The FDA has accepted for review a biologics license application for the use of toripalimab in combination with gemcitabine and cisplatin in the frontline treatment of patients with advanced recurrent or metastatic nasopharyngeal carcinoma, and for use as a single agent in the second- or later-line treatment of patients with recurrent or metastatic nasopharyngeal carcinoma following platinum-containing chemotherapy.
The FDA has accepted for review a biologics license application (BLA) for the use of toripalimab in combination with gemcitabine and cisplatin in the frontline treatment of patients with advanced recurrent or metastatic nasopharyngeal carcinoma, and for use as a single agent in the second- or later-line treatment of patients with recurrent or metastatic nasopharyngeal carcinoma following platinum-containing chemotherapy.1
The application is based on data from the phase 2 POLARIS-02 trial (NCT02915432), and the phase 3 JUPITER-02 trial (NCT03581786).
Results from the phase 2 trial indicated that the use of toripalimab resulted in an objective response rate (ORR) of 20.5% (95% CI, 15.0%-27.0%) per independent review committee (IRC) among 190 patients with previously treated recurrent or metastatic nasopharyngeal carcinoma.2
Data from the phase 3 trial showed that the addition of toripalimab to gemcitabine/cisplatin resulted in a median progression-free survival (PFS) of 11.7 months (95% CI, 11.0–not evaluable) by blinded IRC and per RECIST v1.1 criteria vs 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
The regulatory agency is expected to decide on the BLA by April 2022 under the Prescription Drug User Fee Act.
“Nasopharyngeal carcinoma is an aggressive tumor that currently has no FDA-approved immuno-oncology treatment options, and we believe that toripalimab in combination with chemotherapy, if approved, will establish a new standard of care for first-line treatment of advanced [disease,]” Denny Lanfear, chief executive officer of Coherus BioSciences, Inc., stated in a press release. “Toripalimab is a PD-1 cornerstone of our immuno-oncology strategy, and we are pleased that the FDA has accepted the BLA for review.”
An anti–PD-1 monoclonal antibody, toripalimab was designed to block PD-1 interactions with its ligands PD-L1 and PD-L2, and to strengthen receptor internalization. By blocking these interactions, it is hypothesized that the agent recharges the ability of the immune system to eliminate cancer cells.
In the multicenter phase 1b/2 POLARIS-02 trial, investigators set out to examine the safety and efficacy of toripalimab in patients with relapsed metastatic nasopharyngeal cancer, head and neck cancer, gastric cancer, and esophageal cancer.
To be eligible for enrollment, patients needed to be refractory to previous standard chemotherapy or have experienced progressive disease within 6 months following adjuvant chemotherapy or chemoradiotherapy. Patients also needed to be at least 18 years of age, have measurable disease, an ECOG performance status of 0 or 1, and acceptable organ function.
If patients received anticancer monoclonal antibody therapy within 4 weeks prior to the start of treatment, any anticancer therapy within 2 weeks before treatment initiation, previous immune checkpoint inhibitors, systemic corticosteroid therapy within 1 week prior to the start of treatment, or if they had any additional known malignancies or active central nervous system metastases, they were excluded.
Study participants were given toripalimab at a dose of 3 mg/kg every 2 weeks. Treatment was administered until progressive disease, unacceptable toxicity, or voluntary withdrawal of informed consent. Patients who experienced disease progression were allowed to receive continued toripalimab under the condition of potential benefit and with the consensus of the study investigator and sponsor.
The primary end point of the trial was ORR per IRC and in accordance with RECIST v1.1 criteria. Key secondary end points included safety, duration of response, disease control rate (DCR), PFS, and overall survival (OS). Exploratory end points included PD-L1 expression, plasma Epstein Barr virus DNA copy number, tumor mutational burden, and genetic biomarkers for efficacy.
Among the 190 patients enrolled, the mean age was 46.4 years (range, 22.0-71.0), 83.2% were male, 65.3% had an ECOG performance status of 1, 95.8% had a nonkeratinizing histology, 70.5% had PD-L1 negativity, and 81.1% of patients had a baseline lactate dehydrogenase level that was ≤ 2 x the upper limit of normal. Moreover, 51.6% of patients previously received 1 line of systemic treatment and 48.4% received 2 or more prior lines.
Additional data from the trial showed that toripalimab resulted in a DCR rate of 40.0% (95% CI, 33.0%-47.3%). The median time to response was 1.8 months (95% CI, 1.8-2.1) and the median DOR was 12.8 months (95% CI, 9.4–not estimable [NE]). Moreover, the median PFS with the agent was 1.9 months (95% CI, 1.8-3.5) and the median OS was 17.4 months (95% CI, 11.7-22.9).
Among the patients who achieved an objective response (n = 39) or stable disease (n = 38) with toripalimab, the median OS had not yet been reached. Among 113 patients who experienced disease progression, the median OS was 8.4 months.
