Neoadjuvant Nivolumab and Chemotherapy Shows Continued Benefit in NSCLC Exploratory Analysis

Numerical, but not statistical improvements, were seen for patients with resectable non–small cell lung cancer (NSCLC), even when definitive surgery was not achieved, and when treated with neoadjuvant nivolumab (Opdivo) plus chemotherapy clinical outcomes were approved, according to an exploratory analysis from the phase 3 CheckMate 816 trial (NCT02998528) presented at the 2023 ASCO Annual Meeting.¹

In those who completed definitive surgery after neoadjuvant chemotherapy plus nivolumab, the median event-free survival (EFS) had not yet been reached (95% CI, 44.4-not reached [NR]) compared with 31.8 months (95% CI, 18.0-NR) in the chemotherapy alone group (HR, 0.67; 95% CI, 0.47-0.95). The median time to death or distant metastasis (TTDM) was NR with neoadjuvant nivolumab and chemotherapy compared with 46.8 months (95% CI, 34.3-NR) with chemotherapy (HR, 0.55; 95% CI, 0.36-0.84). EFS2, defined as time from randomization to objectively documented progression after the next line of therapy or death, was also extended with the nivolumab/chemotherapy combination vs chemotherapy (HR, 0.60; 95% CI, 0.39-0.95).

A higher proportion of patients receiving neoadjuvant nivolumab plus chemotherapy were able to receive definitive surgery compared with those receiving neoadjuvant chemotherapy alone. Of the 179 patients in each arm at baseline, 149 in the nivolumab/chemotherapy arm and 135 in the chemotherapy alone group received definitive surgery, a difference of 14 between groups.

“In this exploratory analysis with 3 years of follow-up, neoadjuvant nivolumab plus chemotherapy demonstrated long-term EFS, TTDM, and EFS2 benefit compared with chemotherapy in patients with definitive therapy,” lead investigator Jonathan Spicer, MD, PhD, FRCPC, from the McGill University Health Center, said in a video that accompanied the poster. “In those without definitive therapy, EFS, TTDM, and EFS2 all trended toward being improved in those who received nivolumab and chemotherapy vs chemotherapy alone; however, patients who completed surgical resection had a very important clinical benefit across both treatment arms.”

In the study, 358 patients were randomly assigned 1:1 to receive nivolumab at 360 mg plus chemotherapy (n = 179) nivolumab at 360 mg every 3 weeks or chemotherapy every 3 weeks alone (n = 179) for 3 cycles. Following neoadjuvant therapy, radiologic restaging was completed followed by surgery within 6 weeks. After surgery, adjuvant therapy with chemotherapy or radiotherapy was optional.

Of those with a definitive surgery, 22% and 44% received a subsequent therapy, in the nivolumab plus chemotherapy and chemotherapy alone arms, respectively. Subsequent treatment in the definitive surgery group for the nivolumab/chemotherapy and chemotherapy alone arms, respectively, included radiotherapy (9% and 19%), surgery (3% and 5%), immunotherapy (9% and 23%), targeted therapy (7% and 17%), and chemotherapy (15% and 21%).

In those without definite surgery, the rate of subsequent therapy use was 57% and 64%, in the nivolumab and chemotherapy alone arms, respectively. In this group, subsequent treatments in the nivolumab plus chemotherapy and chemotherapy alone arms included radiotherapy (37% and 41%), surgery (3% and 2%), immunotherapy (3% and 36%), targeted therapy (17% and 9%), and chemotherapy (47% and 43%).

“Subsequent therapy use was more than twice as common in patients without definitive surgery compared with those with definitive surgery across both treatment arms,” Spicer said. “Use of subsequent systemic therapy was almost more than 3 times more common in those without definitive surgery vs those with definitive surgery amongst those in the nivolumab plus chemotherapy cohort.”

Patient characteristics were similar across groups. In those who received chemotherapy and nivolumab in the definitive surgery group, the median age was 64 years, and 69% were male. A quarter were in North America and the majority were in Asia (50%). The ECOG performance status was 0 (75%) and 1 (25%) and the disease stage was IB-II (37%) and IIIA (63%). Ninety percent of patients were current or former smokers and 10% were never smokers. Tumor PD-L1 expression was less than 1% for 42% of patients and was between 1% and 49% for 29% and 50% or greater for 22%. PD-L1 was not evaluable in 7% of patients. Tumor mutation burden (TMB) was 12.3 mut/Mb or greater for 21% of participants and below this threshold for 30%. TMB was unknown for the remainder of patients.

