Adding an investigational anti-PD-1 drug to perioperative chemotherapy improved event-free survival (EFS) in patients with resectable, stage III non-small cell lung cancer (NSCLC), an interim analysis of a phase III study found.

Among 404 patients receiving perioperative chemotherapy in the so-called Neotorch trial, the median investigator-assessed EFS was not reached in patients assigned to toripalimab, as compared with 15.1 months for those in a placebo arm (HR 0.40, 95% CI 0.277-0.565, P<0.0001), reported Shun Lu, PhD, of the Shanghai Chest Hospital.

The EFS results, at a median follow-up of 18.3 months, were consistent across key subgroups, with a greater benefit observed in patients with stage IIIB disease, PD-L1 positive tumors, or squamous cell histology.

In addition, toripalimab led to higher rates of major pathologic response (MPR; 48.5% vs 8.4% with placebo) and pathologic complete response (pCR; 24.8% vs 1.0%; P<0.0001 for both), as was a favorable trend in overall survival (OS), Lu said during an American Society of Clinical Oncology (ASCO) virtual plenary.

While OS data were not mature, initial results showed a median OS not reached in the investigational arm compared with 30.4 months in the placebo arm (HR 0.62, 95% CI 0.381-0.999, P=0.0502).

“Periadjuvant chemoimmunotherapy with one cycle given postoperatively appears beneficial in stage III patients and may eliminate micrometastatic disease in subgroups with a poorer prognosis,” commented ASCO discussant Tina Cascone, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston. She noted that EFS rates by pCR status and residual viable tumor percentage weren’t available in this analysis, but added they are “absolutely critical to guide therapy and minimize clinical and financial toxicity.”

Optimal Number of Cycles?

Cascone pointed out that the three neoadjuvant cycles of chemoimmunotherapy delivered in Neotorch — every 3 weeks, followed by surgery and one postoperative cycle — were comparable to the number tested in CheckMate-816, which evaluated nivolumab (Opdivo) plus neoadjuvant chemotherapy in resectable NSCLC and led to FDA approval of the regimen in 2022.

“Administration of an additional cycle of chemoimmunotherapy in the adjuvant phase of Neotorch makes the total number of cycles — four — comparable to the number tested in other phase III randomized perioperative trials,” she said. “But here in Neotorch, the fourth cycle is given postoperatively when residual micrometastatic disease may be present, and perhaps responsible for disease relapse.”

While two to four cycles of neoadjuvant chemoimmunotherapy have been used in most trials, “there is really no consensus on the optimal number and sequence” in this setting, she added.

Cascone noted that the neoSCORE trial evaluated the outcome of two versus three cycles of neoadjuvant sintilimab with platinum-based chemotherapy in resectable IB-IIIA NSCLC patients and showed that three cycles of treatment provided a 14.5% increase in the MPR rate compared with two cycles. She also pointed out that like Neotorch, the phase III AEGEAN trial tested four cycles of chemoimmunotherapy, but with different perioperative schedules “that may impact long-term survival outcomes.”

Despite the different schedules and/or numbers of cycles of chemoimmunotherapy used in the current study, the MPR and pCR rates were comparable to those in CheckMate-816 and AEGEAN, she observed.

Neotorch Details

Participants in the study were randomized 1:1 to receive neoadjuvant platinum-based chemotherapy plus either toripalimab or placebo every 3 weeks for three cycles. Following surgery, patients went on to receive one postsurgical cycle of combination therapy, and then maintenance therapy with toripalimab or placebo every 3 weeks for up to 13 cycles.

Patients in the study had a median age of 62 years, 90% were men, and 88% were current or former smokers. Most had squamous cell histology (78%), and about two-thirds had stage IIIA disease.

Investigator-assessed EFS rates at 1 and 2 years were 84% and 65% in the toripalimab arm, as compared with 57% and 39% in the placebo arm. By independent review, those rates were 81% and 67% versus 56% and 46%, respectively.

One- and 2-year OS rates were 94% and 81% in the toripalimab arm, as compared with 90% and 74% in the placebo arm.

As for safety, the incidence of adverse events (AEs) tended to be higher in the toripalimab arm, including grade ≥3 AEs (63.4% vs 54.0% with placebo), immune-related AEs (42.1% vs 22.8%), serious AEs (40.6% vs 28.2%), fatal AEs (0.5% vs 0%), and AEs leading to drug discontinuation (9.4% vs 7.4%).

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