Toripalimab Add-On Extends PFS/OS of Frontline Chemotherapy in Advanced NSCLC

Adding toripalimab (Tuoyi) to chemotherapy improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone in patients with advanced non–small cell lung cancer (NSCLC), according to results from the CHOICE-01 study presented during the ASCO Plenary Series: March 2022 Session.¹

“The addition of toripalimab to chemotherapy in patients with treatment-naïve and advanced non–small cell lung cancer provides a superior clinical outcome than chemotherapy along with manageable safety profile. The PFS and OS benefits were observed regardless of PD-L1 expression,” said Jie Wang, MD, of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, during the presentation.

Toripalimab/chemotherapy achieved a median PFS of 8.4 months compared with only 5.6 month in the control arm (HR, 0.49; 95% CI, 0.39-0.61; 2-sided P < .0001), according to investigator assessment. The media OS observed with the addition of toripalimab was not reached compared with 17.2 months in the control arm (HR, 0.69; 95% CI, 0.52-0.92; 2-sided P =.0099). The study therefore achieved both its primary end point and 1 key secondary end point.

CHOICE-01 is a randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial (NCT03856411), which enrolled 450 patients with advanced NSCLC, without activated EGFR mutation and ALK fusions.^1,2

Patients were randomized 2:1 to received either toripalimab plus chemotherapy or chemotherapy with placebo. Toripalimab was administered at 240 mg in combination with chemotherapy for 4 to 6 cycles, and the placebo control arm received matching dose levels with the same dosing schedule. Treatment with either toripalimab and chemotherapy or placebo and chemotherapy were followed by maintenance toripalimab or placebo in combination with standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment.²

Stratified by PD-L1 expression status, histology, and smoking status, patients were assessed for the primary end point of PFS, with secondary efficacy end points including OS, PFS by blinded independent review committee, objective response rate (ORR), duration of response (DOR), disease control rate, time to response. Safety assessed by the incidence of adverse events (AEs) and serious AEs was also a secondary end point of the study.

Of the 450 patients, 309 were randomized to receive the toripalimab combination and 156 were randomized to the placebo/chemotherapy arm. In the toripalimab arm, the median age was 63 years (range, 36-75) and 79.9% of patients were male. In terms of the stratification factors, 52.4% had nonsquamous histology while 47.6% had squamous disease. The smoking status was notably frequent for 68.9% of the group, and 65.0% of patients in the toripalimab arm have PD-L1 expression of ≥ 1%.

In the control arm, the median age was 61 years (range, 29-75), and the population was 83.3% male. Like the experimental arm, more patients had nonsquamous disease versus squamous disease, smoking status was frequent for 68.6%, and 66.0% of patients had PD-L1 expression of ≥ 1%.¹

The data cutoff date for the prespecified final PFS analysis was October 31, 2021. Per investigator assessment, the addition of toripalimab to chemotherapy significantly extended PFS in comparison with the placebo arm, including in subgroup population of patients with various histologies and those with PD-L1 expression. The PFS rate at 1 year was 36.7% in the toripalimab arm versus 17.2% in the placebo arm.

The interim OS analysis showed that the improvement in OS was also significant with toripalimab plus chemotherapy versus placebo with chemotherapy.

Adding toripalimab to chemotherapy also led to better responses compared with placebo. The ORR observed with the toripalimab combination was 65.7% (95% CI, 60.1%-71.0%) compared with 46.2% (95% CI, 38.2%-54.3%) for a difference of 19.5% (95% CI, 10.1%-28.8%; stratified log-rank P <.0001). All responses in both treatment arms were partial responses.

The median DOR among patients in the toripalimab arm was 8.4 months (95% CI, 6.9-12.9) versus 4.2 months (95% CI, 4.0-5.6) in the placebo arm (HR, 0.38; 95% CI, 0.28-0.53; stratified log-rank P <.0001).

Grade ≥ 3 AEs in the study occurred in 78.6% of the toripalimab arm versus 82.1% of the placebo arm, showing the incidence was similar between the 2 groups. Toripalimab was discontinued in 14.3% of patients as a result of AEs compared with. 3.2% of the placebo arm. AEs led to death in 5.5% of the toripalimab-treated patients compared with 2.6% of those given placebo.

A total of 394 of the study subjects had whole-genome sequencing to identify correlative biomarkers for survival. Of those patients tested, those with high tumor mutational burden had a significantly better PFS benefit with toripalimab. The median PFS in this subgroup was 13.1 months with toripalimab versus 5.5 months with the control (interaction P = .026). Further, in the subgroup of patients with mutations in the FAK-PI3K-Akt pathway or IL-7 signaling pathways both PFS and OS were significantly better with toripalimab plus chemotherapy compared with placebo and chemotherapy (interaction P ≤ .01).

“We've made tremendous progress over the last 2 decades in the management of patients with metastatic non–small cell lung cancer. Overall survival has significantly increased from under a year in 2002. With the use of combination chemotherapy to over 2 years now with the integration of immunotherapy. Long-term outcomes confirm that we are making a meaningful difference in overall survival. Five-year percentages are greater than 30% at this point in time for patients diagnosed with stage IV disease,” said Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, University of Pennsylvania, Abramson Cancer Center, in response to Dr. Wang’s presentation during the March 2022 Session.

_REFERENCES:

_{1. 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.}

_{2. A study to evaluate the efficacy and safety of toripalimab or placebo combined with chemotherapy in treatment-naive advanced NSCLC. Clinicaltrials.gov. Updated September 30, 2020. Accessed March 15, 2022.}