First-Line Toripalimab Plus Chemotherapy Elicits Survival Benefit in NSCLC Irrespective of PD-L1 Status

Adding toripalimab (Tuoyi) to chemotherapy in the frontline setting demonstrated improved progression-free survival (PFS) vs placebo plus chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) without EGFR or ALK mutations, regardless of PD-L1 status, according to a biomarker analysis of the phase 3 CHOICE-01 trial (NCT03856411).¹

The findings presented at the 2022 ASCO Annual Meeting showed that patients with PD-L1 expressed in at least 50% of tumor cells achieved a median PFS of 10.3 months with toripalimab plus chemotherapy (n = 72) compared with 5.6 months with chemotherapy alone (n = 28; HR, 0.45; 95% CI, 0.27-0.78). The 12-month PFS rates for these patients were 46.4% and 20.3% in the toripalimab and placebo arms, respectively.

In patients with PD-L1 expressed in less than 50% of tumor cells, toripalimab achieved a median PFS of 8.4 months (n = 128) vs 6.7 months for placebo (n = 75; HR, 0.56; 95% CI, 0.40-0.78). The 12-month PFS rates were 39.4% and 20.8% for the toripalimab and placebo groups, respectively.

In patients with PD-L1 expressed in less than 1% of tumor cells, the median PFS for the toripalimab (n = 98) and placebo (n = 41) arms was 8.2 months and 5.6 months, respectively (HR, 0.47; 95% CI, 0.32-0.71). The 12-month PFS rates were 25.9% and 10.3% for the toripalimab and placebo arms, respectively.

For patients with an unknown PD-L1 status, toripalimab elicited a median PFS of 8.4 months (n = 11) compared with 5.5 months for placebo (n = 12; HR, 0.62; 95% CI, 0.21-1.79). The 12-month PFS rates were 37.5% and 11.4%, respectively.

"The addition of toripalimab to chemotherapy in patients with treatment-[naïve] advanced NSCLC provided superior PFS and OS [overall survival vs] chemotherapy alone with a manageable safety profile,” presenting study author Jie Wang, MD, of the State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, said in the presentation.

In March 2022, the final PFS analysis of CHOICE-01 demonstrated that toripalimab plus chemotherapy achieved a meaningful improvement in median PFS in all patients of 8.4 months, compared with 5.6 months for chemotherapy plus placebo (HR, 0.49; 95% CI, 0.39-0.61; P < .0001). The interim OS analysis revealed a median OS that was not reached (NR) for toripalimab plus chemotherapy compared with 17.1 months for placebo plus chemotherapy (HR, 0.69; 95% CI, 0.52-0.92; P = .0099).

CHOICE-01 was a double-blind, placebo-controlled, multicenter trial evaluating toripalimab plus chemotherapy in untreated patients with advanced squamous and nonsquamous stage IIIB and IV NSCLC. Patients were required to be treatment naïve in the locally advanced or metastatic setting, have no known EGFR or ALK mutations, have measurable disease per RECIST v1.1, have an ECOG performance status of 0 or 1, and have tumor tissue available for PD-L1 testing.

Patients were randomized to receive 240 mg of intravenous toripalimab or placebo on day 1 of every 3-week cycle for up to 2 years. All patients with nonsquamous NSCLC also received pemetrexed plus cisplatin or carboplatin for 4 to 6 cycles, followed by pemetrexed. All patients with squamous NSCLC received nab-paclitaxel plus carboplatin for 4 to 6 cycles.

The primary end point was investigator-assessed PFS per RECIST v1.1, and secondary end points included OS, PFS per blinded independent review committee, overall response rate, disease control rate, time to recurrence, and safety.

Additional data from the biomarker analysis showed patients with a high tumor mutational burden (TMB) experienced an increased survival benefit in the toripalimab arm. For patients with a high TMB, toripalimab induced a median PFS of 13.1 months (n = 77), compared with 5.5 months with placebo (n = 45; HR, 0.34; 95% CI, 0.21-0.54). The 12-month PFS rates were 52.5% in the toripalimab arm and 15.3% in the placebo arm.

The median OS was NR in the TMB-high subgroup median OS for patients assigned to toripalimab compared with 41.1% in the placebo arm (HR, 0.67; 95% CI, 0.38-1.19). The 24-month OS rates were 52.2% and 41.1% in the toripalimab and placebo arms, respectively.

For patients with low TMB, the median PFS was 8.3 months and 6.5 months for the toripalimab (n = 187) and placebo (n = 85) arms, respectively (HR, 0.62; 95% CI, 0.46-0.83). The 12-month PFS rates were 32.8% and 18.5%, respectively.

The median OS was not evaluable (NE) for the toripalimab arm in this subgroup compared with 16.2 months in the placebo arm (HR, 0.68; 95% CI, 0.47-0.98). The 24-month OS rates were 51.3% and 35.0%, respectively.

Furthermore, patients with FA/PI3K/AKT mutations saw additional benefits in PFS and OS in the toripalimab arm. Patients harboring those mutations who received toripalimab (n = 83) achieved a median PFS of 9.69 months (95% CI, 8.15-18.53) compared with 8.34 months (95% CI, 6.93-9.69) for patients without FA/PI3K/AKT mutations (n = 181). The median OS for those patient populations was NE (95% CI, 22.87-NE) and 22.87 months (95% CI, 21.03-NE), respectively.

Patients with IL-7 alterations also achieved additional PFS and OS benefits in the toripalimab arm. Patients with IL-7 alterations who received toripalimab (n = 60) saw a median PFS of 10.87 months (95% CI, 8.08-22.57) compared with 8.34 months (95% CI, 7.16-9.69) in patients without IL-7 alterations (n = 204). The median OS for those groups was NE (95% CI, 12.93-NE) and 22.87 months (95% CI, 21.18-NE), respectively.

Finally, patients with SWI/SNF gene alterations who received toripalimab (n = 45) had a median PFS of 9.92 months (95% CI, 8.08-NE) compared with 8.34 months (95% CI, 7.16-9.69) for patients without those alterations (n = 219). The median OS for those groups was 22.87 months (95% CI, 15.05-NE) and NE (95% CI, 21.88-NE), respectively.

In May 2022, the FDA issued a complete response letter (CRL) regarding the biologics license application for toripalimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced recurrent or metastatic nasopharyngeal carcinoma, as well as for toripalimab monotherapy in the second-line or later treatment of recurrent or metastatic NPC after platinum-containing chemotherapy.²

In the letter, the agency asked Coherus Biosciences, Inc and Shanghai Junshi Biosciences Co, Ltd. to alter their quality processes. At the time, the companies planned to meet with the FDA directly and could re-submit this summer.

References

1. Wang J. 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: 2022 ASCO Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 362936.
2. Coherus and Junshi Biosciences receive complete response Letter from US FDA for toripalimab BLA. News release. May 2, 2022. Accessed June 9, 2022. https://bit.ly/3ORWbun