Neoadjuvant Nivolumab Provides Sustained Efficacy in Resected NSCLC


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Treatment with neoadjuvant nivolumab led to encouraging 5-year recurrence-free survival and overall survival rates compared with historical outcomes in patients with non–small cell lung cancer who underwent surgical resection.

Samuel Rosner, MD

Samuel Rosner, MD

Treatment with neoadjuvant nivolumab (Opdivo) led to encouraging 5-year recurrence-free survival (RFS) and overall survival (OS) rates compared with historical outcomes in patients with non–small cell lung cancer (NSCLC) who underwent surgical resection, according to a final analysis of a phase 1b/2 trial (NCT02259621).

At a median follow-up of 63 months, 60% (n = 12) of the 20 patients in this trial who underwent surgical resection after receiving neoadjuvant nivolumab were recurrence free at 5 years, and 80% (n = 16) were alive at 5 years.Both patients with pathological complete response (pCR) after neoadjuvant nivolumab were alive and disease free at 5 years.1

“Results from this long-term follow-up analysis show favorable clinical outcomes after just 2 doses of neoadjuvant nivolumab prior to resection, highlighting the durability of this agent in the perioperative setting,” Samuel Rosner, MD, of the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, Maryland, said to OncLive®.

In 2018, Patrick M. Forde, MBBCh, of the Johns Hopkins Sidney Kimmel Cancer Center, and colleagues, published initial data from this phase 1/2 trial, which was the first clinical trial to evaluate a neoadjuvant PD-1 inhibitor in any cancer type. This trial showed this treatment to be safe and feasible, as it produced a major pathological response (MPR) in 45% (95% CI, 23%-68%) of patients and a pCR in 10% of patients with completely resected tumors, regardless of PD-L1 status, with few adverse effects (AEs).2 The 5-year clinical outcomes from this trial represent the longest follow-up data for neoadjuvant PD-1 inhibitors in any cancer type.1

This trial enrolled patients at least 18 years of age with resectable stage I-IIIA NSCLC. A total of 21 patients received 2 doses of nivolumab at 3 mg/kg for 4 weeks prior to planned surgery. One patient was subsequently deemed inoperable because of primary disease progression and passed away from their cancer within 9 months after enrollment.

In total, 6 patients received standard-of-care adjuvant therapy in the form of 3 to 4 cycles of cisplatin-based chemotherapy per study protocol. No patients received adjuvant radiotherapy or targeted therapy.

The primary end points of this trial were safety and feasibility of neoadjuvant nivolumab, which have been previously reported. This updated analysis described the 5-year outcomes of all patients who successfully underwent definitive NSCLC resection after study treatment. The key exploratory end points were pathological markers of response, including pCR, defined as 0% residual viable tumor, and MPR, defined as 10% or less residual viable tumor; RFS, measured from the date of surgery; and OS, measured from the date of surgery.

Patients had a median age of 67 years (range, 55-84). Regarding clinical stage at diagnosis, 22% (n = 2), 56% (n = 5), and 22% (n = 2) of patients with MPR had stage I, II, or IIIA disease vs 18% (n = 2), 45% (n = 5), and 36% (n = 4) of patients without MPR, respectively. In patients with and without MPR, respectively, 33% (n = 3) and 36% (n = 4) had PD-L1 status of at least 1%, 22% (n = 2) and 55% (n = 6) had PD-L1 status of less than 1%, and 44% (n = 4) and 9% (n = 1) had unevaluable PD-L1 status.

“Exploratory subgroup analysis suggests patients with MPR and pCR after neoadjuvant nivolumab had superior clinical outcomes,” Rosner said. Nine patients had an MPR after treatment, 89% (n = 8) of whom were alive and disease free at 5 years of follow-up.

At the 5-year analysis, MPR and PD-L1 positivity in pre-treatment tumors trended toward improved RFS, with HRs of 0.61 (95% CI, 0.15-2.44) and 0.36 (95% CI, 0.07-1.85), respectively.

Among the 7 observed disease recurrences, 86% (n = 6) occurred in patients without an MPR after neoadjuvant nivolumab. Of the 6 patients with disease recurrence and available pre-treatment PD-L1 assessment, 4 had PD-L1–negative disease.

Patients with stage I/II NSCLC had numerically favorable RFS vs those with stage IIIA disease (HR, 0.42; 95% CI, 0.11-1.62).

An exploratory analysis that evaluated an alternative pathological response threshold of 50% of residual viable tumor, or partial pathologic response, showed a favorable RFS association (HR, 0.36; 95% CI, 0.09-1.51). When assessed as a continuous variable, increasing percentage of residual viable tumor trended toward increasing recurrence risk (HR, 2.9; 95% CI, 0.51-16.57).

In the 11 patients with available tumor samples for sequencing analysis, mean tumor mutational burden, when assessed as a continuous variable, was not associated with RFS or OS improvements, with respective HRs of 1.0 (95% CI, 0.99-1.01) and 1.01 (95% CI, 1.00-1.02).

Seven tumor recurrences occurred during the observation period, 57% (n = 4) of which occurred over 1 year after surgery. Three patients experienced intrathoracic recurrences. Of the 7 total patients with recurrences, 4 remained alive at 5 years following treatment for NSCLC recurrence, 3 of whom received successful definitive local treatment for metachronous oligometastatic disease.

As previously reported, treatment with adjuvant nivolumab induced few AEs and did not cause surgical delays. One patient experienced a late-onset grade 3 dermatologic immune-related AE, dermatitis herpetiformis with alopecia universalis, 16 months after their last dose of nivolumab. This AE was successfully managed by immunosuppression. The investigators observed no other late-onset immune-related AEs.

No cancer-related deaths occurred among patients with MPR. However, 1 patient with MPR without NSCLC recurrence died at 2 months from secondary effects from a traumatic head injury. Of the 11 patients without MPR, 6 had tumor relapse and 3 died.

“This analysis is certainly limited by the small cohort size and overall low recurrence rate, but nonetheless further reinforces the growing role of immune checkpoint inhibitors in the pre-operative treatment of early-stage NSCLC, while highlighting additional biomarkers of response that correspond with other larger-scale prospective studies in this setting. While we await longer-term follow-up from pivotal studies such as the [phase 3] CheckMate-816 trial [NCT02998528], prolonged follow-up from pilot studies such as this may offer us a glimpse into the future of this rapidly evolving treatment setting,” Rosner concluded.


  1. Rosner S, Reuss JE, Zahurak M, et al. Five-year clinical outcomes after neoadjuvant nivolumab in resectable non–small cell lung cancer. Clin Cancer Res. 2023;29:705-710. doi:10.1158/1078-0432.CCR-22-2994
  2. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976-1986. doi:10.1056/NEJMoa1716078
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