FDA Approval Sought for Toripalimab Plus Chemotherapy for Metastatic Nasopharyngeal Carcinoma Treatment

A rolling submission of a biologics license application has been completed for toripalimab in combination with gemcitabine cisplatin for consideration as a front-line treatment for patients with metastatic nasopharyngeal carcinoma. The BLA also seeks FDA approval for toripalimab as monotherapy for the second-line or above treatment of recurrent or metastatic following platinum-based chemotherapy, Shanghai Junshi Biosciences Co., Ltd announced in a press release.¹

This submission follows a breakthrough therapy designation granted to toripalimab combined with gemcitabine and cisplatin for the front-line treatment of locally advanced or primary metastatic non-keratinizing nasopharyngeal carcinoma in 202 and as monotherapy or patients with recurrent or metastatic non-keratinizing nasopharyngeal carcinoma whose disease progressed on or after platinum-based chemotherapy.

Findings from both the POLARIS-02 (NCT02915432) and JUPITER-02 (NCT03581786) studies support the BLA for toripalimab in both settings of nasopharyngeal carcinoma.

“Toripalimab was approved for marketing early this year in China as the world’s first immune checkpoint inhibitor to treat advanced NPC, an aggressive tumor with limited treatment options,” said Patricia Keegan, MD, chief medical officer of Junshi Biosciences, in a press release. “Toripalimab showed remarkable efficacy in the treatment of advanced NPC according to the results from POLARIS-02 and JUPITER-02 studies, as recognized by inclusion in plenary and other presentations at leading international medical professional conferences and publications in highly respected scientific journals. We look forward to working closely with the FDA in the review of this BLA and with our US partner, Coherus, to bring this new treatment option forward as expeditiously as possible for patients in the US.”

Durable clinical responses were observed with toripalimab monotherapy given at 3 mg/kg once every 2 weeks in patients with chemorefractory metastatic nasopharyngeal carcinoma in the single-arm, multicenter phase2 POLARIS-02 trial.²

The purpose of the study was to explore the primary end point of objective response rate (ORR), and the secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

In 190 patients in the intent-to-treat population, the ORR per RECIST v1.1 was 20.5% (95% CI, 15.0%-27.0%), which included complete response in 2.5%, partial responses in 17.9%, stable disease in 19.5% and progressive disease in 45.3%. The disease control rate was 40.0% (95% CI, 33.0%-47.3%). The median DOR was 12.8 months (95% CI, 9.4 to not estimable months).

In terms of safety, the median PFS was 1.9 months (95% CI, 1.8-3.5 months), and the median overall survival OS was 17.4 months (95% CI, 11.7-22.9 months).

Patients received a median of 8 doses of toripalimab (range, 1-69 doses) during the study. Toripalimab was discontinued by 4 patients due to the emergence of treatment-related adverse events (TRAEs), and 7 patients had dose interruptions due to TRAEs.

Overall, TRAEs occurred in 74.2% of patients. The most common any-grade TRAEs observed in the study were hypothyroidism (23.7%), and anemia (15.3%). Grade 3 to 5 TRAEs also occurred in 14.2% of patients who received toripalimab. The key immune-related AEs seen in the study 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%).

In the randomized double-blind, phase 3 JUPITER-02 study, PFS by Independent Revie Committee was explored as the primary end point. The study also looked at ORR, DOR, and OS as secondary end points.³

According to results from an interim analysis of the study, the addition to toripalimab to gemcitabine and cisplatin achieved a longer PFS compared with gemcitabine and cisplatin alone. In addition, a higher rate of responses and more durable responses were observed when toripalimab was added to chemotherapy.

In 289 patients randomized to receive either the toripalimab combination 9n = 146) or chemotherapy (n=143), the median PFS was 11.7 versus 8.0 months (HR, 0.52; 95% CI, 0.36-0.74; 2-sided P =.0003). A 1 year, the PFS rate was 49% in the toripalimab combination arm compared with 28% in the chemotherapy-only arm. Improvement in PFS was irrespective of PD-L1 expression status.

Toripalimab plus gemcitabine and cisplatin also achieved an ORR of 77.4% in the study compared with only 66.4% in the chemotherapy-only arm (P =.033). The median DOR observed during the study was 10.0 months with added toripalimab versus 5.7 months without toripalimab (HR, 0.50; 95% CI, 0.33-0.78). OS data had not matured at the time of the interim analysis, however, 25 patients in the toripalimab arm had died compared with 35 patients in the chemotherapy only arm, signaling a potential improvement in OS with the addition of toripalimab to chemotherapy (HR,0.68; 95% CI, 0.41-1.14; P = 0.14)

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In terms of safety, grade 2 AE occurred n 89.0% of the experimental arm compared with 89.5% of the control arm. Discontinuation of treatment occurred in 7.5% of patients in the experimental arm versus 4.9% of the chemotherapy arm, and fatal AEs occurred in 2.7% versus 2.8%, respectively. The 2 treatment arms were overall similar in terms of AEs with the exception of IRAEs. In the toripalimab arm, IRAEs occurred in 7.5% of patients compared with the control arm, in which only 0.7% of patients had an IRAE. Overall, the safety profile of toripalimab plus gemcitabine and cisplatin was manageable in patients with advanced nasopharyngeal carcinoma treatment in the frontline setting.

“Toripalimab, the foundation stone of our emerging immuno-oncology franchise, demonstrated compelling efficacy in the pivotal studies supporting the BLA for nasopharyngeal carcinoma,” said Denny Lanfear, CEO of Coherus, in a press release.¹ “As data read out from the extensive set of pivotal clinical trials potentially supporting a broad range of additional indications, we expect toripalimab to maintain a consistently strong efficacy profile. We will continue to work with our partner, Junshi Biosciences, to advance toripalimab through FDA approval."

_References:

_{1. Junshi Biosciences announce completion of rolling bla submission to FDA for toripalimab. News release. Junshi Biosciences. September 1, 2021. Accessed September 2, 2021. https://bit.ly/3kGA6kg}

_{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.20.02712}

_{3. Xu RH, Mai HQ, Chen QY, 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 18). doi: 10.1200/JCO.2021.39.15_suppl.LBA2}