Siravatinib/Tislelizumab Signals Efficacy in Patients With Platinum-Resistant Ovarian Cancer

Preliminary data showed that the combination of sitravatinib (MGCD516) and tislelizumab (BGB-A317) is well tolerated and may promote antitumor activity when administered to patients with platinum-resistant ovarian cancer, according to a press release from BieGene, Ltd, which reported data from a phase Ib study at the 2019 European Society of Oncology (ESMO) Immuno-Oncology Congress in Geneva, Switzerland.¹

Of the 17 patients who were enrolled in the ovarian cancer cohort of the trial and evaluable for response, there were 7 partial responses (PRs)—which included 4 confirmed PRs—resulting in an overall response rate of 23.5% with the combination (4/17; 95% CI, 6.8%-9.9%). An additional 8 patients demonstrated stable disease. The median duration of response was not reached among evaluable patients. The results from 20 patients showed a median progression-free survival (PFS) of 18 weeks (95% CI, 12.29-not reach). The PFS rate at 3 months was 88.2% (95% CI, 60.6%-96.9%). At 6 months, the PFS rate decreased to 35.5% (95% CI: 9.0%-63.8%).

There was a high occurrence of all-grade treatment-emergent adverse events (TEAEs) in this study, with all 20 patients experiencing toxicity.¹Seventy-five percent of participants had at least 1 grade ≥3 TEAE, the most common being hypertension (25%) and fatigue (10%). Immune-related TEAEs were also observed in this study including hypothyroidism (20%), diarrhea (15%), and rash (15%). Six people discontinued treatment with sitravatinib due to the emergence of AEs as compared with 3 patients who stopped treatment because of AEs.²Additionally, 2 patients died as a result of TEAEs. The toxicities reported in the deceased patients were abdominal pain and respiratory failure, which were both considered unrelated to treatment by the study investigators.

The investigators of the phase Ib study concluded that the combinations had a manageable safety profile and promising antitumor activity in patients with advanced ovarian cancer.

“Tislelizumab and sitravatinib have both demonstrated antitumor activity as single agents, so we’re encouraged by the early evidence showing the potential for these 2 agents to work together to treat advanced solid tumors, including platinum-resistant ovarian cancer,” said Yong (Ben) Ben, MD, chief medical officer, Immuno-Oncology at BeiGene. “We continue to make progress in the collaboration with Mirati Therapeutics and we look forward to continued enrollment in the trial and further clinical data on the combination of tislelizumab and sitravatinib, a compound that has a unique tyrosine kinase inhibition profile.”

The study subjects with various solid tumors were treated with intravenous tislelizumab 200 mg every 3 weeks and oral sitravatinib 120 mg once daily. The data cutoff date for this analysis of patients with ovarian tumors (cohort E) was July 17, 2019.¹There was 1 primary end point, which was the number of participants with AEs and serious AEs. The overall goal of the study was to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of sitravatinib/tislelizumab in patients with solid tumors, including a cohort of patients with platinum-resistant ovarian cancer (NCT03666143).

To be included in the phase Ib study, individuals were required to be at least 18 years of age, have at least 1 measurable disease lesion, have an ECOG performance status ≤ 1, and adequate hematologic and end-organ function.

Patients were excluded from the study due to unacceptable toxicity from a prior anti—PD-1 or PD-L1 therapy, active leptomeningeal disease or uncontrolled brain metastases, active autoimmune diseases or history of autoimmune diseases that may relapse, another active malignancy, conditions requiring systemic treatment, and certain infections and disorders. The study also excluded individuals who had prior allogeneic stem cell transplantation and those with hypersensitivity to either drug in the study combination.

BieGene has entered into a partnership agreement with Mirati Therapeutics, Inc. to continue developing sitravatinib in multiple countries, including the United States, Australia, New Zealand, and parts of Asia. Both sitravatinib and tislelizumab are being studied in other cancers.¹

“We were eager to enter into this collaboration with BeiGene because we believe sitravatinib, a spectrum-selective receptor tyrosine kinase inhibitor, may help increase the activity of anti—PD-1 antibodies such as tislelizumab in patients whose solid tumors exhibit resistance,” said Charles M. Baum, MD, PhD, president and chief executive officer, Mirati Therapeutics, Inc. “The initial results from this phase 1b trial suggest further development of this combination for the treatment of advanced solid tumors, including platinum-resistant ovarian cancer, is warranted.”

References

1. BeiGene Announces Clinical Data on Investigational Anti-PD-1 Antibody Tislelizumab in Combination with Sitravatinib at European Society for Medical Oncology Immuno-Oncology (ESMO I-O) Congress 2019 [press release]. Cambridge, MA and Beijing, China: BeiGene, Ltd,; December 13, 2019. https://bit.ly/36BiTjF. Accessed December 13, 2019.
2. Gao B, Goh J, Markman B, et al. Safety and antitumor activity of sitravatinib in combination with tislelizumab in patients with advanced solid tumors: Ovarian cancer cohort data. Presented at: 2019 ESMO Immuno-Oncology Congress; December 11; Geneva, Switzerland. Abstract 94O.