FDA Issues Complete Response Letter to Toripalimab for Nasopharyngeal Carcinoma

The FDA is seeking the approval of toripalimab plus gemcitabine and cisplatin in the frontline treatment of patients with advanced recurrent or metastatic nasopharyngeal carcinoma and for use as a monotherapy in the second-line and later treatment of those with recurrent or metastatic disease.

The FDA has issued a complete response letter (CRL) to the biologics license application (BLA) seeking the approval of toripalimab for use in combination with gemcitabine and cisplatin in the frontline treatment of patients with advanced recurrent or metastatic nasopharyngeal carcinoma and for use as a monotherapy in the second-line and later treatment of those with recurrent or metastatic disease following platinum-containing chemotherapy.1

In the letter, the agency has requested a quality process change. Coherus and Junshi Biosciences shared plans to meet with the FDA and to subsequently resubmit the application by mid-summer 2022.

The review timeline for a resubmission would be 6 months because required onsite inspections have been delayed by travel restrictions associated with the COVID-19 pandemic in China, according to the CRL.

The BLA was based on findings yielded from the phase 2 POLARIS-2 trial (NCT02915432) and the phase 3 JUPITER-02 trial (NCT03582786). The phase 2 data showed that toripalimab produced an objective response rate (ORR) of 20.5% (95% CI, 15.0%-27.0%) per independent review committee (IRC) assessment in those with previously treated recurrent or metastatic nasopharyngeal carcinoma (n = 190).2

The phase 3 data revealed that when toripalimab was combined with the chemotherapy backbone of gemcitabine and cisplatin, it resulted in a median progression-free survival (PFS) of 11.7 months (95% CI, 11.0–not evaluable) per blinded IRC assessment and by RECIST v1.1 criteria compared with 8.0 months (95% CI, 7.0-9.5) with chemotherapy alone (stratified HR, 0.52; 95% CI, 0.36-0.74; P = .0003).3

“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,” Denny Lanfear, chief executive officer of Coherus, stated in a press release. “We plan to first meet with the FDA, and directly thereafter, to resubmit the BLA. The FDA has indicated that the existing toripalimab clinical data are supportive of the BLA submission, and we eagerly await scheduling and completion of the required inspections in China that have been impeded to date by COVID-related travel restrictions.”

The multicenter, phase 1b/2 POLARIS-02 trial enrolled patients with relapsed metastatic nasopharyngeal cancer, head and neck cancer, gastric cancer, and esophageal cancer who were refractory to prior standard chemotherapy or who had progressed within 6 months of adjuvant chemotherapy or chemoradiation. To be eligible for enrollment, patients needed to be at least 18 years of age, have measurable disease, an ECOG performance status of 0 to 1, and adequate organ function.

Patients who received treatment with a monoclonal antibody within 4 weeks or any anticancer therapy within 2 weeks before they started study treatment, were excluded. Patients could not have previously received immune checkpoint inhibition, systemic corticosteroids within 1 week of treatment initiation, and they could not have any additional known malignancies or active central nervous system metastases.

Toripalimab was administered at 3 mg/kg every 2 weeks until disease progression, intolerable toxicity, or withdrawn consent. Select patients who experienced progressive disease were permitted to continue the agent if they were deriving benefit from the treatment.

IRC-assessed ORR by RECIST v1.1 criteria served as the primary end point of the trial. Secondary end points comprised safety, duration of response, disease control rate (DCR), PFS, and overall survival (OS). Exploratory end points included PD-L1 expression, tumor mutational burden, and genetic biomarkers for efficacy with toripalimab, among others.

The mean age among study participants was 46.4 years (range, 22.0-71.0). The majority of patients were male (83.2%), had an ECOG performance status of 1 (65.3%), had nonkeratinizing histology (95.8%), PD-L1–negative disease (70.5%), and a baseline lactate dehydrogenase level that was ≤ 2 x the upper limit of normal. Additionally, 51.6% of patients received 1 prior line of systemic therapy and 48.4% received 2 or more prior lines.

Toripalimab was found to result in a 40.0% (95% CI, 33.0%-47.3%) DCR rate, have a median time to response of 1.8 months (95% CI, 1.8-2.1), and a median DOR of 12.8 months (95% CI, 9.4–not estimable [NE]). The agent resulted in a median PFS of 1.9 months (95% CI, 1.8-3.5) and a median OS of 17.4 months (95% CI, 11.7-22.9). In those who experienced an objective response (n = 39) or achieved stable disease (n = 38), the median OS had not yet been reached. In those who experienced progressive disease (n = 113), the median OS was 8.4 months.

