Perioperative Nivolumab Regimen Improves EFS, Resection Rates in Stage III N2/non-N2 NSCLC

Neoadjuvant nivolumab (Opdivo) plus chemotherapy, followed by surgery and adjuvant nivolumab, showed a significant improvement in event-free survival (EFS) in patients with stage III N2 and stage III non-N2 non–small cell lung cancer (NSCLC), according to exploratory results from the phase 3 CheckMate 77T trial (NCT04025879) that were presented at the 2024 ASCO Annual Meeting.¹

Data showed that in patients with stage III N2 disease, the median EFS was 30.2 months (95% CI, 26.9-not reached [NR]) with nivolumab (n = 91) compared with 10.0 months (95% CI, 8.1-15.1) with placebo (n = 90), leading to a 54% improvement in EFS with the nivolumab regimen (HR, 0.46; 95% CI, 0.30-0.70). The 12-month EFS rates were 70% (95% CI, 58%-78%) and 45% (95% CI, 34%-55%), respectively.

For those with stage III non-N2 disease, the median EFS from randomization was NR (95% CI, 24.2-NR) with nivolumab (n = 55) compared with 17.0 months (95% CI, 10.6-NR) with placebo (n = 57; HR, 0.60; 95% CI, 0.33-1.08). The 12-month EFS rates were 74% (95% CI, 60%-84%) and 62% (95% CI, 48%-74%), respectively.

Additional results showed that the pathologic complete response (pCR) rate in patients with stage III N2 disease was 22.0% (95% CI, 14.0%-31.9%) compared with 5.6% (95% CI, 1.8%-12.5%) in the placebo arm. In those with stage III non-N2 disease, the pCR rates were 25.5% (95% CI, 14.7%-39.0%) and 5.3% (95% CI, 1.1%-14.6%), respectively.

Findings also showed that patients with stage N2 disease had similar rates of surgical feasibility as patients with non-N2 disease following neoadjuvant nivolumab and chemotherapy. In the stage IIII N2 subgroup, 77% of nivolumab-treated patients underwent surgery vs 73% of those on placebo. pCR rates in this group were 28.6% (95% CI, 18.4%-40.6%) vs 7.6% (95% CI, 2.5%-16.8%) with nivolumab vs placebo, respectively. Resection results were similar in the stage III non-N2 subgroup; 82% of those on nivolumab and 79% of those on placebo underwent resection, with pCR rates of 31.1% (95% CI, 18.2%-46.6%) and 6.7% (95% CI, 1.4%-18.3%), respectively.

“These findings, along with previously reported results from the CheckMate 77T study, further support perioperative nivolumab as a potential new treatment for patients with resectable NSCLC, including those with poor prognosis such as stage III N2,” senior study author Tina Cascone, MD, PhD, of The University of Texas MD Anderson Cancer Center, in an oral presentation of the data.

In February 2024, the FDA accepted a supplemental biologics license application seeking the approval of neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab as a perioperative treatment of patients with resectable stage IIA to IIIB NSCLC, based on earlier CheckMate 77T results.²

Previous findings from CheckMate 77T showed that perioperative nivolumab led to a significant improvement in EFS vs placebo in patients with stage II to IIIB resectable NSCLC by blinded independent central review (HR, 0.58; 95% CI, 0.42-0.81; P = .00025).³ At 12 and 18 months, the EFS rates with nivolumab were 73% and 70% vs 59% and 50% with placebo. Additionally, the pCR rates were 25.3% with nivolumab and 4.7% with placebo; the molecular pathologic response (MPR) rates were 35.4% and 12.1%, respectively.

At the 2024 ASCO Annual Meeting, Cascone reported on the clinical outcomes from CheckMate 77T for patients with baseline stage III N2 and non-N2 NSCLC.¹ Stage IIIA to B resectable NSCLC is generally linked with poor survival outcomes, with 5-year overall survival (OS) rates ranging from 24% to 41%.

A total 461 patients were randomized 1:1 to receive nivolumab at 360 mg or placebo every 3 weeks plus chemotherapy every 3 weeks for 4 cycles. Upon radiologic restaging, both arms went onto surgery within 6 weeks of post-neoadjuvant treatment. In the experimental arm, nivolumab was then given at 480 mg every 4 weeks for 13 cycles and those in the placebo arm received placebo for the same number of cycles and duration. Chemotherapy regimen was based on histology. Those with nonsquamous disease received cisplatin plus pemetrexed, carboplatin plus pemetrexed, or carboplatin plus paclitaxel. Those with squamous disease received cisplatin plus docetaxel or carboplatin plus paclitaxel.

To be eligible for enrollment, patients had to have resectable, stage IIA (>4 cm) to stage IIIB (N2) NSCLC as per the American Joint Committee on Cancer 8th edition, as well as an ECOG performance status of 0 to 1. Patients could not have received prior systemic anticancer therapy nor harbor EGFR mutations or known ALK alterations.

