Exploratory Analysis Shows Perioperative Nivolumab Confers Benefit in Resectable NSCLC, Irrespective of Neoadjuvant Treatment Cycles

Mark Awad, MD, PhD

An exploratory analysis of the phase 3 CheckMate 77T trial (NCT04025879) demonstrated that neoadjuvant nivolumab (Opdivo) plus platinum-based chemotherapy, followed by adjuvant nivolumab, improved efficacy vs neoadjuvant chemotherapy plus placebo, followed by adjuvant placebo, in patients with resectable non–small cell lung cancer (NSCLC), irrespective of the number of completed cycles of neoadjuvant treatment.¹

Findings presented at the 2024 European Lung Cancer Congress showed that among patients who completed 4 cycles of neoadjuvant treatment, those in the nivolumab arm (n = 191) experienced a pathological complete response (pCR) rate of 26.7% compared with 5.4% for those in the placebo arm (n = 205). Additionally, for patients in this population who proceeded to resection, the pCR rates for the nivolumab arm (n = 158) and placebo arm (n = 168) were 32.3% and 6.5%, respectively.

In patients who received less than 4 cycles of neoadjuvant therapy, those in the nivolumab arm (n = 38) achieved a pCR rate of 18.4% compared with 0% for those in the placebo arm (n = 27). In the 7 patients who experienced pCR in the nivolumab arm, 3 patients received 3 neoadjuvant treatment cycles, and 4 patients were administered 2 cycles. In patients who underwent resection, the pCR rates were 35.0% for the nivolumab group (n = 20) and 0% for the placebo group (n = 10).

“These results further support perioperative use of nivolumab as a potential new treatment option for our patients [with resectable NSCLC], building upon the standard of care of using chemoimmunotherapy in the neoadjuvant setting,” lead study author Mark A. Awad, MD, PhD, said in a presentation of the data. Awad is a physician, director of Clinical Research, program director of Advanced Fellowship in Thoracic Oncology, and associate chief of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

Previously reported data from CheckMate 77T showed that perioperative nivolumab plus neoadjuvant chemotherapy elicited a statistically significant and clinically meaningful improvement in event-free survival (EFS) compared with perioperative placebo plus neoadjuvant chemotherapy (HR, 0.58; 97.36% CI, 0.42-0.81; P = .00025), meeting the study’s primary end point. Patients in the nivolumab arm (n = 229) achieved 12- and 18-month EFS rates of 73% and 70%, respectively. In the placebo arm (n = 232), those rates were 59% and 50%, respectively.²

Additionally, the pCR rates for the overall populations in the nivolumab and placebo arms were 25.3% and 4.7%, respectively. The rates of major pathological response (MPR) were 35.4% and 12.1%, respectively.

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, for the perioperative treatment of patients with resectable stage IIA to IIIB NSCLC, and the European Medicines Agency validated a type II variation application for the regimen in the same indication. These applications were based on the prior data from CheckMate 77T.³

The randomized, double-blind study enrolled patients at least 18 years of age with suspected or histologically confirmed stage IIA to IIIB NSCLC that was considered resectable. Other key inclusion criteria included surgical or biopsy tumor tissue for biomarkers; and an ECOG performance status of 0 or 1. Patients could not have brain metastases, and prior systemic therapy for NSCLC was not permitted.⁴

Key exclusion criteria included active, known, or suspected autoimmune disease; any positive test for hepatitis B, hepatitis C, or HIV; and any prior treatment with any agent specifically targeting T-cell co-stimulation or checkpoint pathways.⁴ Patients with EGFR mutations or ALK alterations were not allowed to enroll.²

Patients were randomly assigned 1:1 to receive 360 mg of nivolumab plus chemotherapy once every 3 weeks for up to 4 cycles as neoadjuvant treatment; or placebo plus chemotherapy once every 3 weeks for up to 4 cycles. Following radiological restaging, patients underwent surgery within 6 weeks of the completion of neoadjuvant therapy. In the experimental arm, adjuvant nivolumab was given at 480 mg once every 4 weeks for up to 1 year, and in the control arm, adjuvant placebo was administered once every 4 weeks for up to 1 year.

EFS per blinded independent central review was the trial’s primary end point. Secondary end points included pCR and MPR by blinded independent pathological review; overall survival; and safety. EFS by pCR/MPR and by adjuvant treatment served as exploratory end points.

Eighty-three percent of patients in the experimental arm and 88% of patients in the control arm completed 4 cycles of neoadjuvant treatment. Among patients in the nivolumab arm who received less than 4 cycles of neoadjuvant therapy, reasons for discontinuation included study drug toxicity (55%; immune-mediated adverse effect [AE], 13%; peripheral neuropathy, 18%; other AE, 24%), disease progression (8%), and other (26%). In the control arm, reasons for discontinuation included study drug toxicity (41%; peripheral neuropathy, 7%; other AE, 33%), disease progression (11%), and other (41%).¹

Additional data from the exploratory analysis showed that in patients who completed 4 cycles of neoadjuvant therapy, the MPR rate in the nivolumab and placebo arms was 38.2% and 13.7%, respectively. In patients who underwent resection, those rates were 46.2% and 16.7%, respectively.