A leading cause of definitive surgery cancellation was disease progression. In the nivolumab/chemotherapy group, this accounted for 19 patients cancelling surgery and for 27 in the chemotherapy group. Other patients also received definitive radiotherapy instead of surgery.

“A majority of these patients [who cancelled surgery for progression] were male and had stage IIIA disease a baseline,” Spicer said. “Of note, no patients with stage IB disease missed surgery due to disease progression and only 4 had stage IIA or IIB disease. A higher proportion of patients without definitive surgery had a baseline ECOG performance status of 1 [60%] or were from Europe [40%].”

In those receiving definitive surgery after neoadjuvant nivolumab and chemotherapy, the 1-, 2-, and 3-year EFS rates were 83%, 69%, and 62% respectively. In patients who received chemotherapy alone and had definitive therapy, the 1-, 2-, and 3-year EFS rates were 71%, 54%, and 49%. At the 1-, 2-, and 3-year marks, 90%, 80%, and 77% of patients remained free of distant metastasis in the nivolumab/chemotherapy group compared with 80%, 68%, and 59% in the chemotherapy arm, respectively.

In patients who did not receive definitive surgery, the median EFS was 6.7 months (95% CI, 2.7-24.9) with nivolumab/chemotherapy compared with 4.1 months (95% CI, 2.5-11.2) with chemotherapy alone (HR, 0.75; 95% CI, 0.44-1.28). The 1-, 2-, and 3-year EFS rates in the nivolumab arm were 44%, 40% and 8% compared with 35%, 13%, and 10% in the chemotherapy group, respectively. At 1-, 2-, and 3-years, 66%, 56% and 36% of patients were free of distant metastasis in the nivolumab/chemotherapy arm, compared with 63%, 21%, and 13% for chemotherapy, respectively.

In patients receiving definitive surgery, the median EFS2 was not yet reached in either arm. The 1-, 2-, and 3-year EFS2 rates were 93%, 86%, and 80% with nivolumab compared with 90%, 75%, and 69% with chemotherapy. In those without definitive surgery, the median EFS2 was 12.3 months (95% CI, 8.4-37.8) with nivolumab/chemotherapy compared with 15.5 months (95% CI, 10.2-18.6) with chemotherapy alone (HR, 0.94; 95% CI, 0.53-1.66). In this group, the 1-, 2-, and 3-year EFS2 rates with nivolumab/chemotherapy were 56%, 41%, and 33% compared with 56%, 26%, and 24% with chemotherapy, respectively.

“With regard to time to death or distant metastasis, patients who received nivolumab plus chemo had an impressive and sustained improvement at 3 years, whether they received surgery or not in comparison to those who received neoadjuvant chemotherapy,” Spicer said. “EFS2 also appeared to favor treatment with nivolumab and chemotherapy vs chemotherapy for those who had definitive therapy.”

Of those who went on to receive definitive therapy, treatment-related adverse events (TRAE) of grade 3 or 4 in severity occurred in 38% of those in the nivolumab/chemotherapy arm compared with 36% of those in the chemotherapy alone group. Treatment-related serious adverse events (SAEs) of grade 3/4 were experienced by 15% of patients in the nivolumab/chemotherapy arm compared with 11% in the chemotherapy alone group. Grade 3 or 4 surgery-related adverse events were reported in 11% of those in the nivolumab/chemotherapy group compared with 15% in the chemotherapy arm. Across all patients, there were 3 treatment-related deaths in the chemotherapy arms and none in the nivolumab/chemotherapy groups.

For those who did not undergo definitive surgery, the grade 3/4 TRAEs occurred in 26% of patients in the nivolumab/chemotherapy arm compared with 46% in the chemotherapy alone arm. Grade 3/4 SEAs were reported in 11% and 15% of patients in either arm, respectively.

^Reference

^{Spicer J, Forde PM, Provencio M, et al. Clinical outcomes with neoadjuvant nivolumab (N) + chemotherapy (C) vs C by definitive surgery in patients (pts) with resectable NSCLC: 3-y results from the phase 3 CheckMate 816 trial. J Clin Oncol. 2023;41 (suppl 16):8521. doi:10.1200/JCO.2023.41.16_suppl.8521}