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Toripalimab for the Treatment of Nasopharyngeal Carcinoma

The FDA accepted for review the Biologics License Application (BLA) for toripalimab in combination with gemcitabine and cisplatin for the first-line treatment of patients with advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) and toripalimab monotherapy for the second-line or above treatment of recurrent or metastatic NPC after platinum-containing chemotherapy. The FDA has granted Priority Review Designation for the toripalimab BLA and set a Prescription Drug User Fee Act (PDUFA) action date for April 2022. The FDA is not currently planning to hold an advisory committee meeting to discuss the application.

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The toripalimab BLA is supported by the results from two clinical studies. The POLARIS-02 study is a multi-center, open-label, pivotal Phase II clinical study. The JUPITER-02 study is a randomized, double blind, placebo-controlled, international multi-center Phase III clinical trial.


In August 2021, the FDA granted Breakthrough Therapy Designation (BTD) of toripalimab in combination with chemotherapy (gemcitabine and cisplatin) for the first-line treatment of recurrent, locally advanced or primary metastatic non-keratinizing NPC.


In September 2020, the organization granted BTD of toripalimab monotherapy for patients with recurrent or metastatic non-keratinizing NPC with disease progression on or after platinum-containing chemotherapy. The toripalimab BLA has been granted priority review with a 6-month target action date, as compared to a 10-month standard review timeline.


Toripalimab is an anti-PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 is thought to recharge the immune system's ability to attack and kill tumor cells. More than 30 company-sponsored toripalimab clinical studies covering more than 15 indications have been conducted globally, including in China, the United States, Southeast Asia, and European countries. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney, and skin.


IND Application for Novel TEAD Inhibitor IK-930

The FDA accepted an Investigational New Drug (IND) application to study a TEAD inhibitor candidate, IK-930, for the treatment of cancers harboring genetic mutations in the Hippo signaling pathway. It is being developed as a potential targeted therapy for patients with cancers that exhibit genetic alterations across the Hippo pathway.


IK-930 is designed to selectively bind TEAD and to disrupt TEAD-dependent transcription of key genes involved in cancer progression, metastases, and therapeutic resistance. Preclinical research, presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2021, suggests that IK-930 is a potent and selective TEAD inhibitor that could prove effective both as a monotherapy and in combination with multiple targeted agents, such as EGFR and MEK inhibitors, in multiple hard-to-treat cancers.


The planned Phase I clinical trial includes patients with tumor types with a high frequency of Hippo pathway alterations, including NF2-deficient malignant mesothelioma and some soft tissue sarcomas with YAP/TAZ genetic fusions, including epithelioid hemangioendothelioma, a rare form of soft tissue sarcoma that has a significant unmet medical need with no currently approved therapy for advanced or metastatic disease. As supported by preclinical work, researchers also plan to explore combinations of IK-930 with other targeted agents for the treatment of solid tumors, such as EGFR-mutant non-small cell lung cancer and KRAS-mutant solid tumors.


Parsaclisib for Relapsed/Refractory Non-Hodgkin Lymphomas

The FDA has accepted a New Drug Application (NDA) for parsaclisib, an investigational novel potent, highly selective, next-generation oral inhibitor of phosphatidylinositol 3-kinase delta (PI3K[delta]), for the treatment of patients with relapsed or refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL).


The submission is based on data from several Phase II studies (CITADEL-203, -204, and -205) evaluating parsaclisib as a treatment for relapsed or refractory non-Hodgkin lymphomas (NHLs) (FL, MZL, and MCL). The inhibitor was generally well-tolerated in all studies with a manageable safety profile.


Parsaclisib has been granted Priority Review by the FDA for the treatment of adult patients with relapsed or refractory MZL who have received at least one prior anti-CD20-based regimen and for the treatment of adult patients with MCL who have received at least one prior therapy.


The FDA grants Priority Review to medicines that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. This designation shortens the review period by 4 months as compared to Standard Review, so the Prescription Drug User Fee Act (PDUFA) target action date for these indications is April 30, 2022.


The NDA for use of parsaclisib in adult patients with relapsed or refractory FL who have received at least two prior systemic therapies will have a Standard Review and a PDUFA target action date of August 30, 2022.


Confirmatory Phase III studies are in preparation for parsaclisib in patients with MCL (CITADEL-310), as well as relapsed or refractory FL and MZL (CITADEL-302).


* CITADEL-203 (NCT03126019) is evaluating patients with relapsed or refractory FL Grade 1, 2, or 3a who received at least two prior systemic therapies, had an ECOG performance status (ECOG PS) <=2, and were ineligible for hematopoietic stem cell transplantation.


* CITADEL-204 (NCT03144674) is evaluating patients with relapsed or refractory MZL who received at least one prior systemic therapy and were Bruton's tyrosine kinase (BTK) inhibitor treatment-naive. Patients with prior ibrutinib treatment were initially allowed to enroll; however, the cohort was terminated due to slow enrollment. Eligible patients had radiologically measurable lymphadenopathy or extranodal lymphoid malignancy (or histologically confirmed bone marrow infiltration in cases of splenic MZL), and an ECOG PS <=2.


* CITADEL-205 (NCT03235544) is evaluating patients with relapsed or refractory MCL, who received 1-3 prior systemic therapies and were either naive to or were previously treated with a BTK inhibitor. Eligible patients had an ECOG PS <=2 and radiologically measurable lymphadenopathy or extranodal lymphoid malignancy.



Patients eligible for each trial were allocated to receive parsaclisib 20 mg once daily for 8 weeks followed by either 20 mg once weekly (weekly dosing group [WG]) or 2.5 mg once daily (daily dosing group [DG]). Subsequently, daily dosing was selected as the preferred regimen and the WG patients were allowed to switch to DG. Prophylaxis for Pneumocystis jirovecii pneumonia was required.


Parsaclisib is a potent, highly selective, next-generation investigational novel oral inhibitor of phosphatidylinositol 3-kinase delta (PI3K[delta]). It is currently under evaluation as a monotherapy in several ongoing Phase II trials as a treatment for non-Hodgkin lymphomas (follicular, marginal zone, and mantle cell), and autoimmune hemolytic anemia. Pivotal trials of parsaclisib in combination with ruxolitinib for the treatment of patients with myelofibrosis are underway; and there are plans to initiate trials to evaluate parsaclisib in combination with tafasitamab, including a pivotal trial in B-cell malignancies.