CheckMate-77T: Perioperative nivolumab benefit for NSCLC
Dr Tina Cascone – MD Anderson Cancer Center, Houston, USA
Hello my name is Tina Cascone, I am a thoracic medical oncologist at the University of Texas MD Anderson Cancer Center in Houston, Texas. At this ESMO 2023 Congress I presented the results of the CheckMate-77T. This is a Phase III study comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or a placebo for a previously untreated resectable stage 2-3b non-small cell lung cancer. The rationale for this study stems from the evidence that nivolumab plus chemo is the standard of care neoadjuvant treatment for eligible patients with resectable non-small cell lung cancer based on improvements in EFS and pCR, as compared to chemo in the CheckMate-816 study. So, a perioperative treatment approach including adjuvant nivolumab could potentially further reduce the risk of disease relapse and improve the clinical benefit in patients with resectable non-small cell lung cancer.
The CheckMate-77T study is a global randomised double-blind phase III study that is evaluating neoadjuvant nivolumab plus chemo followed by surgery and adjuvant nivolumab versus neoadjuvant chemo placebo followed by surgery and adjuvant placebo in patients with resectable stage 2-3b disease. The results I presented at this ESMO Congress are from the prespecified EFS interim analysis as well as results of secondary endpoints and key expert re-analysis. This study included patients with resectable stage 2a-3b disease at presentation according to an AJCC8 edition. The patients also had to have no prior systemic inter-cancer treatment, an ECOG performance status of 0 to 1, and no EGFR mutations or known ALK alterations. Stratification factors were tumour histology, disease stage, and tumour PD-L1 expression. A total of 461 patients were randomised one to one to receive neoadjuvant nivolumab plus chemo every three weeks for four cycles, followed by adjuvant nivolumab for one year given every four weeks, or neoadjuvant placebo plus chemo followed by adjuvant placebo. After the last neoadjuvant treatment, as well as radiologic restaging, surgery had to be performed within six weeks.
The primary endpoint of the study was EFS by blinded independent central review, and the secondary endpoints were pCR and NPR, OS, and safety. An expert analysis included EFS by pCR and NPR status, and EFS by adjuvant treatment status. The data presented at ESMO 2023 were based on the September 6th 2023 database lock with a median follow-up of 25.4 months. The prespecified interim analysis of EFS was scheduled to take place when 185 events had occurred. As of this database lock, 189 events have occurred, and, as of this database lock, overall survival is not yet being formally tested and continues to mature.
As far as the baseline patient characteristics in the study, those were generally balanced between treatment arms. More than 50% of patients were from Europe and more than 20% were from Asia. Approximately two-thirds of patients had stage 3 disease, and about 90% of patients in both arms currently smoke or have smoked in the past. More than 50% of patients had tumour PD-L1 expression of 1% or more, while about 40% had tumour PD-L1 expression of less than 1%. Most patients received carboplatin-based chemotherapy in both arms.
Almost all patients in each arm received neoadjuvant treatment with at least 85% completing four treatment cycles, and the study drug toxicity was the most common reason for neoadjuvant treatment discontinuation in both arms. 78% of patients in the nivolumab arm and 77% of patients in the chemo arm received definitive surgery. The most common reason for cancellation of surgery was disease progression in both arms, but with more cancellations seen in the chemo arm. Only 3% of patients in the nivolumab arm and 2% of patients in the chemo arm cancelled surgery due to adverse events. Nearly two-thirds of patients across both arms received adjuvant treatment with a median number of thirteen doses administered in both arms. Toxicity was the most common reason for not receiving adjuvant nivolumab while disease progression was the most common reason for not receiving adjuvant placebo.
Of the patients who received adjuvant treatment, 60% of those in the nivolumab arm and in the chemo arm completed one year of therapy. The most common reason for discontinuing adjuvant therapy were study drug toxicity in the nivolumab arm and disease progression in the chemo arm. As far as surgical outcomes, lobectomy was the most common type of surgery, it was performed in 80% of patients in the nivolumab arm and 72% of patients in the chemo arm, while 9% and 14% of patients in the respective arms underwent pneumonectomy. About 90% of patients in both arms had an R0 resection.
CheckMate-77T met its primary endpoint at a median follow-up of 25.4 months. Perioperative nivolumab demonstrated a statistically significant and a clinically meaningful improvement in EFS as compared to chemo placebo. Median EFS was not reached in the nivolumab arm and was 18.4 months in the chemo arm, resulting in a hazard ratio of 0.58 with a significant p-value of 0.00025. The 12-month EFS rates were 73% with perioperative nivolumab versus 59% with chemo placebo, and the 18-month EFS rates were 70% versus 50%, suggesting greater benefit for patients over time. The EFS per investigator assessment also favoured nivolumab versus chemo based on a hazard ratio of 0.56. The EFS benefit wtih nivolumab versus chemo was observed across most subgroups; nivolumab appeared to improve EFS versus chemo regardless of disease stage, and in particular in patients with stage 3 disease. Patients with nodal disease, including those with both single and multi-station N2 status had improved EFS with nivolumab compared with chemo. EFS favoured nivolumab versus chemo regardless of tumour histology, with a particular clear benefit in patients with squamous disease. In patients who currently or previously smoked, nivolumab appeared to improve EFS versus chemo, while the opposite was observed in patients who never smoked. But given the limited sample size in this patient subgroup, results should be taken with caution.
