Renal carcinoma is the third most common malignancy of the urinary system globally, and RCC accounts for 80%~90% of all cases of renal carcinoma. There were approximately 77,000 new cases of and 46,000 deaths due to renal carcinoma in China in 2022. Distant metastasis occurred in about one-third of renal carcinoma patients at initial diagnosis, and in 20%-50% of localized patients after nephrectomy. According to the risk classification of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), the median overall survival (“OS”) of patients with low, medium and high risk metastatic RCC receiving anti-vascular targeted treatment were 35.3, 16.6 and 5.4 months, respectively. Therefore, compared to low-risk patients, the clinical needs for new treatment options are more urgent for patients with medium and high risk advanced RCC.

The approval of the sNDA is mainly based on data from the RENOTORCH study (NCT04394975), a multi-center, randomized, open-label, active-controlled Phase 3 clinical study led by principal investigators Professor Jun GUO from Peking University Cancer Hospital and Professor Yiran HUANG from Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The study was conducted across 47 medical centers, and represents the first pivotal Phase 3 clinical study of immunotherapy for patients with advanced RCC in China.

A total of 421 randomized patients with medium to high risk unresectable or metastatic RCC were enrolled in the study and randomly assigned in a 1:1 ratio to receive toripalimab in combination with axitinib (n=210) or sunitinib alone (n=211). The primary endpoint is progression free survival (“PFS”) as assessed by the Independent Review Committee (“IRC”), and secondary endpoints include PFS as assessed by investigators, objective response rate (“ORR”) as assessed by IRC or investigators, duration of response (“DoR”), disease control rate (DCR), OS, safety profile, etc.

Previously, the study results of RENOTORCH made its debut at the Proffered Paper Session of the European Society for Medical Oncology (ESMO) congress 2023. The full text was simultaneously published in Annals of Oncology, the official journal of ESMO. The study data showed that, based on the assessment results of IRC, compared with sunitinib monotherapy, toripalimab in combination with axitinib for the treatment significantly prolonged the PFS of patients by nearly twofold (median PFS: 18.0 vs. 9.8 months, P=0.0028), and the risk of disease progression or death was reduced by 35% (hazard ratio [HR]=0.65; 95% CI: 0.49, 0.86). In addition, the ORR was higher (56.7% vs. 30.8%, P<0.0001) and the DoR was longer (median DoR: not reached vs 16.7 months; HR=0.61) in the toripalimab group. The OS of the toripalimab group also showed a clear trend of benefit (median OS: not reached vs 26.8 months), and the risk of death was reduced by 39% (HR=0.61; 95%CI: 0.40, 0.92). In terms of safety, toripalimab in combination with axitinib demonstrated a favorable safety and tolerability profile, and no new safety signals were observed.

“From a global perspective, targeted therapy in combination with immunotherapy has become the standard treatment approach for advanced RCC,” said Professor Jun GUO from Peking University Cancer Hospital. “However, no such treaments have been approved in China. The approval of toripalimab’s new indications opens a new chapter in combined targeted therapy and immunotherapy in China, and it will transform current clinical practices for advanced RCC and introduce new treatment options for medium to high-risk patients!”

“The treatment methods for advanced RCC are limited, especially for medium to high risk patients, who often face suboptimal prognoses,” said Professor Yiran HUANG from Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine “The approval of toripalimab combined with axitinib addresses the gap in first-line immunotherapy for renal cancer in China. Compared to targeted monotherapy, toripalimab combined with targeted therapy will significantly improve patients’ PFS, offering promising prospects for many advanced RCC patients in China.”

“Thank you to all medical professionals, patients, and R&D personnel involved in the RENOTORCH study for their contributions,” said Dr. Jianjun ZOU, CEO of Junshi Biosciences. “Their dedication has led to a pioneering breakthrough in renal cancer, first of its kind in China! Junshi Biosciences will remain committed to addressing domestic clinical needs and continue investing in research and development to help patients live longer and better!”

