Targeted cancer treatment blocks essential biochemical pathways or mutant proteins that are required for tumor cell growth and survival. Historically, targeted therapies can suppress tumor progression and induce regression with achieved high rates of anti-tumor responses. The complexity of immune cells with progressing tumors makes targeted therapies unlikely to address the major mechanisms that impede anti-tumor immunity in all patients. The combination of therapies that target distinct steps of anti-tumor immunity may be synergistic and could result in stronger and more sustained responses in tumor destruction. We believe that combining immuno-oncology (I-O) agents with targeted treatments may lead to more durable responses and improved survival rates.
We are developing an I-O agent, tislelizumab (BGB-A317), a PD-1 inhibitor, and three targeted therapeutics including zanubrutinib (BGB-3111), a new generation of BTK inhibitor; pamiparib (BGB-290), a highly selective PARP inhibitor; and BGB-283 (a RAF mutation and dimer inhibitor), which are currently in clinical studies. Based on our own as well as others’ preclinical research in mouse cancer treatment models, tislelizumab in combination with zanubrutinib has profound effect on tumor microenvironment changes and tumor growth inhibition in colorectal cancer and diffuse large B-cell lymphoma models. The combination with BGB-283 exhibits potent therapeutic activities promoting lymphocyte infiltration in tumor and inhibiting tumor growth in the RAF/RAS mutated lung cancer model. And the combination with pamiparib has synergistic efficacy in BRAC1/2 deficient or platinum-sensitive ovarian cancer. In addition, we are developing more I-O and targeted agents in the preclinical pipeline such as PD-L1, Tim3 antibodies and agents against undisclosed targets, which we believe will create a great potential to expand our I-O combination capacity. With our innovative cancer biology platform and mouse cancer models built to test I-O combination therapies efficiently, BeiGene is well positioned for the next generation of cancer treatment.
Combination Opportunities with Our Portfolio
- BGB-A317 (PD-1) serves as one of the cornerstones for combinations
- Strong rationale to combine with each of our 3 other clinical stage assets
- Additional preclinical programs target weak points in the immunity cycle
BGB-3111 in Combination with Obinutuzumab (Gazyva)
We have investigated the effect of BGB-3111 in combination with Obinutuzumab, a second generation anti-CD-20 antibody, in mantle cell lymphoma tumor models. Preclinical data shows that BGB-3111 is a potent inhibitor of tumor growth, while Obinutuzumab was inactive in the model. However, the combination of BGB-3111 and Obinutuzumab was significantly more efficacious than either single agent.
BGB-A317 in Combination with BGB-290
Based on the observation that germ-line BRCA mutant tumors often have been reported to have genome instability and increased effector T-cells in tumors, we have initiated the study of BGB-290 in combination with BGB-A317 for the treatment of cancers with mutations or deficiencies in the breast cancer gene (BRCA), or deficiencies in homologous recombination or mismatch repair, including ovarian, breast, prostate, colorectal, and pancreatic cancers, as well as platinum-sensitive ovarian cancer homologous recombination (HR) gene, or mismatch repair (MMR) gene, such as ovarian, breast, pancreatic, and prostate cancers; small cell lung cancer; and glioblastoma. This is the first combination study exclusively based on BeiGene’s internal drug candidates.
BGB-A317 in Combination with BGB-3111
We have also initiated combination studies of BGB-3111 with BGB-A317, our PD-1 antibody, on June 30, 2016, based on encouraging synergistic effects observed in our preclinical models. In our primary diffuse large B-cell lymphoma tumor models, we observed enhancement of anti-tumor activity of BGB-A317, our PD-1 antibody, by BGB-3111 in both PD-L1-positive and especially in PD-L1-negative diffuse large B-cell lymphoma tumor models, thus supporting our combination strategy.