At the end of June, Novartis announced the latest data readouts in a long string of successes for tislelizumab. BioSpace spoke with Ken Kato, an investigator on the most recent RATIONALE 306 trial.
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At the end of June, Novartis announced the latest data readouts in a long string of successes for its anti-PD1 monoclonal antibody, tislelizumab, demonstrating the therapeutic’s efficacy in combination with chemotherapy in patients with unresectable, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC).
In patients with ESCC, cancerous cells form in the tissue of the esophagus which can cause difficulty swallowing, cough and indigestion. If ESCC is not detected early, it carries a poor prognosis.
“ESCC is the most common type of esophageal cancer globally, with an estimated 604,000 new cases and 544,000 deaths from esophageal cancer internationally in 2020,” Ken Kato, M.D., Ph.D., chief of the department of head and neck, and esophageal medical oncology, and gastrointestinal medical oncology at the National Cancer Center Hospital in Tokyo, Japan told BioSpace. “People living with rare cancers such as ESCC can face significant unmet needs. There are few immunotherapies currently approved by the FDA for ESCC, and people living with ESCC are in need of new treatment options.”
Tislelizumab Showing Positive Signs in ESCC
Novartis’ Phase III RATIONALE 306 trial, being conducted in collaboration with BeiGene, is the latest in the company’s efforts to bring treatment to those with ESCC. The trial included approximately 649 participants with unresectable, locally advanced recurrent or metastatic ESCC. Participants were randomized to either receive tislelizumab with chemotherapy or a placebo with chemotherapy.
Patients dosed in the trial showed a median overall survival of 17.2 months versus 10.6 months for those taking chemotherapy plus placebo. The drug also reduced the risk of death by 34% in patients.
“This survival benefit was consistent across all other subgroups, including race, region and choice of chemotherapy,” Kato, an investigator on the trial, said.
In a subset of patients with a greater than 10% programmed death-ligand 1 (PD-L1), a protein that prevents the immune system from attacking cancerous cells, tislelizumab plus chemotherapy showed a median overall survival of 16.6 months and reduced death by 38%. Overall, the treatment regimen significantly improved progression-free survival with an objective response rate of 63.5%.
“This is the seventh positive clinical trial readout for tislelizumab, reinforcing its clinical profile as a proven immunotherapy in multiple cancer types and lines of therapy,” Kato said. “Tislelizumab plus chemotherapy had a manageable safety profile in patients with advanced or metastatic ESCC, with no new safety signal identified. By exploring the potential of combination therapies with tislelizumab, we can aim to efficiently discover new ways to improve cancer care in difficult-to-treat diseases.”
In September 2021, the company announced that the FDA had accepted its Biologics License Application (BLA) submission for review in this indication. The COVID-19 pandemic has thrown a wrench into the process, however, as the regulator has pushed back action on the BLA, citing ” travel restrictions and the inability to complete inspections” as the reasoning for the delay.
The application was based on the Phase III RATIONALE 302 clinical trial, which investigated the use of tislelizumab as a monotherapy in patients with ESCC who had received prior systemic therapy. The results demonstrated that tislelizumab decreased the risk of death in patients by 30% and extended median overall survival by 2.3 months compared to chemotherapy. Already, tislelizumab is approved as a second-line treatment for patients with ESCC in China.
Tislelizumab’s Broad Potential
Tislelizumab works by minimizing binding to Fc-gamma receptors on macrophages. Kato explained that in pre-clinical studies, binding to Fc-gamma receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies. PD-1 and PD-L1 are involved in a pathway within tumor microenvironments that prevent the immune system from attacking it.
Thus far, the drug appears to have broad potential.
“These results are a promising outcome in the treatment of this aggressive cancer,” Kato said. “The significant overall survival benefit was observed across all patient subgroups in the trial, indicating that tislelizumab plus chemotherapy may be a viable treatment option for patients regardless of their PD-L1 score.”
Novartis is studying tislelizumab in a variety of cancers, including small cell lung cancer, hepatocellular carcinoma, nasopharyngeal carcinoma and gastric cancer, all of which are in Phase III clinical trials. This year alone, the company reported successful data readouts with tislelizumab in recurrent or metastatic nasopharyngeal cancer (RM-NPC) and gastric or gastroesophageal junction cancer (GI/GEJ). In RM-NPC, patients receiving tislelizumab plus chemotherapy achieved an average of 9.6 months without disease progression. In GI/GEJ cancer, the therapeutic plus Leap Therapeutics’ DKN-01 drove enhanced clinical response and survival benefits for patients.
BeiGene and Novartis Alliance
BeiGene penned a collaboration agreement with Novartis in January 2021 which aimed to accelerate the drug’s development and marketing in Europe, Japan and North America. Novartis is also in collaboration with BeiGene for ociperlimab, a humanized monoclonal antibody designed to produce an antitumor immune response. The therapeutic is currently being evaluated in combination with tislelizumab in a variety of advanced or metastatic solid tumors.
Meanwhile, BeiGene has also been busy signing collaborations with other companies to test tislelizumab alongside a variety of other therapies to provide more options for patients. In June, the company announced a clinical trial agreement with Antengene to evaluate the latter’s selinxor with tislelizumab in patients with T and NK-cell lymphoma. BeiGene is also in collaboration with Asieris, which recently presented positive data from its study of APL-1202 in combination with tislelizumab in patients with muscle-invasive bladder cancer.
Robust Anti-Cancer Portfolios
Beyond tislelizumab, both BeiGene and Novartis are making progress in other therapeutics for cancer patients. BeiGene has been making headway with Brukinsa, a small molecule inhibitor, which is being studied as a monotherapy and in combination with other therapies for B-cell malignancies. Brukinsa is approved in 50 markets, including the United States, for B-cell malignancies.
In the first half of 2022, Novartis received FDA approval for its prostate cancer drug Pluvicto (lutetium Lu 177 vipivotide tetraxetan) and just recently got the regulator’s nod for a combination treatment of Tafinlar plus Mekinist for the treatment of adults and children with unresectable or metastatic solid tumors with a BRAF V600E mutation.
