FDA Does Not Approve Frontline Toripalimab +/- Chemo for Advanced/Metastatic Nasopharyngeal Carcinoma


A complete response letter from the FDA has been issued regarding the biologics license application for toripalimab with or without chemotherapy for the treatment of advanced recurrent or metastatic nasopharyngeal carcinoma.

The FDA has issued a complete response letter (CRL) regarding the biologics license application for toripalimab in combination with 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.1

In the CRL, the FDA is requesting for Coherus Biosciences, Inc and Shanghai Junshi Biosciences Co, Ltd. Alter their quality process. In response, the companies plan to meet with the FDA directly and may resubmit the BLA by mid-summer of 2022. For the FDA to conduct another review of a BLA submission for toripalimab, the timeline is 6 months due to travel restrictions resulting from COVID-19.

“We will continue to work closely with our partner, Junshi Biosciences, to facilitate the completion of the FDA’s review of the toripalimab BLA. In late April, we responded quickly to an FDA request for a quality process change and implemented required actions,” said Denny Lanfear, chief executive officer of Coherus, in a press release.

The BLA for toripalimab with or without chemotherapy for the treatment of advanced recurrent or metastatic NPC was granted priority review by the FDA in November 2021. The application was supported by findings from the phase 2 POLARIS-02 trial (NCT02915432) and the phase 3 JUPITER-02 trial (NCT03581786).2

For the toripalimab monotherapy indication, results from the POLARIS study demonstrated that toripalimab has a manageable safety profile and can acheivee durable clinical responses in patients with advanced NPC.2

In the single-arm, multicenter phase 2 study, a total of 190 patients were included. Patients received 3 mg/kg toripalimab once every 2 weeks until confirmed disease progression or unacceptable toxicity. Patients were assessed for the primary end point of objective response rate (ORR), as well as the secondary end points of safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The ORR observed in the study was 20.5% (95% CI, 15.0%-27.0%), and the disease control rate (DCR) was 40.0% (95% CI, 33.0% -47.3%). Also, there was a 38.4% decrease in target lesions from baseline.

In terms of the secondary end points, the median DOR was 12.8 months (95% CI, 9.4 to not estimable), the median PFS was 1.9 months (95% CI, 1.8-3.5), and the median OS was 17.4 months (95% CI, 11.7-22.9).

The most common treatment-related adverse events (TRAEs) observed with toripalimab were hypothyroidism (23.7%), anemia (15.3%), and aspartate aminotransferase increase (15.3%).

For the toripalimab plus chemotherapy indication, supporting results are from the randomized, placebo-controlled, double-blinded JUPITER-02 study. The study included 289 patients with advanced NPC in the recurrent or metastatic setting who had not received prior chemotherapy. Patients were randomized 1:1 to receive either toripalimab 240 mg in combination with chemotherapy of gemcitabine 1000 mg/m2 or cisplatin 80 mg/m2 every 3 weeks or matching placebo in combination with either gemcitabine or cisplatin. The primary end point of the study was PFS, and the secondary end points included ORR, DOR, and OS.3

Updated study results were presented during the AACR Annual Meeting 2022 and showed a superior progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) with toripalimab plus chemotherapy compared with chemotherapy alone in frontline advanced NPC.

There was a 13.2-month improvement in PFS (HR, 0.52; 95% CI, 0.37-0.73; P < .0001), and an 11.7% improvement in ORR (95% CI, 1.7-21.2; P = .0221) with toripalimab and chemotherapy compared with placebo and chemotherapy. Responses in the toripalimab arm were more durable and both PFS and ORR results were deemed significant. OS rates at year 1 and 2 were both higher with the addition of toripalimab vs chemotherapy only.

The median PFS observed with toripalimab was 21.4 months compared with 8.2 months in the placebo arm. At 1 year, the PFS rate in the toripalimab arm was 59.0% vs 32.9% in the placebo arm. Median OS was not yet reached at the data cutoff date but trended in favor of toripalimab (HR, 0.59; 95% CI, 0.37-0.94; P = .0238).

At 1 year, the OS rate in the toripalimab arm was 91.6% (95% CI, 85.6%-95.1%) vs 87.1% (95% CI, 80.4%-91.7%) in the placebo arm. The 2-year OS rate observed with toripalimab was 75.1% (95% CI, 65.5%-82.4%) compared with 63.9% (95% CI, 54.2%-72.1%) with placebo.

In patients treated with toripalimab, the ORR was 78.8%% vs 67.1% in the placebo arm. Response to toripalimab and chemotherapy were complete responses (CRs) in 26.7% of patients and partial responses (PRs) in 52.1%. In the placebo/chemotherapy arm, 13.3% of patients has CRs and 53.8% had PRs. The median DOR was 18.0 months (95% CI, 10.5 to not evaluable [NE]) in the toripalimab arm compared with only 6.0 months (95% CI, 5.6-8.3) in the placebo arm (stratified HR, 0.49, 0.33-0.72; P = .0003).

In terms of safety, no new safety signals were seen in the study as of the data cutoff date. Grade 3 or higher AEs were observed in 89.7% of the toripalimab arm compared with 90.2% of the control arm. AEs were fatal in 2.7% of the toripalimab arm vs 2.8% of the placebo arm. Investigator-determined immune-related AEs were seen in 53.4% of the toripalimab arm vs 21.7% of the placebo arm. The immune-related AEs were mainly low grade with 8.9% of the toripalimab arm having experienced grade 3 or higher cases vs 1.4% of the placebo arm.

“We believe toripalimab addresses an important unmet need for patients with NPC for whom there are currently no approved immunotherapies in the United States, and the FDA has stated that this indication warrants regulatory flexibility with respect to the sufficiency of single country clinical data,” Lanfear stated.


1. Coherus and Junshi Biosciences receive complete response Letter from U.S. FDA for toripalimab BLA. News release. May 2, 2022. Accessed May 2, 2022. https://bit.ly/3ORWbun

2. Wang FH, Wei XL, Feng J, et al. Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase ii clinical trial (POLARIS-02). J Clin Oncol. 2021; 39(7): 704-712. doi: 10.1200/JCO.20.0271

3. Mai H, Chen Q, Chen D, et al. Final progression-free survival analysis of JUPITER-02, a randomized, double-blind, phase 3 study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. Presented at: American Association for Cancer Research 2022 Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT226.

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