Toripalimab Plus Chemotherapy Offers EFS Benefit in Patients With Resectable Stage III NSCLC

Shun Lu, MD, PhD

The addition of the anti–PD-1 monoclonal antibody toripalimab to perioperative chemotherapy led to a statistically significant improvement in event-free survival (EFS) for patients with stage III non–small cell lung cancer (NSCLC). Findings from the interim EFS analysis of the phase 3 Neotorch study (NCT04158440) were presented during the 2023 April ASCO April Plenary Series.¹

At the November 30, 2022 data cutoff, at a median follow-up of 18.25 months, the median EFS for patients with stage III disease who received toripalimab plus chemotherapy (n = 202) was not estimable (NE; 95% CI, 24.4-NE) by investigator assessment vs 15.1 months (95% CI, 10.6-21.9) for patients who received placebo plus chemotherapy (n = 202; HR, 0.40; 95% CI, 0.277-0.565; 2-sided P < .0001). The 1-year EFS rates were 84.4% vs 57.0%, respectively, and the 2-year EFS rates were 64.7% vs 38.7%, respectively.

“A significant improvement in EFS was observed in the toripalimab arm over the placebo [arm],” Shun Lu, MD, PhD, the chief of the Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiaotong University in China, said during a presentation of the findings. “The HR was 0.40, representing a 60% risk reduction in disease progression, disease recurrence, or death. The P value crossed the prespecified stopping boundary of 0.01683.”

Neotorch was a double-blind, placebo-controlled study that randomly assigned adults aged 18 to 70 years patients with newly diagnosed, resectable stage II or III NSCLC to receive perioperative toripalimab plus platinum-based chemotherapy followed by maintenance with toripalimab or perioperative chemotherapy alone. Patients needed to be EGFR/ALK wild-type, biopsy tissue available for biomarker analysis, measurable lesions, and an ECOG performance status of 1 or less to be eligible for the study.^1,2

In the investigational arm, patients were treated with neoadjuvant toripalimab at a dose of 240 mg plus chemotherapy every 3 weeks for 3 cycles, followed by surgery, then adjuvant toripalimab 240 mg plus chemotherapy every 3 weeks for 1 cycle, concluding with maintenance therapy with toripalimab 240 mg every 3 weeks up to 13 cycles. Patients in the control arm received the same treatment schedule of chemotherapy and surgery with placebo in place of toripalimab.

Patients were stratified by disease stage (II vs IIIA vs IIIB), PD-L1 tumor cell expression (≥ 1% vs < 1% or NE), histology (nonsquamous vs squamous), and surgery (lobectomy vs pneumonecomy).¹

Baseline characteristics of the patients with stage III disease were well balanced between the 2 arms; the median age was 62 years (range 31-70) and 61 years (range, 29-70) in the toripalimab and placebo arms, respectively. Most patients in both arms were men (89.6% vs 93.6%), former smokers (71.3% vs 78.2%), had an ECOG performance status of 1 (65.3% vs 63.9%), had squamous histology (77.7% vs 77.7%), had PD-L1 expression of 1% or more (65.8% vs 65.3%), and had stage IIIA disease (67.3% vs 67.3%).¹

The coprimary end points of the trial were EFS by investigator assessment and major pathological response (MPR) rate by blinded independent pathological review (BIPR), in both the stage III and stage II/III populations. Secondary end points included overall survival (OS), disease-free survival (DFS), pathological complete response (pCR) rate by BIPR, and safety and feasibility of surgery.^1,2

Additional findings from the study showed the median EFS by independent review committee was NE (95% CI, NE-NE) compared with 15.5 months (95% CI, 9.9-NE) in the toripalimab and placebo arms, respectively (HR, 0.40; 95% CI, 0.271-0.572; nominal P < .0001). The 1-year EFS rates were 80.7% vs 66.7%, respectively, and the 2-year rates were 66.7% vs 46.1%, respectively.¹

Notably, the EFS benefit was observed regardless of PD-L1 status; patients with a PD-L1 expression of at least 1% (HR, 0.31; 95% CI, 0.197-0.481) and those with a PD-L1 expression of less than 1% or NE (HR, 0.59; 95% CI, 0.327-1.034) both experienced an EFS improvement with the addition of toripalimab to chemotherapy. Moreover, the EFS benefit over chemotherapy alone was observed across all of the key subgroups that were examined, including disease stage, age, sex, and smoking history.