The primary end point was EFS by BICR, and secondary end points were pCR and MPR—both by blinded independent pathology review—OS, and safety. Exploratory analyses, data of which were presented at the meeting, evaluated clinical outcomes by clinical stage III N2 or non-N2 status.

The median follow-up was 25.4 months (range, 15.7-44.2), with a database lock date of September 6, 2023.

Regarding baseline characteristics in the stage III N2 cohort, the median age was 65 years (range, 37-86) and 67.5% of patients were male. Patients were from North America (9%), Europe (57.5%), Asia (23.5%), or rest of world (10.5%). Most patients had an ECOG performance status of 0 (70%), and more than half had disease stage IIIA (58%) and nonsquamous disease (57%). A total 87.5% of patients were current or former smokers. PD-L1 expression was not evaluable (3%), less than 1% (42%), 1% or greater (55%), between 1% and 49% (36%), or 50% or greater (18.5%).

In the stage III non-N2 cohort, the median age was 65.5 years (range, 35-81) and 76% of patients were male. Patients were from North America (12.5%), Europe (55%), Asia (24%), or rest of world (8%). Most patients had an ECOG performance status of 0 (57%), and all patients had stage IIIA disease; 42% had nonsquamous disease. Ninety-five percent of patients were current or former smokers. PD-L1 expression was not evaluable (2%), less than 1% (46.5%), 1% or greater (51.5%), between 1% and 49% (28.5%), or 50% or greater (23%).

The EFS benefit with nivolumab was also seen in patients single-station N2 disease (HR, 0.49) and multi-station N2 (HR, 0.43).

Landmark EFS was also analyzed from the time point of definitive surgery “in an attempt to understand the contribution of the adjuvant therapy component to the clinical benefit,” Cascone said. Here, the median EFS in patients with stage III N2 disease was NR (95% CI, 23.8-NR) with nivolumab (n = 70) compared with 8.9 months (95% CI, 6.1-15.6) with placebo (n = 66; HR, 0.32; 95% CI, 0.19-0.54). For patients with stage III non-N2 disease, the median EFS was NR (95% CI, 21.4-NR) with nivolumab (n = 45) compared with 25.0 months (95% CI, 12.5-NR) with placebo (n = 45; HR, 0.61; 95% CI, 0.30-1.24).

EFS was further evaluated by single-station and multi-station subgroups. In the stage III N2 single-station setting, the median EFS was NR (95% CI, 23.7-NR) with nivolumab (n = 45) compared with 10.5 months (95% CI, 6.0-NR) with placebo (n = 37; HR, 0.40; 95% CI, 0.20-0.78). In the multi-station group, the median EFS was NR (95% CI, 18.2-NR) and 7.8 months (95% CI, 4.7-16.5) with nivolumab (n = 24) and placebo (n = 29), respectively (HR, 0.23; 95% CI, 0.09-0.58).

The landmark EFS analysis from definitive surgery was also studied by pCR status. In stage III N2 disease, EFS was notably improved in those on nivolumab without a pCR (HR, 0.48; 95% CI, 0.27-0.86). In the stage III non-N2 subgroup, the HR for those without a pCR was 0.86 (95% CI, 0.41-1.84).

Additionally, landmark EFS HRs for patients without a pCR was 0.59 for those with single-station N2 disease and 0.36 for patients with multi-station N2 disease.

Further findings showed that in stage III single-station N2 patients, the pCR was 18.6% and 7.5% for nivolumab- and placebo-treated patients, respectively. In the patients who went to resection (nivolumab arm, 76%; placebo, 70%), the pCR rates were 24.4% and 10.8%, respectively.

Secondly, in patients with stage III multi-station N2 disease, the pCR rates were 29.0% (95% CI, 14.2%-48.0%) and 2.7% (95% CI, 0.1%-14.2%) for nivolumab- and placebo-treated patients, respectively. In those who underwent resection (nivolumab, 77%; placebo, 78%), the pCR rates were 37.5% (95% CI, 18.8%-59.4%) and 3.4% (95% CI, 0.1%-17.8%), respectively.

Investigators also evaluated downstaging in the stage III setting. Of these patients on nivolumab (n = 115) who experienced any downstaging (52%), 46% had downstaging to ypN0. In the placebo arm (n = 111), 45% of patients had any downstaging with 36% being downstaged to ypN0.

Specifically, in patients with clinical stage N2 disease, 57% had downstaging and 64% had downstaging to ypN0. In the placebo arm, these rates were 44% and 56%, respectively.