According to the Chinese Guidelines for Lipid Management (2023), cardiovascular disease, particularly atherosclerotic cardiovascular disease (“ASCVD”), is the leading cause of death among urban and rural residents in China. The rise of low-density lipoprotein cholesterol (“LDL-C”) levels is a dangerous factor in causing ASCVD. Reducing LDL-C levels can significantly lower the incidence of ASCVD and the risk of death. Despite statins currently being the cornerstone of lipid-lowering treatment, approximately 9.1% of patients clinically exhibit statin intolerance, with a disproportionately higher prevalence observed in Asian populations. Discontinuation of statins or the use of only tolerable doses in patients with statin intolerance may lead to suboptimal LDL-C levels, potentially hindering ASCVD risk reduction in affected patients.

Heterozygous familial hypercholesterolemia (“HeFH”), a common type of familial hypercholesterolemia with an estimated prevalence of 1:250 – 1:200, is a diagnosis that refers to individuals with significantly elevated LDL-C levels and an increased risk of early-onset coronary artery disease. Compared to patients with non-familial hypercholesterolemia, patients with HeFH exhibit higher baseline LDL-C levels and lower target levels recommended by guidelines. Failure to achieve target LDL-C levels with treatments such as statins will result in patients being at high cardiovascular risk. As a new lipid-lowering drug to effectively reduce LDL-C levels, the PCSK9 inhibitor has been recommended in the guidelines for the management of lipids in China and overseas and is widely recognized by clinicians.

The sNDAs are mainly based on two registered clinical trials (JS002-005 and JS002-007). JS002-005 (NCT05325203) is a randomized, double-blind, placebo-controlled Phase III clinical study in adult patients with HeFH. JS002-007 (NCT05621070) is a randomized, double-blind, placebo-controlled Phase III clinical study in adult patients with primary hypercholesterolemia and mixed hyperlipidemia who are unable to tolerate or contraindicated for statin therapy.

This NDA was submitted through Project Orbis, an initiative of the US Food and Drug Administration (FDA)’s Oncology Center of Excellence (OCE). Project Orbis provides a collaborative mechanism and framework between the FDA and regulatory partners in other countries and regions for concurrent submission and review of oncology drugs. At present, eight regulatory agencies have joined Project Orbis, including the FDA, the Australia Therapeutic Goods Administration (“TGA”), HSA, Health Canada (HC), the U.K. Medicines and Healthcare products Regulatory Agency (“MHRA”), etc.

Project Orbis currently accepts applications for oncology indications. An application should generally qualify for FDA priority review, meaning that the drug is intended to treat a serious disease and, if approved, would significantly improve the safety or efficacy of the treatment and offer notable clinical benefits. Under the framework of Project Orbis, collaboration between international regulators may expedite patient access to new cancer treatments in other countries.

Toripalimab for the treatment of NPC meets these application requirements and is the first Chinese oncology drug to be included in Project Orbis. Previously, two NDAs for toripalimab for the treatment of NPC had been submitted to the TGA through Project Orbis and were successfully accepted. Junshi Biosciences will explore accelerated marketing opportunities in countries and regions where it is applicable.

The NDA is supported by results from JUPITER-02, a randomized, double-blind, placebo-controlled, multinational multi-center Phase 3 clinical study (NCT03581786), for the first-line treatment of NPC, as well as results from POLARIS-02, a multi-center, open-label, pivotal Phase 2 clinical study (NCT02915432), for second-line or later treatments for recurrent or metastatic NPC.

Results from JUPITER-02, the first international, multi-center, double-blind, randomized, placebo-controlled Phase 3 clinical study using immunotherapy for the treatment of NPC with the largest sample size, were presented at the plenary session of the 2021 American Society of Clinical Oncology (ASCO) annual meeting (#LBA2), and published in Nature Medicine and the Journal of the American Medical Association (JAMA). The study found that compared to chemotherapy alone, toripalimab in combination with chemotherapy for the first-line treatment of metastatic or recurrent NPC significantly improved progression-free survival (PFS) and overall survival (OS), with a median PFS of 21.4 months, and a 3-year OS rate of 64.5%; it also reduced the risk of disease progression or death by 48% and the risk of death by 37%, all while demonstrating a manageable safety profile.

