Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial

Abstract

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown.

Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone.

Design, setting, and participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022.

Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles.

Main outcomes and measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events.

Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups.

Conclusions and relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile.

Trial registration: ClinicalTrials.gov Identifier: NCT04158440.

Figure 1.. Patient Selection and Flow in Trial of Perioperative Toripalimab Plus Chemotherapy for Stage III Non–Small Cell Lung Cancer

^aSome patients had more than 1 reason for not meeting eligibility criteria; data do not sum. Additional details appear in eTable 1 in Supplement 3. ^bPatients were randomized at a 1:1 ratio and stratified by disease stage (II vs IIIA vs IIIB), programmed cell death ligand 1 expression status (≥1% vs <1% or not evaluable), planned surgical approach (pneumonectomy vs lobectomy), and histopathological subtype (squamous vs nonsquamous). The prespecified interim analysis of event-free survival was triggered in patients with stage III cancer. ^cThe group assignment of patients with stage II cancer remained blinded and these patients were excluded from this analysis. ^dThree patients no longer met eligibility criteria and did not undergo surgery, including 2 patients with stage IIIB (N2) disease and 1 patient with stage IIIC (N3) disease that was not resectable at baseline; these patients were misdiagnosed during screening. One patient did not return for treatment and the follow-up visit. ^eFour patients no longer met eligibility criteria and did not undergo surgery, including 2 patients with distant metastases (stage IV) and 2 patients with stage IIIB (N2) disease that was not resectable at baseline; these patients were misdiagnosed during screening.

Figure 2.. Event-Free and Overall Survival

The median follow-up was 18.3 months (IQR, 12.7-22.5 months). The vertical lines on the curves indicate censored patients. All hazard ratios (HRs) were computed using the Cox proportional hazards model. Event-free survival was defined as the time from randomization to first documented disease progression prohibiting surgery, postoperative disease progression, local or distant recurrence, or death due to any cause, whichever occurred first. An MPR was defined as having 10% or less viable tumor cells in the tumor bed.