Tislelizumab Metastatic ESCC BLA Now Under FDA Consideration for Approval

The FDA has accepted the biologics license application for tislelizumab (BGB-A317), an anti-PD-1 immune checkpoint inhibitor for the treatment of unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) in previously treated patients, according to a press release by Novartis.1

The humanized IgG4 anti-PD-1 monoclonal antibody is designed to minimize binding to FcyR on macrophages. Preclinical studies have found that FcyR compromises the anti-tumor activity of PD-1 antibodies by the activation of antibody-dependent macrophage-mediated killing of T effector cells. 

"This is an encouraging step forward in our mission to deliver transformative therapies for people living with cancer, and especially for people with esophageal cancer, an aggressive disease with limited treatment options," said Jeff Legos, executive vice president of Global Head of Oncology and Hematology Development at Novartis, in a press release. “We are advancing tislelizumab as a key cornerstone of our immunotherapy program and PD-1 backbone for combination therapy. We will work with regulatory authorities to ensure it is available for people with esophageal cancer as soon as possible.”

The acceptance is based on the results of the phase 3 RATIONALE 302 study (NCT03430843). The randomized, open-label study has an actual enrollment of 513 participants. The primary end point is overall survival (OS). Secondary end points include overall response rate (ORR), progression-free survival (PFS), duration of response (DoR), health-related quality of life, and adverse events (AEs).2

During the study, patients were randomized into 1 of 2 arms. In the experimental arm, patients received tislelizumab 200 mg intravenously every 21 days. In the control arm, patients received investigators choice of chemotherapy.

The median age of participants is 62 (range, 35-86). The 512 patients included in the analysis were split evenly between the control (n = 256) and the experimental (n = 256) arms. The median follow-up in the experimental arm was 8.5 months compared to 5.8 months in the control arm. The median OS in the experimental arm was 8.6 months compared to 6.3 months in the control arm (P =.0001). The ORR in the experimental arm was also higher, 20.3%, compared to 9.8% in the control arm. The DoR for the experimental group was 7.1 months compared with 4 months in the control arm.3 

In terms of safety, the rate of Grade 3 or higher AEs was 46% in the experimental arm and 68% in the control arm. In the experimental arm, 19% of these AEs were treatment-related compared with 56% in the control arm. The Rate of discontinuation due to treatment-related AEs was 7% in the experimental arm and 14% in the control arm.

In order to participate in the study, patients must have a confirmed diagnosis of ESCC, progression during or after first-line treatment, have at least 1 measurable lesion, an ECOG score of 0 or 1 prior to randomization, and adequate organ function. Patients who had receive 2 or more prior systemic treatments, received prior PD-1 or PD-L1 treatment, brain metastasis, an active autoimmune disease, cardiovascular risks, or a known history of HIV are not eligible to participate.

_REFERENCES:

_{1.Novartis announces first FDA filing acceptance for anti-PD-1 antibody tislelizumab for people with esophageal cancer. News release. Novartis. September 13, 2021. Accessed September 13, 2021. https://bit.ly/3tAj8bn}

_{2.A study of tislelizumab (BGB-A317) versus chemotherapy as second line treatment in participants with advanced esophageal squamous cell carcinoma. ClinicalTrials.gov. Accessed September 13, 2021. https://bit.ly/3Ego4H6}

_{3.Shen L, Kato K, Kim S, et al. RATIONALE 302: Randomized, phase 3 study of tislelizumab versus chemotherapy as second-line treatment for advanced unresectable/metastatic esophageal squamous cell carcinoma. J Clin Oncol. 2021;39(15):4012. doi: 10.1200/JCO.2021.39.15_suppl.4012}