The POLARIS-02 results were published online in January 2021 in the Journal of Clinical Oncology. These findings showed that toripalimab demonstrated durable antitumor activity in patients with recurrent or metastatic NPC who failed previous chemotherapy, with an objective response rate (ORR) of 20.5%, a median duration of response (DoR) of 12.8 months, and a median OS of 17.4 months while maintaining a manageable safety profile.

So far, toripalimab has been approved for 7 indications in China, with 3 supplementary new drug applications (sNDA) currently under regulatory review. Internationally, it has been approved for 2 NPC indications in the US, and marketing approval applications are currently under regulatory review in the European Union, UK, Australia and Singapore.

About NPC

NPC is a malignant tumor that occurs in the nasopharyngeal mucosal epithelium and is one of the most common types of head and neck cancer. According to the World Health Organization, the number of newly diagnosed NPC cases in 2020 exceeded 130,000 worldwide. Due to the location of the primary tumor, surgery is rarely an option, while radiotherapy alone or in combination with chemotherapy are the main treatment options for localized cancers.

NEOTORCH is the world’s first phase III clinical study of a anti-PD-1 monoclonal antibody for NSCLC perioperative treatment (including neoadjuvant and adjuvant) with positive EFS results. NEOTORCH’s latest study results were announced in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Plenary Series held last April, as well as during the 2023 ASCO annual meeting.

“Whether it is clinical diagnosis and treatment level or clinical research ability, we have gradually transformed from a ‘follower’ to an ‘equal,’ even becoming a ‘leader’ in certain aspects. An increasing number of innovative solutions are originating from China and going global, ultimately changing international treatment standards. The publication of NEOTORCH by JAMA is a starting point. China’s ‘3+1+13’ perioperative treatment model has the highest evidence-based medical value and will establish new treatment standards for patients, bringing transformative changes to the diagnosis and treatment landscape of lung cancer in China and beyond,” said NEOTORCH’s principal investigator, Dr. Shun LU of the Shanghai Chest Hospital within Shanghai Jiaotong University.

As a phase 3 clinical study of perioperative treatment, NEOTORCH enrolled the largest sample of resectable stage III NSCLC patients in China. Of the 501 randomized patients, 404 stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) were included in this interim analysis. Patients were randomized in a 1:1 ratio to receive toripalimab or placebo, once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before and 1 cycle after surgery, followed by toripalimab only or placebo for up to 13 cycles.

As of November 30, 2022 (median follow-up of 18.3 months), results showed that the addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC, and this treatment strategy had a manageable safety profile. For the primary outcome of event-free survival (assessed by investigator), the median length was not estimable in the toripalimab group compared with 15.1 months in the placebo group (hazard ratio, 0.40 [95%CI, 0.28-0.57], P<0.001). The major pathological response rate (another primary outcome assessed by blinded, independent pathological review) was 48.5% in the toripalimab group compared with 8.4% in the placebo group. The pathological complete response rate (secondary outcome assessed by blinded, independent pathological review) was 24.8% in the toripalimab group compared with 1.0% in the placebo group.

Of the 82.2% (166/202) of patients in the toripalimab group and 73.3% (148/202) of patients in the placebo group who underwent surgery, 95.8%and 92.6%, respectively, had their resections classified as R0. Among the patients who underwent surgery, the median length of disease-free survival (assessed by the investigators) was not estimable vs. 19.3 months, respectively (HR, 0.50 [95% CI, 0.33-0.76], P<0.001). The median length of overall survival was not estimable in the toripalimab group compared with 30.4 months in the placebo group (HR, 0.62 [95% CI, 0.38-1.00]).

“NEOTORCH’s significant research findings have been published by JAMA, underscoring the international academic community’s recognition of toripalimab and the world’s first ‘3+1+13’ perioperative immunotherapy model for lung cancer. We anticipate that toripalimab will guide China’s perioperative lung cancer treatment into a new era. Junshi Biosciences will also continue to innovate, and we aim to bring more advanced and improved treatment options to patients,” said Dr. Jianjun ZOU, General Manager and Chief Executive Officer of Junshi Biosciences.