Pathologic Response Is Key Indicator of EFS Benefit With Neoadjuvant Nivolumab Plus Chemotherapy in Resectable NSCLC

Neoadjuvant nivolumab in combination with platinum-based doublet chemotherapy extended event-free survival in patients with stage IB-IIA non–small cell lung cancer who had pathologic complete response, according to a post hoc analysis of the phase 3 CheckMate 816 trial.

Neoadjuvant nivolumab (Opdivo) in combination with platinum-based doublet chemotherapy extended event-free survival (EFS) in patients with stage IB-IIA non–small cell lung cancer (NSCLC) who had pathologic complete response (pCR), according to a post hoc analysis of the phase 3 CheckMate 816 trial (NCT02998528).1

Mariano Provencio-Pulla, PhD, head of medical oncology at Hospital Universitario Puerta de Hierro in Madrid, Spain, presented the findings during the 2022 ASCO Annual Meeting. CheckMate 816 is the first in-depth assessment of pathological regression and EFS in a phase 3 trial of neoadjuvant immunotherapy, he said.

“Patients who achieve pCR status in the primary tumor had better EFS than those without—93% in patients who achieved pCR vs 58% at 2 years,” Provencio-Pulla said. He added that patients who had major pathologic response (mPR) also experienced an EFS benefit (HR, 0.26; 95% CI, 0.14.-0.50).

Investigators analyzed the association between pCR in the primary tumor only and EFS, as well as whether degree of pathological regression could be predictive for EFS. Major pathologic complete response (mPR) was a secondary end point.

At a median follow-up of 29.5 months, 46 patients in the experimental arm had a pCR compared with 95 who did not. The median EFS for those with a pCR was not reached (NR; 95% CI, 30.6-NR) compared with 27.8 months (95% CI, 20.0-NR) for those who did not have pCR (HR, 0.18; 95% CI, 0.07-0.46).

Similarly, the median EFS was superior among those who had pCR with chemotherapy treatment compared with those who did not (NR vs 26.2 months).

“Certainly, we have known that pCR correlates with EFS, and that has been presented,” said discussant Jyoti Patel, MD, a professor of medicine at Northwestern University and associate vice-chair for clinical research in the Department of Medicine, as well as medical director of thoracic oncology and assistant director for clinical research in the Lurie Cancer Center in Chicago, Illinois. “Although the numbers, even for the patients who reach pCR [with] chemotherapy alone, [are] quite small, clearly, that indicates better outcome.

“But this analysis is commended to help us go beyond such a binary view, and helps us understand whether the amount of pathologic response can be correlated to further stratify what we do for our patients.”

Provencio-Pulla said investigators conducted receiver operating characteristic (ROC) curve analysis as a continuous variable to assess EFS by depth of pathological regression, which was measured by percent of residual volume of tumor (RVT). Depth of pathological regression appeared to be predictive in the experimental arm (area under the curve [AUC], 0.74) but not for chemotherapy (AUC, 0.54).

“The EFS according to RVT categories was 90% at 2 years for patients with RVT 0% to 5%, 60% for patients with RVT 5% to 30%, 57% in patients with RVT 30% to 80%, and 39% in patients with more than 80% RVT,” Provencio-Pulla said.

Investigators also assessed the association between pCR and EFS by baseline disease stage. Among patients with stage IB/II disease, the median EFS was again superior among those who had a pCR compared with those who did not (NR vs 27.8 months). The same was true for those with baseline stage IIIA disease who had a pCR (NR vs 30.2 months). The 2-year EFS rate was 90% vs 56% among patients with stage IB/II disease and 96% vs 59% in those with stage IIIA disease, in favor of patients who had pCR.

As assessed by PD-L1 expression, the 2-year EFS rate was 86% among those who were PD–L1-negative (< 1%) and had pCR vs 47% for those who did not. The median EFS was 30.6 vs 23.4 months, respectively.

For patients who were PD–L1-positive (≥ 1%), the 2-year EFS rate was 97% vs 72% in favor of those who had pCR. The median EFS was NR in both groups.

“Checkmate 816 is an important study as it is the largest phase 3 trial reported to date to show a significant EFS and pCR advantage for neoadjuvant nivolumab plus chemotherapy doublet followed by surgery in patients with early-stage NSCLC,” J. Marie Suga, MD, MPH, medical director, Kaiser Permanente Oncology Clinical Trials, said in an email to OncLive®. “This presentation focuses on the key secondary endpoint of pathologic response and its relationship with EFS. Understanding the link between pathology results at time of surgery and survival will be critical to determining whether those results could be useful as an early surrogate biomarker to predict clinical benefit for our patients with lung cancer.”

The FDA approved this combination for patients with resectable NSCLC in March 2022 based on results from CheckMate 816.2 Previous data showed the median EFS with nivolumab plus chemotherapy was 31.6 months (95% CI, 30.2-NR) vs 20.8 months (95% CI, 14.0-26.7) with chemotherapy alone (HR, 0.63; 95% CI, 0.45-0.87; P = .0052).3

The nivolumab combination induced a pCR in 24% (95% CI, 18.0%-31.0%) of patients vs 2.2% (95% CI, 0.6% -5.6%) of patients who received chemotherapy alone (estimated treatment difference 21.6; 95% CI, 15.1-28.2; P < .0001). Results from a prespecified interim analysis for overall survival resulted in a HR of 0.57 (95% CI, 0.38-0.87), which did not cross the boundary for statistical significance.

The open-label, multicenter, CheckMate 816 trial enrolled patients with newly diagnosed, resectable, stage IB to IIIA NSCLC who had an ECOG performance status of 0 or 1 and no known sensitizing EGFR mutations or ALK alterations.

A total of 358 participants were randomly assigned to receive 360 mg nivolumab every 3 weeks plus platinum-doublet chemotherapy every 3 weeks for 3 doses, or to chemotherapy alone. Patients then underwent radiologic restaging, went on to undergo surgery within 6 weeks after treatment, went on to receive optional adjuvant chemotherapy with or without radiotherapy, and then entered follow-up.


  1. Provencio-Pulla M, Spicer J, Taube JM, et al. Neoadjuvant nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) versus chemo for resectable (IB–IIIA) non-small cell lung cancer (NSCLC): association of pathological regression with event-free survival (EFS) in CheckMate 816. J Clin Oncol. 2022,40;(suppl 17):LBA8511. doi:10.1200/JCO.2022.40.17_suppl.LBA8511
  2. US Food and Drug Administration approves Opdivo (nivolumab) with chemotherapy as neoadjuvant treatment for certain adult patients with resectable non-small cell lung cancer. News release. Bristol Myers Squibb; March 4, 2022. Accessed June 6, 2022.
  3. Forde PM, Spicer J, Lu S, Provencio-Pulla M, et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170