FDA Decision on Toripalimab for Advanced Nasopharyngeal Carcinoma Pending Due COVID-19 Travel Restrictions

The FDA was unable to grant approval to toripalimab in combination with gemcitabine and cisplatin as first-line treatment for patients with advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) and for toripalimab monotherapy for the second-line or later treatment of recurrent or metastatic NPC after platinum-containing chemotherapy on its Perscription Drug User Fee act action date (December 23, 2022).

The FDA cited COVID-19-related travel restrictions as the reason for a delay on its decision. The travel restrictions have made it impossible for the FDA to inspect the manufacturing site for the drug on time.¹

No complete response letter was issued regarding the biologics license application (BLA) for toripalimab, and the application is still under review. However, an on-site manufacturing site inspection is an FDA requirement for approval.

“There is a significant unmet need for those living with NPC, and toripalimab has demonstrated significant and clinically meaningful improvement as recognized by the FDA’s Breakthrough Therapy Designation. Both Coherus and the FDA are highly committed to bringing toripalimab to NPC patients in the [United States] as quickly as possible,” said Theresa LaVallee, PhD, Coherus’ chief development officer, in a press release. “We are working closely and collaboratively with the FDA to schedule inspections of the manufacturing facility quickly and understand the need to ensure the safety of their inspectors. We continue to support the FDA as needed to allow for their assessment of toripalimab to be finalized.”

Junshi Biosciences announced that although there is a delay in a decision on toripalimab, it may not be long before the drug is approved.

“Although toripalimab’s BLA review process has been impacted by the COVID-19 pandemic, we believe the impact is temporary,” said Dr. Sheng Yao, senior vice president of Junshi Biosciences, in the press release. “Together with our partner Coherus, we are working with the FDA to expedite the facility inspection so it may be conducted safely as soon as possible in order to provide NPC patients with a treatment that has been demonstrated to be safe and effective. Our production operations are well prepared for the inspection.”

Findings from the randomized, double blind, placebo-controlled, international multi-center, phase 3 JUPITER-02 (NCT03581786) and the multi-center, open-label, pivotal phase 2 POLARIS-02 study support the BLA for the 2 potential toripalimab indications.

JUPITER-02

In JUPITER-02, 289 chemotherapy-naïve patients with recurrent or metastatic NPC. The patients were randomized 1:1 to receive toripalimab at 240 mg and gemcitabine plus cisplatin every 3 weeks for a minimum of 6 treatment cycles. Following this dose, patients received toripalimab maintenance at 240 mg every 3 weeks. In the control arm, patients received chemotherapy combined with placebo every 3 weeks for 6 cycles followed by placebo maintenance every 3 weeks. Roughly 80% of patients continued with maintenance therapy of either toripalimab or placebo following the completion of chemotherapy completion.

Patients were assessed for the primary end point of progression-free survival (PFS) as assessed by a blinded central review committee. The secondary end points of the study were overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety.

The median PFS observed was in the toripalimab arm was 11.7 months (95% CI, 11.0-not evaluable [NE]) per blinded independent review committee assessment vs 8.0 months (95% CI, 7.0-9.5) in the chemotherapy alone arm (stratified HR, 0.52; 95% CI, 0.36-0.74; P =.0003). Moreover, the combination showed a median overall survival (OS) that was NE in both arms (stratified HR, 0.603; 95% CI, 0.364-0.997; P = .0462), according to a presentation at the 2021 American Society of Clinical Oncology Annual Meeting.

OS data were immature at data cutoff, but a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR, 0.603; 95% CI, 0.364-0.997).

At 1 year, the PFS rate in the toripalimab arm was 49.4% (95% CI, 36.4%-61.1%) compared with 27.9% (95% CI, 18.0%-38.8%) in the control arm. The 1-year OS rate observed was 91.6% (95% CI, 85.6%-95.1%) vs 87.1% (95% CI, 80.4%-91.7%) with chemotherapy alone. The OS rate at 2-years with the toripalimab combination was 77.8% (95% CI, 68.0%-85.0%) compared with 63.3% (95% CI, 49.8%-74.1%) with chemotherapy.

Regarding the safety of toripalimab in the JUPITER-02 study, any-grade adverse events (AEs) were observed in all patients. Grade 3 or higher AEs occurred in 89.0% vs 89.5%, respectively with the most frequently reported grade 3 or higher AEs included leukopenia (61.6% vs 58.0%), neutropenia (57.5% vs 63.6%), and anemia (47.3% vs 39.9%).

If toripalimab is granted approval, the JUPITER-02 findings would support the toripalimab combination as treatment of patients with patients with advanced recurrent or metastatic, in the frontline setting.

POLARIS-02

The POLARIS-02 study included 190 patients who received toripalimab 3 mg/kg once every 2 weeks until confirmed disease progression or unacceptable toxicity. The primary end point of the trial was ORR, with secondary end points of safety, DOR, PFS, and OS.

According to findings published in the Journal of Clinical Oncology, the ORR shown in the study was 20.5% (95% CI, 15.0%-27.0%), the DCR was 40.0% (95% CI, 33.0% -47.3%), and that there was a 38.4% decrease in target lesions from baseline. 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).

Treatment-related AEs occurred in 74.2% of patients. The most common treatment-related adverse events (TRAEs) observed in patients who received toripalimab were hypothyroidism (23.7%), anemia (15.3%), and aspartate aminotransferase increase (15.3%). Regarding, immune-related AEs, the event shown were hypothyroidism (23.7%), hyperthyroidism (2.6%), abnormal liver function (1.6%), interstitial lung disease (1.6%), dermatomyositis (0.5%), and autoimmune myocarditis (0.5%).

The POLARIS-02 results would support the use of toripalimab monotherapy in patients with second-line or later treatment of recurrent or metastatic NPC after platinum-containing chemotherapy, if toripalimab is granted FDA approval.

_REFERENCES:

_{1. Coherus and Junshi Biosciences share update on the FDA review of the biologics license application (BLA) for toripalimab as treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC). News release. December 24, 2022. Accessed December 24, 2022. https://bit.ly/3WlZn4T}

_{2. 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.}

_{3. 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}