Hello, my name is Tina Cascone. I'm a thoracic medical oncologist at the University of Texas, MD Anderson Cancer Center in Houston, Texas. This year at ESMO 2023, I presented the results of CheckMate-77T, a phase three study comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or placebo for previously untreated resectable, stage two 3B non-small cell lung cancer.

The rationale for this study stems from the evidence that nivo plus chemo is the standard of care in neoadjuvant treatment for eligible patients with resectable non-small cell lung cancer having demonstrated statistically significant and the clinically meaningful improvements in the EFS and the PCR as compared to chemo in the Checkmate 816 study.

Perioperative treatment approach including adjuvant nivo, could potentially further reduce the risk of disease relapse and improve clinical benefit in patients with resectable non-small cell lung cancer. CheckMate-77T is a global, randomized, double-blind phase three study evaluating neoadjuvant nivo plus chemo followed by adjuvant nivo versus chemo placebo followed by adjuvant placebo in patients with resectable stage two 3B non-small cell lung cancer. And at ESMO 2023, I will be presenting the results of the pre-specified EFS interim analysis along with secondary endpoints as well as the key exploratory analysis.

The CheckMate-77T included patients with resectable stage two A 3B disease presentation according to the AJCC eighth edition. Patients also had to have no prior systemic anti-cancer treatment and ECOG performance status of zero to one and no EGFR mutations or non-ALK alterations. Stratification factors included histology, disease stage and the tumor PD-L1 expression. A total of 461 patients were randomized one-to-one to receive neoadjuvant nivo plus chemo every three weeks for four cycles, followed by adjuvant nivo every four weeks for one year, or a neoadjuvant placebo plus chemo followed by adjuvant placebo for one year.

Following the last neoadjuvant treatment and radiologic restaging, patients had to have surgery within six weeks. The primary endpoint of the study was EFS per blinded independent central review and the secondary points were PCR and NPR, OS and safety. Exploratory analysis included EFS by PCR and NPR status and the EFS by adjuvant treatment status.

The data presented at ESMO 2023 are based on the September 6, 2023 database lock with a median follow up of 25.4 months. The pre-specified interim analysis of EFS was scheduled to take place once 185 events had occurred. And at time of database lock 189 events had occurred. And as of this database lock, OS has not yet been formally tested and continues to mature.

As far as baseline patient characteristics on this study, these characteristics were well-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 three disease presentation and about 90% of patients currently smoke or had smoked in the past.

More than 50% of patients had tumor PD-L1 expression of 1% or more, while about 40% had tumor PD-L1 expression less than 1%. And most patients receive carboplatin based chemotherapy in both arms. Almost all patients in each arm received neoadjuvant treatment with at least 35% completing four treatment cycles. And the study drug toxicity was the most common reason for a neoadjuvant treatment discontinuation in both arms.

78% of patients in the nivo arm and 77% of patients in the chemo arm received definitive surgery. And the most common reason for cancellation of surgery was disease progression in both arms, but more cancellations were seen in the chemo arm. And only 3% of patients in the nivo arm and 2% of patients in the chemo arm canceled surgery due to adverse events. Nearly two thirds of patients across both arms received adjuvant treatment with a median number of 13 doses administered in both arms. Toxicity was the most common reason for not receiving adjuvant nivo while disease progression was the most common reason for not receiving adjuvant placebo.

Of patients who received adjuvant treatment, 60% of those in the nivo arm and in the chemo arm completed one year of therapy. And the most common reasons for discontinuing adjuvant therapy were a study drug toxicity in the nivo arm and disease progression in the chemo arm. As far as surgery outcomes, lobectomy was the most common type of surgery was performed in 80% of patients in the nivo arm and 72% of patients in the chemo arm. While 9% and 14% of patients in the respective arms underwent pneumonectomy and the R0 resection rates were approximately 90% in both arms.

At a median follow-up of 25.4 months, perioperative nivo demonstrated a statistically significant in clinical meaningful improvement in EFS versus chemo placebo. Median EFS was now reached with perioperative chemo and was 18.4 months in the chemo arm resulting in an assay ratio of 0.58 with a significant p-value of 0.00025. The 12 month EFS rates were 73% with perioperative nivo versus 59% with chemo placebo. And the 18 month TFS rates were 70% versus 50%, suggesting greater benefit for patients over time. And EFS per investigative assessment also favor nivo versus chemo based on assay ratio of 0.56.