Nivolumab also appeared to improve EFS as compared to chemo in patients with tumour PD-L1 expression of less than 1%, and even more profoundly, in those with tumour PD-L1 expression of 1% or more. In patients with stage 2 disease at baseline, median EFS was not reached with either nivolumab or chemo, with a hazard ratio of 0.81. In patients with stage 3 disease at baseline, a clear EFS benefit with nivolumab versus chemo was seen, with a median EFS of 30.2 months in the nivolumab arm, versus 13.4 months in the chemo placebo arm with a hazard ratio of 0.51. In patients with tumour PD-L1 expression of less than 1%, the median EFS in the nivolumab arm was 29 months compared to 19.8 months in the chemo arm with a hazard ratio of 0.73 in favour of perioperative nivolumab. The magnitude of EFS benefit with nivolumab versus chemo was numerically greater in patients with tumour PD-L1 expression of 1% or more, with a median EFS not reached with nivolumab, versus 15.8 months with chemo with a hazard ratio of 0.52.
Very importantly, a pCR was observed in 25.3% of patients in the nivolumab arm, as compared to 4.7% of patients in the chemo arm in the intention to treat population. An NPR was observed in 35.4% of patients in the nivolumab arm versus 12.1% of patients in the chemo arm in the intention to treat population. Improvements in pCR with nivolumab were observed across most subgroups as defined by stage, tumour histology, current or former smoking status, and PD-L1 expression.
We also performed an expert reanalysis of EFS by pCR and NPR status. EFS clearly favoured nivolumab versus chemo in patients with pCR based on a hazard ratio of 0.33, with a trend towards improved EFS with nivolumab as compared to chemo in patients without a pCR with a hazard ratio of 0.79. Similar results were seen also in patients with an NPR. To better evaluate the clinical benefit of perioperative nivolumab, we also performed an expert reanalysis of EFS by adjuvant treatment status. In patients who received adjuvant therapy those in the perioperative nivolumab arm had an improved EFS compared to patients in the chemo placebo arm with a hazard ratio of 0.45. Among patients who could not receive adjuvant therapy after neoadjuvant treatment, EFS still favoured nivolumab as compared to chemo based on a hazard ratio of 0.55. In patients who received adjuvant treatment, EFS was improved with perioperative nivolumab versus chemo in both patients who had a pCR and who did not have a pCR. Populations of patients in these subgroups are heterogeneous, so results of this analysis have to be taken with some caution.
As far as the safety outcomes, the incidence of all cause adverse events and treatment related adverse events was overall similar between patients treated with nivolumab or chemo. Similar safety outcomes were seen with neoadjuvant treatment, while any grade treatment related adverse events were reported in 50% of patients treated with adjuvant nivolumab, and in 30% of patients treated with adjuvant placebo. Any grade surgery related adverse events occurred in 41% and 39% of patients in the nivolumab and chemo arms respectively, and treatment related deaths occurred in two patients in the nivolumab arm, both due to pneumonitis occurring during the neoadjuvant period. The immune related adverse events were generally infrequent and mild, hyperthyroidism and thyroiditis were reported in 11% and 2% of patients in the nivolumab and chemo arms respectively.
In summary, CheckMate-77T met its primary endpoint. Neoadjuvant nivolumab plus chemo followed by surgery and adjuvant nivolumab demonstrated a statistically significant and clinically meaningful EFS improvement as compared to neoadjuvant chemo placebo followed by surgery and adjuvant placebo in patients with resectable non-small cell lung cancer. The EFS benefit was seen across most key subgroups, and pCR and NPR rates were also improved.
In expert re-analysis, perioperative nivolumab favoured EFS in patients with a pCR, with a trend towards improved EFS also in patients without a pCR. Among patients who were eligible for adjuvant therapy, perioperative nivolumab improved EFS versus chemo placebo regardless of pCR status. Neoadjuvant nivolumab plus chemo continued to provide benefit over chemo in patients who were not able to receive adjuvant treatment. Perioperative nivolumab-based regiments showed no new safety signals; surgical feasibility was similar between treatment arms. So the CheckMate-77T is the first phase III perioperative study to build on the standard-of-care of neoadjuvant nivolumab plus chemo, and supports perioperative nivolumab as a potential new treatment option for patients with resectable non-small cell lung cancer.
What’s next for the study?
I’m very enthusiastic about these results because the CheckMate-77T builds on the current standard-of-care of neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for our patients with resectable non-small cell lung cancer. I am excited to see how the data matures. Our next steps will focus on identifying those patients as well as the disease characteristics that will tell us who are the individuals who can benefit most from a neoadjuvant chemoimmunotherapy approach alone, and who are the patients who instead require more a intensified adjuvant treatment approach, including the perioperative strategy that we have in CheckMate-77T, or a switch agent type of adjuvant regimen. Really the goal here is to try to cure early stage lung cancer for our patients and I think going forward, this is going to be a goal with more rational studies.