The MPR rate by BIPR was 48.5% (95% CI, 41.4%-55.6%) vs 8.4% (95% CI, 5.0%-13.1%) in the investigational and control arms, respectively, for a difference between the 2 arms of 40.2% (95% CI, 32.2%-48.1%; P < .0001). The pCR by BIPR was 24.8% (95% CI, 19.0%-31.3%) vs 1.0% (95% CI, 0.1%-3.5%), respectively, for a difference between the 2 arms of 23.7% (95% CI, 17.6%-29.8%; P < .0001).

Findings from the OS analysis revealed that patients in the toripalimab arm achieved a median OS of NE (95% CI, NE-NE) vs 30.4 months (95% CI, 29.2-NE) in the placebo arm (HR, 0.62; 95% CI, 0.381-0.999; nominal P = .0502). The 1-year OS rates were 94.4% vs 89.6%, respectively, and the 2-year rates were 81.2% vs 74.3%, respectively.¹

“[These OS results] show a favorable trend towards [improvement with] toripalimab,” Lu said.

Most patients in both the toripalimab and placebo arms underwent surgery (82.2% vs 73.3%). R0 resection occurred in 95.8% (95% CI, 91.5%-98.3%) and 92.6% (95% CI, 87.1%-96.2%) of patients, respectively, for a difference between the 2 arms of 3.2% (95% CI, –2.0% to 8.4%).

Regarding safety, treatment-emergent adverse events (TEAEs) of any grade were reported in 99.5% of patients in the toripalimab arm. TEAEs of grade 3 or greater were reported in 63.4% of patients, with TEAEs leading to death (3.0%), interruption of toripalimab (28.2%), and discontinuation of toripalimab (9.4%) observed. Immune-related adverse effects (irAEs) of any grade occurred at a rate of 42.1%, grade 3 or higher irAEs were present in 11.9% of patients, and 3.5% experienced infusion-related reactions. Serious adverse events (SAEs) occurred in 40.6% of patients.¹

In the placebo arm, any grade TEAEs were present in 98.5% of patients, with grade 3 or higher TEAEs occurring at a rate of 54.0%. TEAEs leading to death, interruption of placebo, or discontinuation of placebo were reported in 2.0%, 14.4%, and 7.4% of patients, respectively. irAEs of any grade and grade 3 or higher were present in 22.8% and 3.0% of patients, respectively. SAEs occurred in 28.2% of patients.

Following surgery, adverse events (AEs) of any grade were present in 74.4% and 70.3% of patients in the toripalimab (n = 166) and placebo arms (n = 148), respectively. Grade 3 or higher AEs (21.7% vs 20.3%), AEs leading to discontinuation of toripalimab/placebo (1.8% vs 2.7%), and AEs leading discontinuation of toripalimab/placebo (6.6% vs 1.4%) were reported postoperatively in both arms.¹

“The safety profile of toripalimab was manageable and no new safety signals were detected,” Lu said.

At the time of data cutoff, 26 patients in the toripalimab arm remained on treatment with 176 patients discontinuing therapy. Reasons for discontinuation included completing treatment (n = 89), withdrawal (n = 30), disease progression before surgery (n = 5), relapse or progression after surgery (n = 19), TEAEs (n = 21), and death (n = 2).

In the placebo arm, 20 patients remained on treatment and 182 patients had discontinued. Reasons for discontinuation included completing treatment (n = 66), withdrawal (n = 23), disease progression before surgery (n = 30), relapse or progression after surgery (n = 40), TEAEs (n = 15), and death (n = 1).

References

1. Lu S, Wu L, Zhand W, et al. Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): interim event-free survival (EFS) analysis of the phase III Neotorch study. J Clin Oncol. 2023;41(suppl 36):425126. doi:10.1200/JCO.2023.41.36_suppl.425126
2. Phase III study of toripalimab versus placebo plus chemotherapy in resectable NSCLC. ClinicalTrials.gov. Updated November 3, 2022. Accessed April 25, 2023. https://clinicaltrials.gov/ct2/show/NCT04158440