The EFS benefit with nivo versus chemo was observed across most subgroups. Nivo appeared to improve EFS versus chemo regardless of the disease stage and in particular in patients with stage three disease. Patients with nodal disease, including those with both single and multi-station N2 status had an improved EFS with nivo compared with chemo. And the EFS favored nivo versus chemo regardless of tumor histology with a particular clear benefit in patients with squamous disease.

In patients who currently or previously smoked, nivo appear to improve EFS versus chemo, while the opposite was seen in the patients who never smoked. However, given the limited sample size in this subgroup of patients, results should be taken with caution. And nivo also appeared to improve EFS versus chemo in patients with tumor PD-L1 expression less than 1%. And even more profoundly in those patients with PD-L1 expression levels of 1% or more.

Patients with stage two disease at baseline had a median EFS that was now reached with either nivo or chemo with an assay ratio of 0.81. And in patients with stage three disease at baseline, a clear EFS benefit was seen with nivo versus chemo with a median EFS of 30.2 months in the nivo arm and 13.4 months in the chemo arm with another ratio of 0.51 in patients.

With tumor PD-L1 expression less than 1%, the median EFS was 29 months in the nivo arm and the 19.8 months in the chemo arm with an assay ratio of 0.73 in favor of perioperative nivo. And the magnitude of EFS benefit with nivo versus chemo was numerically greater in those patients with tumor PD-L1 expression equal to or greater than 1% with a median EFS known reached in the nivo arm versus 15.8 months in the chemo arm and an assay ratio of 0.52.

Very importantly, a PCR was observed in 25.3% of patients in the nivo arm versus 4.7% of patients in the chemo arm in the intention to treat population, representing more than a fourfold increase. And NPR was seen in 35.4% of patients in the nivo arm versus 12.1% of patients in the chemo arm in the intention to treat population, representing almost a twofold increase.

We saw PCR improvements with nivo across subgroups defined by stage, tumor histology, current and former smoking status as well as a PD-L1 expression. And we also performed an exploratory analysis of EFS by PCR and NPR status clearly favor nivo versus chemo in patients with PCR based on an assay ratio of zero point 33. With a trend towards improved EFS with nivo versus chemo in patients without a PCR with an assay ratio of 0.79. And similar results were also seeing in patients with an NPR.

And to better evaluate the clinical benefit of perioperative nivo, we performed an exploratory analysis of EFS by adjuvant treatment status. We noted that in patients who received the adjuvant treatment, those in the perioperative nivo arm had an improved EFS versus patients in the chemo placebo arm with an assay ratio zero point 45. And among patients who could not receive adjuvant treatment after neoadjuvant therapy, EFS still favor nivo versus chemo based on an assay ratio of 0.55.

Populations of patients in these subgroups are heterogeneous. And the results of this analysis, which are exploratory are to be taken with caution. But we saw that in patients who receive adjuvant treatment, EFS improved with perioperative nivo versus chemo in both patients who had a PCR or who did not have a PCR.

As far as safety outcomes, the incidents of all cause adverse events and treatment related adverse events was overall similar between patients treated with nivo or chemo and the similar safety outcomes were seen in the neoadjuvant treatment. While any grade treatment related ease was reported in 50% of patients treated with adjuvant nivo and in 30% of patients treated with adjuvant placebo.

Any grade related adverse events occurred in 41% and the 39% of patients in the nivo and the chemo arms respectively. And treatment related deaths occurred in two patients in the nivo arm, both due to pneumonitis occurring during the neoadjuvant period. And as far as immune-mediated ease, those were generally infrequent and mild. Hypothyroidism and thyroiditis were reported in 11% and 2% of patients in the nivo and the chemo arms respectively.

In summary, neoadjuvant nivolumab plus chemo followed by surgery and adjuvant nivo demonstrated statistically significant and clinically meaningful EFS improvement versus 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 subgroups and the PCR and NPR rates were also improved. And in exploratory analysis, peri-operative nivo favor EFS in patients with a PCR, with a trend toward improved EFS in patients without a PCR.

Among those patients eligible for adjuvant therapy, perioperative nivo improved EFS versus chemo placebo regardless of PCR status. And neoadjuvant nivo plus chemo continued to provide benefit over chemo in patients who were not able to receive adjuvant therapy. Overall, perioperative nivo based regimen show non-use safety signal and the surgical feasibility was similar between treatment arms.

In conclusion, the CheckMate-77T is the first phase three perioperative study to build on the standard of care neoadjuvant nivo plus chemo and supports perioperative nivo as a potential new treatment option for patients with resectable non-small cell lung cancer.