N Engl J Med 2024;390:1816-1818.