Adding toripalimab to chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) without EGFR/ALK mutations provides superior progression-free survival (PFS) and overall survival (OS) as compared to chemotherapy alone, and with a manageable safety profile, according to a new study.
"Toripalimab plus chemotherapy represents a first-line treatment option for patients with advanced NSCLC without driver mutations," said lead author Jie Wang, MD, PhD, from the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College in Beijing, China.
Toripalimab is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed in China. CHOICE-01 is a randomized, double-blind, placebo-controlled, multicenter, Phase III trial conducted in China that included 465 patients, median age 62 years, with advanced NSCLC without EGFR/ALK mutations who had not yet undergone systematic treatment for metastatic disease. Patients were randomized to receive toripalimab 240 mg (309 patients) or placebo (156 patients) in combination with chemotherapy for 4-6 cycles, followed by maintenance of toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment.
Stratification factors included PD-L1 expression status, histology, and smoking status. The primary endpoint was PFS by investigator per RECIST v1.1. Secondary endpoints included PFS by a blinded independent review committee, OS, and safety. Patient characteristics were well-balanced between the two arms, she said. PD-L1 positivity rate was about 65 percent in both arms. Wang presented the final results of the trial at the March 2022 American Society of Clinical Oncology (ASCO) Plenary Series (Abstract 362936).
Study Results
At the prespecified final PFS analysis, PFS was 8.4 months in the toripalimab arm compared to 5.6 months in the placebo arm. The 1-year PFS rate was 36.7 percent in the toripalimab arm and 17.2 percent in the placebo arm.
"A significant improvement as assessed by investigators was seen in the toripalimab arm over the control arm," said Wang. "The PFS effect favored the toripalimab arm in all major subgroups, including histology, PD-L1 expression, and tumor mutational burden (TMB)."
There was also significant improvement in overall response rate with toripalimab (65.7%) versus placebo (46.2%). "The median duration of response was double in the toripalimab arm (8.4 vs. 4.2 months)," she noted.
At the interim OS analysis, median OS had not yet been reached in the toripalimab arm compared to 17.1 months in the placebo arm. "The improvement in OS was observed despite a high crossover rate," said Wang. "The crossover rate was the highest of any clinical trial involving first-line immunotherapy in NSCLC." In the placebo arm, 92 percent received toripalimab upon disease progression and 65.4 percent received subsequent anti-PD-1/PD-L1 treatment.
"The OS effect favored the toripalimab arm in most subgroups, including PD-L1 expression and TMB high or low," said Wang.
The incidence of treatment-related adverse events (TRAEs) of Grade 3 or higher was similar between the two arms, around 80 percent. In the toripalimab arm compared to the placebo arm, there were more TRAEs leading to discontinuation (14.3% vs. 5.5%) and more fatal adverse events (5.5% vs. 2.6%).
Whole-exome sequencing was performed to identify correlative biomarkers for survival. Patients with high TMB had significantly better PFS in the toripalimab arm over the placebo arm (13.1 months compared to 5.5 months) and patients with mutations in the FA-PI3K-Akt pathway or IL-7 signaling pathways had significantly better PFS in the placebo arm (8.9 months compared to 4.2 months).
In summary, Wang said: "Toripalimab in combination with chemotherapy provided a significant improvement in PFS and OS compared with chemotherapy alone in advanced NSCLC without EGFR/ALK mutations. No new safety signal was observed. The treatment effects are independent of PD-L1 expression status. Genomic analysis using whole exome sequencing revealed that patients with high TMB were associated with significantly better PFS in the toripalimab arm. Patients with mutations in the FA-PI3K-Akt pathway achieved significantly better PFS and OS in the toripalimab arm."
Maximilian Diehn, MD, PhD, ASCO Expert in Lung Cancer and Professor of Radiation Oncology-Radiation Therapy at Stanford University, shared his thoughts: "These results confirm that the combination of immunotherapy and chemotherapy improves survival of patients with previously untreated advanced non-small-cell lung cancers that do not have driver mutations."
ASCO Discussant Charu Aggarwal, MD, MPH, Associate Director of the Penn Center for Precision Medicine at the University of Pennsylvania, stated: "Immunotherapy has led to a meaningful improvement in OS in NSCLC. Survival outcomes confirm current practice to combine chemotherapy with immunotherapy.
"In 2022, we have choices to no longer consider chemotherapy alone as an adequate control for first-line trials in NSCLC; to prioritize OS as the standard primary endpoint; to focus on innovation that moves the needle, such as efficacy, tolerability, and cost; to invest in partnerships that provide global access to new drugs; and to collaborate to develop biomarkers and identify patients who are both benefited and harmed by immunotherapy," Aggarwal concluded.
Mark L. Fuerst is a contributing writer.