BeiGene Presents Clinical Data on Sitravatinib in Combination with Tislelizumab at the AACR Annual Meeting 2021
- The combination showed preliminary antitumor activity in patients with unresectable or metastatic melanoma refractory or resistant to PD-1/L1 inhibitors and platinum-resistant ovarian cancer in an ongoing Phase 1b clinical trial, with a generally well-tolerated safety profile.
“From the results presented today, we believe that sitravatinib in combination with tislelizumab could potentially provide clinical benefit to patients with advanced solid tumors, which supports our plan to further evaluate this innovative combination in our ongoing clinical trials. In addition, we are excited about the preliminary antitumor activity observed in patients with PD-1/L1 resistant or refractory melanoma,” commented
This open-label, multicohort, Phase 1b trial was designed to evaluate safety/tolerability and preliminary antitumor activity of sitravatinib in combination with tislelizumab in advanced solid tumors. The primary endpoint of the trial was safety/tolerability of the combination; key secondary endpoints include investigator-assessed objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1; overall survival (OS) was also assessed.
Results in Patients with Unresectable or Metastatic Melanoma Refractory or Resistant to PD-1/L1 Inhibitors
“Checkpoint inhibitors have changed the treatment of advanced melanoma, but a significant proportion of patients do not benefit from PD-1 inhibitors due to primary or innate resistance. In this Phase 1b trial, we’re glad to see that the combination of sitravatinib and tislelizumab was generally well-tolerated and demonstrated encouraging preliminary antitumor activity in patients with PD-1/L1 resistant melanoma,” commented Chuanliang Cui, Professor at
At the time of data cutoff on
- All 25 patients (100%) experienced at least one treatment-emergent adverse event (TEAE) of any grade, with the most common (≥20%) being increased alanine transaminase (ALT; 76%), increased aspartate aminotransferase (AST; 68%), increased blood cholesterol (56%), hypertriglyceridemia (52%), hypothyroidism (48%), weight decreased (48%), increased blood creatine kinase (BCK; 40%), diarrhea (40%), increased gamma-glutamyltransferase (GGT; 40%), proteinuria (40%), increased blood bilirubin (BB; 36%), abnormal electrocardiogram T wave (36%), hypertension (36%), palmar-plantar erythrodysesthesia syndrome (32%), increased CK-myocardial band isozyme (CK-MB; 28%), hyperuricemia (28%), upper abdominal pain (24%), vomiting (24%), and hypokalemia (20%);
- Twelve patients (48%) experienced at least one Grade ≥3 TEAE, with the most common (≥5%) being hypertension (12%), increased ALT (8%), and increased GGT (8%);
- One patient (4%) experienced a serious TEAE of anal abscess, associated with sitravatinib;
- Treatment discontinuation due to TEAEs occurred in two patients (8%), with one discontinuing tislelizumab due to vaginal hemorrhage (unrelated to tislelizumab) and the other sitravatinib due to increased BCK (related to sitravatinib);
- Dose interruptions and reductions of sitravatinib occurred in 18 patients (72%) and 13 patients (52%), respectively;
- All 25 patients were evaluable for efficacy and the confirmed ORR was 24% (95% CI: 9.4, 45.1), including six partial responses (PRs), and the disease control rate (DCR) was 88% (95% CI: 68.8, 97.5); and
- The media duration of response (DoR) was not reached, and the investigator-assessed median PFS was 6.7 months (95% CI: 4.07, not evaluable).
