Another China-Developed PD-1 Inhibitor Makes Its Case in NSCLC

Adding the investigational PD-1 checkpoint inhibitor toripalimab to chemotherapy in first-line significantly improved progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients without EGFR/ALK mutations, according to results from a study conducted in China.

Median PFS improved from 5.6 months with chemotherapy alone to 8.4 months with the toripalimab-based combination (HR 0.49, 95% CI 0.39-0.61, P<0.0001), reported Jie Wang, MD, of Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.

An interim overall survival (OS) analysis from the so-called CHOICE-01 trial also showed significantly longer OS for the toripalimab group (HR 0.69, 95% CI 0.52-0.92, P=0.0099), with median OS not reached in the toripalimab arm versus 17.1 months in the placebo arm, according to findings presented at an American Society of Clinical Oncology virtual plenary session.

Study discussant, Charu Aggarwal, MD, MPH, of the University of Pennsylvania in Philadelphia, poured cold water on the positive CHOICE-01 findings, however, noting that they’re unlikely to “move the field forward.”

Aggarwal noted that multiple clinical trials in NSCLC have already confirmed the benefit of first-line immunotherapy alone or with chemotherapy, including quadruplet regimens.

“Additional trials incorporating new PD-1 or PD-L1 agents compared to a standard chemotherapy doublet — unfortunately — do not provide an incremental benefit,” she said. “If this drug were to be approved, I frankly wouldn’t be able to appreciate significant differences between this trial versus other landmark trials that have been performed.”

In the U.S., regulatory prospects for toripalimab in NSCLC are unclear. The FDA granted priority review for the drug in recurrent or metastatic nasopharyngeal carcinoma, but FDA advisors and the agency itself recently expressed considerable skepticism over approving another PD-1 inhibitor in NSCLC, sintilimab, based solely on data from a randomized trial in China.

Similar to the concerns expressed at the recent FDA advisory meeting, Aggarwal questioned the CHOICE-01’s primary endpoint, as well as whether chemotherapy alone is an appropriate control arm in first-line NSCLC trials nowadays. “We should move away from using PFS as a primary endpoint, as it does not translate into an overall survival endpoint,” she said.

In addition, she said, considering that “thousands” of trials have been or are currently being conducted involving immunotherapies, can a new PD-1 or PD-L1 agent demonstrate value? “It could be valuable if it shows better efficacy, but we have yet to see a head-to-head clinical trial of a new PD-1 or PD-L1 agent compared to a current FDA standard,” Aggarwal said.

New anti-PD-1/L1 agents could move the needle if they demonstrate better tolerability or cost, she added.

For the CHOICE-01 trial, 465 patients with previously untreated advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive either toripalimab or placebo in combination with chemotherapy for four to six cycles, followed by maintenance therapy with toripalimab or placebo plus standard of care until disease progression, intolerable toxicity, or completion of 2 years of treatment.

Patients with high tumor mutational burden had significantly improved PFS with toripalimab (13.1 vs 5.5 months with placebo; HR 0.34, 95% CI 0.21-0.54), and the PFS benefit was observed in both PD-L1 positive (HR 0.52, 95% CI 0.39-0.69) and negative (HR 0.49, 95% CI 0.34-0.71) subgroups.

The objective response rate was 65.7% with toripalimab versus 46.2% with placebo.

A subset of patients with mutations in the focal adhesion-PIK3/Akt signaling pathway had significantly better PFS and OS with toripalimab as well.

Regarding safety, the incidence of grade 3 or higher adverse events (AEs) were similar in the two arms – 78.6% in the toripalimab arm and 82.1% in the placebo arm, Wang said. AEs leading to treatment discontinuation were more frequent in the toripalimab arm (14.3% vs 3.2%), as were fatal AEs (5.5% vs 2.6%).