“Similarly, there was a slightly higher proportion of patients with baseline N1 who downstaged to ypN0 in the nivolumab arm vs placebo [at] 78% vs 57%. There was a slightly higher proportion of patients remaining at ypN0 from baseline to post-surgery in the placebo arm vs nivolumab—88% vs 74%,” Cascone explained. “Most of the upstaging from baseline ypN0 in the nivolumab arm was to ypN1.”

In patients with stage III N2 disease, 84% and 74% of patients on nivolumab and placebo, respectively, underwent simple lobectomy; 1% and 14%, respectively, had pneumonectomy. The median duration of surgery was 213.5 minutes (IQR, 180.0-343.5) and 216.0 minutes (IQR, 149.0-292.0), with a median length of hospital stay of 9.0 days (IQR, 6.0-13.0) and 8.0 days (IQR, 5.0-13.0). Eighty-six percent of patients in both arms had R0 resection.

In those with stage III non-N2 disease, simple lumpectomy rates were 80% and 71% for nivolumab and placebo, respectively; 4% and 18%, respectively, underwent an extended lobectomy. The median duration of surgery was 240.0 minutes (IQR, 160.0-323.0) and 249.0 minutes (IQR, 163.0-330.0), with a median length of hospital stay of 8.0 days (IQR, 7.0-14.0) and 9.0 days (IQR, 6.5-11.0). Eighty-four percent of patients on nivolumab and 87% of those on placebo had R0 resection.

Regarding safety, most patients in both arms and subgroups experienced adverse effects (AEs). In the stage III N2 subgroup, all-grade and grade 3 to 4 treatment-related AEs (TRAEs) occurred in 90% and 34%, respectively, of nivolumab-treated patients vs 87% and 26% of placebo-treated patients. All-grade and grade 3 to 4 AEs leading to discontinuation occurred in 31% and 18% of patients vs 9% and 4%, respectively. All-grade and grade 3 to 4 TRAEs that led to discontinuation were reported in 25% and 15% of patients on nivolumab and 7% and 4% of those on placebo. All-grade and grade 3 to 4 serious AEs (SAEs) occurred in 44% and 28% on nivolumab and 27% and 16% on placebo. Finally, all-grade and grade 3 to 4 treatment-related SAEs were reported in 26% and 15%, respectively, of those on nivolumab compared with 11% and 7% of those on placebo.

In the stage III non-N2 subgroup, all-grade and grade 3 to 4 TRAEs occurred in 87% and 29%, respectively, of nivolumab-treated patients vs 84% and 21% of placebo-treated patients. All-grade and grade 3 to 4 AEs leading to discontinuation occurred in 20% and 7% vs 10% and 7%, respectively. All-grade and grade 3 to 4 TRAEs that led to discontinuation were reported in 14% and 6% of patients on nivolumab and 7% and 5% of those on placebo. All-grade and grade 3 to 4 SAEs occurred in 38% and 22% of those on nivolumab and 35% and 21% of those on placebo. Finally, all-grade and grade 3 to 4 treatment-related SAEs were reported in 9% and 6%, respectively, of those on nivolumab compared with 10% and 7% of those on placebo.

Disclosures: Dr Cascone cited honoraria from Bristol-Myers Squibb, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, Peerview, Roche, and the Society for Immunotherapy of Cancer; consulting or advisory roles from Arrowhead Pharmaceuticals. Bristol-Myers Squibb, EMD Serono, Genentech, MedImmune, Merck, and Regeneron; research funding from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, and MedImmune; and travel expenses from Bristol-Myers Squibb, Dava Oncology, IASCLC, IDEOlogy Health, Parker Institute for Cancer Immunotherapy, and the Society for Immunotherapy of Cancer.

References

1. Provencio M, Awad MM, Spicer JD, et al. Clinical outcomes with perioperative nivolumab (NIVO) by nodal status among patients (pts) with stage III resectable NSCLC: Results from the phase 3 CheckMate 77T study. J Clin Oncol. 2024;42(suppl 17; abstr LBA8007):LBA8007. doi:10.1200/JCO.2024.42.17_suppl.LBA8007
2. Bristol Myers Squibb announces acceptance of US and EU regulatory filings for neoadjuvant Opdivo (nivolumab) and chemotherapy followed by surgery and adjuvant Opdivo in resectable non-small cell lung cancer. News release. Bristol Myers Squibb. February 7, 2024. Accessed June 3, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Announces-Acceptance-of-U.S.-and-EU-Regulatory-Filings-for-Neoadjuvant-Opdivo-nivolumab-and-Chemotherapy-Followed-by-Surgery-and-Adjuvant-Opdivo-in-Resectable-Non-Small-Cell-Lung-Cancer/default.aspx
3. Cascone T, Awad MM, Spicer JD, et al. CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Ann Oncol. 2023;34(supp 2):S1295. doi:10.1016/j.annonc.2023.10.050