Results in Patients with Advanced PROC
“It’s common to see patients with ovarian cancer become refractory or resistant to platinum-based therapy after receiving the current standard of care. The combination of sitravatinib and tislelizumab was generally well tolerated and showed promising antitumor activity among patients with advanced PROC, including those who were heavily pretreated. While the sample size is relatively small, we look forward to further evaluating this novel combination in PROC,” said
At the time of data cutoff on
- Fifty-eight patients (97%) experienced at least one TEAE of any grade, with the most common (≥20%) being diarrhea (67%), nausea (57%), fatigue (48%), hypertension (40%), decreased appetite (37%), vomiting (37%), abdominal pain (35%), constipation (33%), increased ALT (30%), urinary tract infection (27%), increased AST (20%), dysphonia (20%), headache (20%), and palmar-plantar erythrodysesthesia syndrome (20%);
- Forty-one patients (68%) experienced at least one Grade ≥3 TEAE, with the most common (≥10%) being hypertension (18%) and abdominal pain (12%);
- Forty-two patients (70%) experienced at least one serious TEAE;
- Treatment discontinuation due to TEAEs occurred in 23 patients (38%), with nine patients (15%) discontinuing tislelizumab and 14 (23%) sitravatinib;
- Dose interruptions and reductions of sitravatinib occurred in 50 patients (83%) and 30 patients (50%), respectively, and dose interruption of tislelizumab occurred in one patient (2%);
- Four fatal TEAEs were reported, with none considered related to study treatment;
- Among the 53 patients who were evaluable for efficacy, the confirmed ORR was 26% (95% CI: 15.3, 40.3), including 14 PRs, and the DCR was 77% (95% CI: 63.8, 87.7);
- The median DoR was 4.7 months (95% CI: 2.8, not estimable); and
- The median PFS and OS was 4.1 months (95% CI: 4.0, 5.1) and 12.9 months (95% CI: 6.3, 17.2), respectively.
Sitravatinib is an investigational, spectrum-selective receptor tyrosine kinase (RTK) inhibitor that can potentially stimulate the body’s immune response to fight cancer. Sitravatinib targets the VEGFR and TAM (TYRO3, AXL, MERTK) receptor families, which are implicated in orchestrating an immunosuppressive tumor microenvironment (TME). Inhibiting these receptors has been shown to stimulate an anti-tumor immune response and potentially re-sensitize patients to checkpoint inhibitor (CPI) therapy in patients who previously developed resistance to CPI therapy. By targeting specific RTKs with sitravatinib, the immunosuppressive TME is converted to an immune-supportive TME, and combining with CPI therapy may help regain an immune response potentially overcoming resistance to CPI therapy. Sitravatinib is being evaluated in multiple clinical trials, including the Phase 3 SAPPHIRE study, in patients with advanced non-small cell lung cancer who are resistant to CPI therapy, and certain patients who are naïve to CPI therapy.
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Tislelizumab (BGB-A317) is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.
In addition, three supplemental Biologics License Applications for tislelizumab have been accepted by the
Currently, 16 potentially registration-enabling clinical trials are being conducted in
Tislelizumab is not approved for use outside of
About the Tislelizumab Clinical Program
Clinical trials of tislelizumab include:
- Phase 3 trial comparing tislelizumab with docetaxel in the second- or third-line setting in patients with NSCLC (NCT03358875);
- Phase 3 trial comparing tislelizumab to salvage chemotherapy in patients with relapsed/refractory classical Hodgkin Lymphoma (NCT04486391);
- Phase 3 trial in patients with locally advanced or metastatic urothelial carcinoma (NCT03967977);
- Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced squamous NSCLC (NCT03594747);
- Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced non-squamous NSCLC (NCT03663205);
- Phase 3 trial of tislelizumab in combination with platinum-based doublet chemotherapy as neoadjuvant treatment for patients with NSCLC (NCT04379635);
- Phase 3 trial of tislelizumab combined with platinum and etoposide versus placebo combined with platinum and etoposide in patients with extensive-stage small cell lung cancer (NCT04005716);
- Phase 3 trial comparing tislelizumab with sorafenib as first-line treatment for patients with hepatocellular carcinoma (HCC; NCT03412773);
- Phase 2 trial in patients with previously treated unresectable HCC (NCT03419897);
- Phase 2 trial in patients with locally advanced or metastatic urothelial bladder cancer (NCT04004221);
- Phase 3 trial comparing tislelizumab with chemotherapy as second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC; NCT03430843);
- Phase 3 trial of tislelizumab in combination with chemotherapy as first-line treatment for patients with ESCC (NCT03783442);
- Phase 3 trial of tislelizumab versus placebo in combination with chemoradiotherapy in patients with localized ESCC (NCT03957590);
- Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment for patients with gastric cancer (NCT03777657);
- Phase 2 trial in patients with MSI-H/dMMR solid tumors (NCT03736889); and
- Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment in patients with nasopharyngeal cancer (NCT03924986).
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding data from the Phase 1b trial of sitravatinib in combination with tislelizumab and the potential clinical benefits that may be demonstrated in further development, the statements about sitravatinib under the caption “About Sitravatinib”, and
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