Toripalimab Plus Chemo Bests Chemo Alone in Treatment-Naïve Metastatic NSCLC

The addition of toripalimab to chemotherapy for the treatment of patients with previously untreated advanced non–small cell lung cancer (NSCLC) derived superior survival outcomes verses chemotherapy alone, according to results from the phase 3 CHOICE-1 trial (NCT03856411) that were presented as part of the American Society of Clinical Oncology (ASCO) Plenary Series.

Final progression-free survival (PFS) analysis revealed a 51% reduction in the risk of disease progression or death with toripalimab vs chemotherapy, with medians of 8.4 months (95% CI, 7.7-9.6) and 5.6 months (95% CI, 5.5-6.8), respectively (HR, 0.49; 95% CI, 0.39-0.61; 2-sided P <.0001). At the interim overall survival (OS) analysis at the data cutoff of October 31, 2021, results had crossed the boundary for significance and favored the toripalimab treatment arm (HR, 0.69; 95% CI, 0.52-0.92; P = .0099).

“The addition of toripalimab to chemotherapy in patients with treatment-naïve advanced non–small cell lung cancer provide superior clinical outcomes over chemotherapy alone with a manageable safety profile,” Jie Wang, MD, of, the National Cancer Center and Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, said during a presentation of the data. “PFS and OS benefit were observed regardless of PD-L1 expression.”

The double-blind, multicenter, randomized trial compared the efficacy and safety of toripalimab vs placebo plus frontline standard chemotherapy in patients with advanced NSCLC, regardless of histology. To be eligible for inclusion on the trial, patients needed to have stage IIIB or IV disease, have no prior treatment for locally advanced or metastatic disease, and have no known sensitizing EGFR mutations or ALK fusions. Patient’s ECOG performance score must have been 0 or 1, and all patients were required to have tissue evaluable for PD-L1 expression.

Stratification factors included PD-L1 expression (expression on ≥1% vs <1% of tumor cell [TCs]), smoking status, and histology (non-squamous vs squamous). The primary end point was PFS per RECIST version 1.1 by investigator assessment with secondary outcome measures of OS, PFS by blinded independent central review, objective response rate (ORR), disease control rate (DCR), time to response (TTR), and safety.

Patients (N = 456) were randomized 2:1 to received either intravenous toripalimab at 240 mg on day 1 of each 3-week cycle plus either pemetrexed and cisplatin/carboplatin for 4 to 6 cycles followed by pemetrexed for patients with non-squamous histology or nab-paclitaxel (Abraxane) plus carboplatin for 4 to 6 cycles in those with squamous histology; those in the control arm received the same chemotherapy regimens as in the experimental arm plus matched placebo. Crossover to toripalimab was allowed for patients who were treated in the placebo arm and had investigator-assessed progressive disease.

Baseline characteristics were well balanced between the 2 arms. Patients in the toripalimab (n = 309) and placebo (n = 156) groups were primarily male (79.9% vs 83.3%), had an ECOG performance status of 1 (78.6% vs 76.9%), had PD-L1 expression of 1% or more TC (65.0% vs 66.0%), and were frequent smokers (68.9% vs 68.6%). About half of patients presented with non-squamous histology (52.4% vs 53.2%) and the most common tumor status at presentation was stage IVA disease (45.6% vs 52.6%).

The PFS rate at 1 year in the toripalimab group was 36.7% (95% CI, 30.9%-42.5%) vs 17.2% (95% CI, 11.4%-24.0%) with the placebo. PFS benefit was maintained across most patient subgroups, including PD-L1 expression subgroups of TC less than 1% (HR, 0.49; P = .0001) and TC 1% or greater (HR, 0.52; P <.0001), nonsquamous (HR, 0.48; P <.0001) and squamous histology (HR, 0.49; P <.0001), and tumor mutational burden (TMB) expression levels of 10 mutations/megabase or more (HR, 0.34; P <.0001) and less than 10 mutations/megabase (HR, 0.62; P = .0011).

Significant improvement in ORR was associated with treatment with toripalimab, at 65.7% (95% CI, 60.1%-71.0%) vs 46.2% (95% CI, 38.2%-54.3%) with placebo; both arms consisted exclusively of partial responses (P <.0001). The median DOR was 8.4 months (95% CI, 6.9-12.9) with the experimental regimen and 4.2 months (95% CI, 4.0-5.6) with the control regimen (HR, 0.38; 95% CI, 0.28-0.53; P <.0001).

Median OS in the intention-to-treat population was not reached (95% CI, 21.7–not estimated) in the toripalimab arm vs 17.1 months (95% CI, 14.4-22.2) with placebo. OR rates at 1 year (74.0% vs 72.8%, respectively) and 24 months (51.2% vs 33.9%) favored the experimental arm. Wang noted that there was a high rate of crossover from the placebo group, with 81 of 88 patients (92.0%) going on to received toripalimab upon disease progression.

Of note, OS benefit of the toripalimab combination was sustained with PD-L1 expression levels of TC less than 1% (HR, 0.70; P = .0497) and TC 1% or greater (HR, 0.68; P <.0844), as well as with TMB of 10 mutations/megabase or more (HR, 0.67; P = .1649) and less than 10 mutations/megabase (HR, 0.68; P = .0335).

The occurrence of grade 3 or greater treatment-emergent adverse events (TEAEs) was greater in the toripalimab group (78.6% vs 82.1%), as were serious AEs (44.8% vs 35.3%) and TEAEs resulting in death (5.5% vs 2.6%). Patients on toripalimab experienced higher rates of therapy discontinuation (14.3% vs 3.2%) and interruption (63.0% vs 55.1%). Investigator-determined immune-related AEs (irAEs) were more common with toripalimab vs placebo (49.4% vs 21.2%) as were grade 3 or greater irAEs (15.6% vs 3.2%). The most common TEAEs in both arms included anemia, neutropenia, leukopenia, thrombocytopenia, alanine aminotransferase increase, aspartate aminotransferase increase, fatigue, decreased appetite, nausea, pyrexia, hypoalbuminemia, musculoskeletal pain, constipation, and vomiting.

Notably, Wang said focal adhesions through PI3K-AKT pathway genes or mutations in the IL-7 signaling pathway enriched both OS and PFS outcomes with toripalimab (P ≤.01).

Reference

Wang J, Wang Z, Wu L, et al. Final progression-free survival, interim overall survival, and biomarker analyses of CHOICE-01: A phase III study of toripalimab versus placebo in combination with first-line chemotherapy for advanced NSCLC without EGFR/ALK mutations. Presented at: ASCO Plenary Series: March 2022 Session; March 15, 2022. Abstract 362936. Virtual. https://bit.ly/3JmgnkY