In those who received toripalimab as second-line or later treatment (n = 92), the agent elicited an ORR of 23.9% (95% CI, 15.6%-33.9%) and a DCR of 41.3% (95% CI, 31.1%-52.1%) per IRC assessment and RECIST v1.1 criteria. In this group, the median DOR with toripalimab was 21.5 months (95% CI, 7.7-NE), the median PFS was 2.0 months (95% CI, 1.8-3.6), and the median OS was 15.1 months (95% CI, 10.4-20.4).

The most common adverse effects (AEs) experienced with toripalimab in patients on the study included hypothyroidism (23.7%), anemia (15.3%), aspartate aminotransferase increase (15.3%), alanine aminotransferase increase (13.7%), asthenia (13.2%), proteinuria (12.6%), leukopenia (10.0%), pyrexia (8.4%), rash (6.3%), and neutropenia (5.3%).

For JUPITER-02, investigators enrolled patients with primary metastatic nasopharyngeal carcinoma or recurrent disease after therapy with curative intent. To participate, patients needed to be between the ages of 18 years and 75 years, have an ECOG performance status of 0 to 1, and have measurable disease per RECIST v1.1 criteria.

Patients were randomized 1:1 to toripalimab at 240 mg in combination with gemcitabine plus cisplatin given every 3 weeks for up to 6 treatment cycles (n = 146) or gemcitabine/cisplatin alone at the same schedule (n = 143).

Those in the toripalimab arm (n = 115) received the agent as maintenance at 240 mg every 3 weeks. Those in the chemotherapy-alone arm (n = 118) received maintenance treatment with placebo. Key stratification factors included recurrent vs primary metastatic disease and performance status of 0 or 1.

PFS per blinded IRC by RECIST v1.1 criteria served as the primary end point of the trial. Secondary end points included investigator-assessed PFS, ORR, DOR, DCR, and OS. Investigators also evaluated PFS and OS rates at 1 year and 2 years.

The median age of those in the investigative arm was 46 years (range, 19-72) vs 51 years (range, 21-72) in the control arm. The majority of patients were male and had an ECOG performance status of 1. Moreover, 58% of those in the toripalimab arm had recurrent disease compared with 61% of those on the chemotherapy-alone arm; 42% and 39% of patients, respectively, had primary metastatic disease.

Data presented during the 2021 ASCO Annual Meeting indicated that the 1-year PFS rate achieved with toripalimab plus chemotherapy was 49.4% (95% CI, 36.4%-61.1%) vs 27.9% (95% CI, 18.0%-38.8%) with chemotherapy alone.

The median OS had not yet been reached in either arm (stratified HR, 0.603; 95% CI, 0.364-0.997; P = .0462). The OS rate at 1 year in the investigative arm was 91.6% (95% CI, 85.6%-95.1%) compared with 87.1% (95% CI, 80.4%-91.7%) in the control arm. The 2-year OS rates in the toripalimab and chemotherapy-alone arms were 77.8% (95% CI, 68.0%-85.0%) and 63.3% (95% CI, 49.8%-74.1%), respectively.

The addition of toripalimab to chemotherapy produced an ORR of 77.4% (95% CI, 69.8%-83.9%) compared with 66.4% (95% CI, 58.1%-74.1%) with chemotherapy alone (P = .0335). The median DOR with toripalimab plus chemotherapy was almost double that observed with chemotherapy alone, at 10.0 months (95% CI, 8.8-NE) and 5.7 months (95% CI, 5.4-6.8), respectively (HR, 0.50; 95% CI, 0.33-0.78; P = .0014).

The most frequent toxicities experienced with the combination of toripalimab plus chemotherapy included leukopenia (91.1%), anemia (88.4%), neutropenia (85.6%), nausea (69.2%), vomiting (67.1%), thrombocytopenia (63.0%), decreased appetite (53.4%), and constipation (39.0%), among others.

“Toripalimab, our PD-1 inhibitor, has demonstrated a compelling clinical profile in studies across multiple tumor types and is currently approved in China for 4 indications,” Ning Li, MD, chief executive officer of Junshi Biosciences, added in the press release. “We fully support our partner, Coherus, in efforts to seek toripalimab approval in the United States for advanced nasopharyngeal carcinoma, as well as in the subsequent commercial launch, if approved. Our respective teams are working diligently together in a well-coordinated effort to achieve these goals as partners.”


  1. Coherus and Junshi Biosciences receive complete response letter from US FDA for toripalimab BLA. News release. Coherus BioSciences Inc. May 2, 2022. Accessed May 2, 2022. https://bit.ly/3LKpXQ0
  2. Wang F-H, Wei X-L, 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.20.02712
  3. Xu R-H, Mai H-Q, Chen Q-Y, et al. JUPITER-02: randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC). J Clin Oncol. 2021;39(suppl 15):LBA2. doi:10.1200/JCO.2021.39.15_suppl.LBA2