Moreover, in the 92 patients who were receiving toripalimab in the second-line or later setting, the agent resulted in an ORR of 23.9% (95% CI, 15.6-33.9), with a DCR of 41.3% (95% CI, 31.1%-52.1%) per IRC and RECIST criteria. Moreover, in this subgroup, the median DOR 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).
Regarding safety, 74.2% of patients reported treatment-related adverse effects (TRAEs), with 14.2% of patients reporting grade 3 to 5 toxicities. The most common toxicities included hypothyroidism (23.7%), anemia (15.3%), increased aspartate aminotransferase (15.3%), increased alanine aminotransferase (13.7%), asthenia (13.2%), proteinuria (12.6%), leukopenia (10.0%), pyrexia (9.5%), pruritus (8.4%), rash (6.3%), and neutropenia (5.3%).
JUPITER-02 enrolled patients with primary metastatic nasopharyngeal carcinoma or recurrent disease following curative-intent therapy. Patients needed to have an ECOG performance status of 0 or 1, be between the ages of 18 years and 75 years, and have measurable disease per RECIST v1.1 criteria.
Study participants were randomized 1:1 to receive either 240 mg of toripalimab plus gemcitabine/cisplatin every 3 weeks for up to 6 cycles or gemcitabine/cisplatin alone for the same dosing schedule. Those in the investigative arm went on to receive toripalimab maintenance, in which the agent was given at 240 mg every 3 weeks. Those in the control arm received maintenance treatment with placebo.
The primary end point of the trial was PFS per blinded IRC and RECIST v1.1 criteria, and key secondary end points comprised investigator-assessed PFS, ORR, DOR, DCR, and OS, as well as 1- and 2-year rates of both PFS and OS. Patients were stratified based on recurrent vs primary metastatic disease and ECOG performance status of 0 vs 1.
Of the 408 patients who underwent screening for the trial, 289 patients ended up undergoing randomization; of these patients, 146 received toripalimab plus chemotherapy and 143 received chemotherapy alone. Moreover, 115 patients in the investigative arm and 118 patients in the control arm went on to receive maintenance treatment. A total of 91 patients were still receiving treatment at a data cutoff date of May 30, 2020, vs 54 patients on the control arm.
The median age of patients on the toripalimab arm vs the placebo arm was 46 years (range, 19-72) and 51 years (range, 21-72), respectively. Across the arms, most patients were male and had an ECOG performance status of 1. Fifty-eight percent of patients on the investigative arm had recurrent disease vs 61% of those on the control arm; 42% vs 39% of patients, respectively, had primary metastatic disease.
Moreover, 52% of those on the toripalimab arm were current or former smokers vs 41% of those on the placebo arm, and 21% and 13% of patients, respectively, were current or former alcohol users. Most patients on both arms had non-keratinizing squamous cell carcinoma and had PD-L1 positivity. Twenty-six percent of those on the investigative arm previously underwent surgery vs 30% of those on the control arm, and 58% and 61% of patients, respectively previously received radiation therapy.
Additional data from the trial were presented during the 2021 ASCO Annual Meeting and showed that the 1-year PFS rates in the investigative and control arms were 49.4% (95% CI, 36.4%-61.1%) and 27.9% (95% CI, 18.0%-38.8%), respectively.
The median OS had not been reached in either arm (stratified HR, 0.603; 95% CI, 0.364-0.997; P = .0462). The 1-year OS rate with toripalimab was 91.6% (95% CI, 85.6%-95.1%) vs 87.1% (95% CI, 80.4%-91.7%) with chemotherapy alone; at 2 years, these rates were 77.8% (95% CI, 68.0%-85.0%) and 63.3% (95% CI, 49.8%-74.1%), respectively.
Additionally, toripalimab plus chemotherapy elicited an ORR of 77.4% (95% CI, 69.8%-83.9%) vs 66.4% (95% CI, 58.1%-74.1%) with chemotherapy alone (P = .0335). The median DOR in the investigative and control arms was 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).
All patients in both arms experienced treatment-emergent AEs; 89.0% and 89.5% of these toxicities, respectively, were grade 3 or higher in severity. Moreover, 95.2% of those on the investigative arm experienced toxicities associated with study drug vs 97.2% of those on the control arm. Moreover, 39.7% of those who received toripalimab experienced immune-related AEs vs 18.9% of those who received chemotherapy alone. Four patients on both arms experienced fatal toxicities.
The most common toxicities reported with 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.
Previously, in August 2021, the FDA granted toripalimab a breakthrough therapy designation for use in combination with chemotherapy in the frontline treatment of patients with recurrent, locally advanced, or primary metastatic non-keratinizing nasopharyngeal carcinoma. In September 2020, the agent received breakthrough therapy designation for single-agent use in patients with recurrent or metastatic non-keratinizing nasopharyngeal carcinoma with disease progression on, or following, platinum-based chemotherapy.