Addition of Adjuvant Nivolumab Improves EFS in NSCLC

Surgery and adjuvant nivolumab (Opdivo) given after a treatment regimen of neoadjuvant nivolumab plus chemotherapy, showed a significant event-free survival (EFS) benefit for patients with previously untreated resectable stage II to IIIB non-small cell lung cancer (NSCLC), according to data presented at the 2023 ESMO Congress.¹

These data came from the phase 3 CheckMate 77T trial (NCT04025879), and after a median follow-up of 25.4 months (range, 15.7-44.2), perioperative nivolumab demonstrated a clinically meaningful improvement in EFS. Median EFS with nivolumab was not reached (NR; 95% CI, 28.9-NR), compared with 18.4 months (95% CI, 13.6-28.1) with placebo (HR, 0.58; 97.36% CI, 0.42-0.81; P = .00025). Per investigator assessment, treatment with nivolumab reduced the risk for recurrence, disease progression, or death by 44%, compared with placebo (HR, 0.56; 95% CI, 0.41-0.76).

“Checkmate 77T is the first phase 3 perioperative study to build on the standard-of-care neoadjuvant nivolumab plus chemo and supports perioperative nivolumab as a potential new treatment option for patients with resectable non-small cell lung cancer,” Tina Cascone MD, PhD, assistant professor in the Department of Thoracic, Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, said during a presentation of the data.

Tina Cascone MD, PhD

Assistant professor in the Department of Thoracic

Head and Neck Medical Oncology

The University of Texas MD Anderson Cancer Center

After a median follow-up of 25.4 months (range, 15.7-44.2), perioperative nivolumab demonstrated a statistically significant and clinically meaningful improvement in EFS. Median EFS with nivolumab was not reached (NR; 95% CI, 28.9-NR), compared with 18.4 months (95% CI, 13.6-28.1) with placebo (HR, 0.58; 97.36% CI, 0.42-0.81; P = .00025). Per investigator assessment, treatment with nivolumab reduced the risk for recurrence, disease progression, or death by 44%, compared with placebo (HR, 0.56; 95% CI, 0.41-0.76).

Further, 18-month EFS was superior with nivolumab vs placebo (70% vs 50%, respectively), “suggesting greater benefit for our patients over time,” Cascone said.

PFS benefit with nivolumab was observed across subgroups, regardless of disease stage — with a particular benefit in those with stage III disease — N2 status (single-station vs multi-station), type of disease (squamous vs non-squamous), smoking status, and PD-L1 status.

“However, given the small sample size of this subgroup, results should be taken with caution,” Cascone noted.

In exploratory analyses, the investigators evaluated EFS by baseline disease stage, tumor PD-L1 expression, pathologic complete response (pCR) and major pathologic response (MPR) status, adjuvant treatment status, and pCR status in patients who received adjuvant treatment.

Among patients with stage II disease, median EFS was NR in both the nivolumab (95% CI, 22.6-NR) and placebo (95% CI, 24.2-NR) arms (HR, 0.81; 95% CI, 0.46-1.43), while those with stage III disease demonstrated a median EFS of 30.2 months (95% CI, 26.9-NR) and 13.4 months (95% CI, 9.8-17.7), respectively. The 12-month EFS rates in patients with stage II disease treated with nivolumab and placebo were 78% and 73%, respectively, and 71% and 52% in those with stage III disease.

When evaluating patients by PD-L1 status, those with <1% induced a median EFS of 29.0 months (95% CI, 21.4-NR) with nivolumab, compared with 19.8 months (95% CI, 13.9-NR) with placebo (HR, 0.73; 95% CI, 0.47-1.15), while those with 1% or greater had a median EFS of NR (95% CI, 28.9-NR) and 15.8 months (95% CI, 9.3-35.1), respectively (HR, 0.52; 95% CI, 0.35-0.78).

Nivolumab, compared with placebo, was superior for both pCR (25.3% vs 4.7%, respectively; odds ratio [OR], 6.64; 95% CI, 3.40-12.97) and MPR (35.4% vs 12.1%; OR, 4.01; 95% CI, 2.48-6.49). The pCR benefit was also seen across the subgroup analysis.

Comparing nivolumab vs placebo, patients with pCR had an HR for EFS of 0.33 (95% CI, 0.08-1.37), while those with no pCR had an HR for EFS of 0.79 (95% CI, 0.58-1.06). In addition, patients with MPR had an HR for EFS of 0.40 (95% CI, 0.16-0.99), while those with no MPR had an HR for EFS of 0.85 (95% CI, 0.62-1.15).

