According to CHOICE-01, a phase III trial in China, the PD-1 inhibitor toripalimab plus chemotherapy improves progression-free survival in patients with untreated non–small cell lung cancer lacking actionable mutations. The findings boost combination chemo–immunotherapy, rather than chemotherapy alone, as the new standard for this population.

Findings from CHOICE-01 indicate that toripalimab (Junshi Biosciences) prolongs the time to disease progression in patients with untreated non–small cell lung cancer (NSCLC) when added to chemotherapy. Data from the phase III trial were presented by Jie Wang, MD, of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, during the March session of the American Society of Clinical Oncology's monthly Plenary Series.

Toripalimab is one of China's domestically developed PD-1 inhibitors. Known there as Tuoyi, it is an approved second-line therapy for melanoma, urothelial cancer, and nasopharyngeal carcinoma. In the United States, it is under priority review for the latter cancer, with a decision expected in April.

CHOICE-01 enrolled 465 patients with advanced or metastatic NSCLC that lacked sensitizing EGFR or ALK mutations. They were randomly assigned 2:1 to receive toripalimab or placebo combined with standard first-line chemotherapy. The median progression-free survival (PFS) with toripalimab was 8.4 months, Wang reported, compared with 5.6 months in the control arm. In subgroup analyses, a high tumor mutation burden further improved PFS among patients given toripalimab, as did the presence of focal adhesions along the PI3K–AKT signaling pathway. Although median overall survival (OS) was not a primary endpoint, in an interim assessment, it was not reached with toripalimab and was 17.1 months with chemotherapy alone.

Discussant Charu Aggarwal, MD, of the University of Pennsylvania in Philadelphia, noted that across multiple NSCLC studies, “long-term outcomes confirm that we're making a meaningful difference in overall survival through our current practice of integrating immunotherapy with chemotherapy.” CHOICE-01's results are “very comparable” to KEYNOTE-189 and KEYNOTE-407, which evaluated pembrolizumab (Keytruda; Merck) alongside chemotherapy in similar patient populations, she said.

More broadly, though, “perhaps we should move away from PFS as a primary endpoint” in trials, Aggarwal observed, citing findings that it only modestly correlates with OS (J Immunother Cancer 2021;9:e002114). If nothing else, “we may want to critically think about whether PFS, as a term, affects patient choice,” she added, “and whether something like ‘progression-free interval’ might better dissociate it from OS,” which is more clinically meaningful (Lancet Oncol 2022;23:328–30).

CHOICE-01 is not unlike ORIENT-11, another Chinese study evaluating a different homegrown PD-1 inhibitor, sintilimab, in NSCLC. A recent commentary questioned the generalizability of such trial data—from a single country with less diverse demographics—to a more heterogenous U.S. population (Lancet Oncol 2022;23:323–5). This opinion was echoed by the FDA's Oncologic Drugs Advisory Committee, which has requested additional studies of sintilimab prior to deciding whether to recommend it for approval.

Asked about this issue, Wang responded that “we believe our findings could be applied to Western populations.” She pointed out the “similar PFS observed in our study, compared with other PD-1 inhibitor trials” and “similar treatment guidelines for advanced NSCLC” between the National Comprehensive Cancer Network and the Chinese Society of Clinical Oncology. As well, she observed that the FDA's own meta-analysis of NSCLC trials did not uncover an appreciable difference between Asian and non-Asian patients in their magnitude of benefit from immune checkpoint inhibitors (J Clin Oncol 37, 2019 [suppl; abstr e20690]).

Even so, looking ahead, “multiregional trials with diverse populations and coordinated worldwide regulatory submissions should definitely be pursued,” Aggarwal said. Meanwhile, CHOICE-01 joins the list of studies establishing that for NSCLC without actionable mutations, “frontline chemo–immunotherapy is the clear standard and should be used as the control—not chemotherapy alone—in new trials, if we are to keep moving the efficacy needle.” –Alissa Poh

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