For patients who received less than 4 cycles of neoadjuvant therapy, the MPR rates were 21.1% and 0% for nivolumab and placebo, respectively. Forty percent of patients in the nivolumab arm who received less than 4 cycles of neoadjuvant therapy and underwent resection achieved a MPR vs 0% of those who received placebo.

The median EFS was not reached (NR) for patients in the nivolumab arm who completed 4 neoadjuvant cycles compared with 19.8 months for the placebo arm (HR, 0.57; 95% CI, 0.42-0.79). The 12-month EFS rates were 76% and 61%, respectively.

In patients who received less than 4 cycles of neoadjuvant therapy, the median EFS was NR for the nivolumab arm and 7.8 months for the placebo arm (HR, 0.51; 95% CI, 0.23-1.11). The 12-month EFS rates were 62% and 36%, respectively.

Furthermore, for the overall study population, the median time to distant metastasis (TTDM) was NR (95% CI, NR-NR) for the nivolumab group and 38.8 months (95% CI, 21.2-NR) for the placebo group (HR, 0.62; 95% CI, 0.44-0.85). In patients who received 4 neoadjuvant treatment cycles, the median TTDM was NR (95% CI, NR-NR) for nivolumab and 38.8 months (95% CI, 22.3-NR) for placebo (HR, 0.61; 95% CI, 0.42-0.88). For the subgroup of patients who underwent less than 4 neoadjuvant treatment cycles, the median TTDM was NR (95% CI, 16.5-NR) for nivolumab vs 10.9 months (95% CI, 3.4-22.2) for placebo (HR, 0.46; 95% CI, 0.22-0.98).

Awad said favorable TTDM trends were observed for nivolumab vs placebo in patients who achieved a pCR (HR, 0.39; 95% CI, 0.07-2.12) and those who did not have a pCR (HR, 0.81; 95% CI, 0.58-1.13), as well as in patients who had a MPR (HR, 0.44; 95% CI, 0.15-1.26) and those who did not experience a MPR (HR, 0.88; 95% CI, 0.62-1.24).

Updated adjuvant safety data showed that 69% of patients in the nivolumab arm who completed 4 neoadjuvant treatment cycles received adjuvant treatment compared with 71% of patients in the placebo arm, and patients in both arms received a median of 13 cycles of adjuvant treatment. In those who completed less than 4 cycles of neoadjuvant treatment, 29% and 26% of patients in the experimental and control arms received adjuvant treatment, respectively. In the nivolumab arm, the median number of adjuvant cycles was 13 (range, 4-13) vs 11 (range, 3-13) for the placebo arm.

In patients who completed 4 cycles of neoadjuvant therapy, 87% of patients in the nivolumab arm and 80% of patients in the placebo arm experienced any-grade AEs during adjuvant treatment. The rates of any-grade treatment-related AEs (TRAEs) were 50% and 30%, respectively. For patients in the experimental arm, the rates of AEs and TRAEs leading to treatment discontinuation were 14% and 10%, respectively. Those rates were 4% and 2%, respectively, in the placebo arm. The rates of adjuvant serious AEs were 22% for nivolumab and 16% for placebo, and the rates of serious TRAEs were 7% and 1%, respectively.

In patients who received less than 4 neoadjuvant treatment cycles, any-grade AEs during adjuvant therapy occurred in 91% of patients in the nivolumab arm and 71% of patients in the control arm. The rates of any-grade TRAEs were 46% and 29%, respectively. Nine percent of patients in the nivolumab arm discontinued adjuvant therapy due to AEs/TRAEs, compared with 14% for the placebo arm. No serious AEs or serious TRAEs were reported in the placebo arm; however, 18% of patients in the nivolumab arm experienced serious AEs, and 9% had serious TRAEs.

“Most patients who could receive adjuvant nivolumab after neoadjuvant chemoimmunotherapy received the full 1 year of [adjuvant] treatment, and [adjuvant nivolumab] had a manageable safety profile,” Awad concluded.

References

1. Awad MM, Cascone T, Spicer JD, et al. Clinical outcomes with perioperative nivolumab (nivo) in patients (pts) with resectable NSCLC from the phase III CheckMate 77T study. Presented at: 2024 European Lung Cancer Congress; March 20-23, 2024; Prague, Czech Republic. Abstract LBA2.
2. 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(suppl 2):S1295. doi:10.1016/j.annonc.2023.10.050
3. 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 March 20, 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
4. A study of neoadjuvant chemotherapy plus nivolumab versus neoadjuvant chemotherapy plus placebo, followed by surgical removal and adjuvant treatment with nivolumab or placebo for participants with surgically removable early stage non-small cell lung cancer. ClinicalTrials.gov. Updated March 4, 2024. Accessed March 20, 2024. https://www.clinicaltrials.gov/study/NCT04025879