When evaluating EFS by adjuvant treatment status, patients who underwent adjuvant therapy in the nivolumab arm demonstrated an EFS of NR (95% CI, NR-NR), compared with 35.1 months (95% CI, 22.0-NR) with placebo (HR, 0.45; 95% CI, 0.29-0.69). Among those who did not undergo adjuvant therapy, the HR was just 0.55 (95% CI, 0.37-0.83).

Lastly, EFS by pCR status in patients who received adjuvant treatment favored nivolumab treatment, demonstrating an HR of 0.22 (95% CI, 0.04-1.08) in those with pCR, vs 0.63 (95% CI, 0.40-0.99) in those without it.

“We know that patients have a better prognosis if pre-surgical treatment of lung cancer leads to tumor disappearance on pathology reports after surgery than if there are still obvious cancer cells present in post-surgical material,” Elene Mariamidze, Todua Clinic, Tbilisi, Georgia, said in a press release issued by ESMO.² “The new results show that adding immunotherapy to chemotherapy before surgery, and then continuing with maintenance immunotherapy for a year after surgery, is more effective than just giving chemotherapy before surgery.”

Any-grade surgery-related adverse events (AEs) occurred in 73 patients (41%) in the nivolumab arm, and 69 patients (39%) patients in the placebo arm, while 21 (12%) patients in each arm experienced grade 3 to 4 AEs. Treatment-related deaths occurred in 2 (1%) patients in the nivolumab arm: 1 due to grade 5 pneumonitis and 1 due to grade 4 pneumonitis, both occurring after completion of neoadjuvant treatment.

Of the 229 patients who received nivolumab plus chemotherapy, 15% discontinued neoadjuvant therapy, while 20% went on to cancel their definitive surgery, and 17% of this arm did not receive adjuvant therapy as a result of study drug toxicity (6%), disease progression (2%), or another reason (9%). In total, 85 patients (60%) in the nivolumab arm completed treatment, compared with 92 patients (60%) in the control arm, and 8 (6%) are ongoing in the study, compared with 8 (5%) with placebo. Nearly two-thirds of patients received adjuvant treatment with a median number of 13 doses administered in each arm, Cascone said.

Nivolumab is the current standard of care for the adjuvant treatment of patients with resectable NSCLC. Thus, Cascone and colleagues believed the agent has a role in the neoadjuvant setting as well. “A perioperative treatment approach, including adjuvant nivolumab, could potentially further reduce the risk of disease relapse and improve clinical benefit in patients with resectable non-small cell lung cancer,” Cascone said.

In the global, randomized, double-blind phase 3 study, the investigators randomized 461 patients 1:1 to receive either:

• 360 mg nivolumab every 3 weeks plus chemotherapy every 3 weeks for 4 cycles (n = 229), followed by surgery within 6 weeks of neoadjuvant therapy (n = 178), and 480 mg nivolumab every 4 weeks for 1 year (n = 142); or
• Placebo plus chemotherapy every 3 weeks for 4 cycles (n = 230), followed by surgery within 6 weeks of neoadjuvant therapy (n = 178), and placebo for 1 year (n = 152).

To be eligible for the trial, patients had to have resectable, stage IIA to IIIB NSCLC, have received no prior systemic anti-cancer treatment, and no EGFR mutation or known ALK alterations. Patients were stratified by disease histology, disease stage, and PD-L1 status.

EFS by blinded independent central review served as the primary end point, while secondary end points included pCR by blinded independent pathological review (BIPR), MPR by BIPR, overall survival, and safety. EFS by pCR/MPR and EFS by adjuvant treatment were also evaluated in an exploratory analysis.

Cascone noted that, in the nivolumab arm, median age was 66 years (range, 37-82), while the majority of patients had stage IIIA-B disease (64%), were current or former smokers (93%), and had either PD-L1 <1% (41%) or PD-L1 1% or greater (56%).

Lobectomy was the most common type of surgery and was performed in 80% of patients in the nivolumab arm and 72% of those in the chemotherapy arm, while 9% and 14% of patients, respectively, underwent pneumonectomy. Approximately 90% of patients in each arm had an R0 resection.

^Reference:

^{1. Cascone T, Awad MM, Spicer J, et al. CheckMate 77T: Phase 3 study comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or placebo for previously untreated, resectable stage II–IIIB NSCLC. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA1.}

^{2. ESMO Press Release. Lung Cancer Treatment Research Enters a New Era. Published: October 17, 2023. Accessed: October 21, 2023. https://bit.ly/45VY14Z.}