Forty Seven, Genentech Continue to Test Triple Immunotherapy Combo in DLBCL

Forty Seven and Genentech are extending their agreement to include a third clinical trial evaluating a combination of the investigational 5F9 plus Rituxan (rituximab) and Tecentriq (atezolizumab) in patients with diffuse large B-cell lymphoma (DLBCL).

The decision builds on prior Phase 1b data, where a combination of 5F9 and Rituxan was safe and eliminated tumors in one-third of DLBCL patients who had already failed two prior treatment approaches. The companies are now including the PD-L1 inhibitor Tecentriq in the combination to optimize responses to treatment.

“There is a large unmet medical need for new therapies for DLBCL patients, particularly for those who are ineligible for current therapies because they have rapidly progressive disease and cannot wait for a therapy that requires an extended time to implement or who are frail and unable to withstand the side effects of current therapies,” Chris Takimoto, MD, PhD, chief medical officer at Forty Seven, said in a press release.

The mainstay treatment for virtually all B-cell non-Hodgkin’s lymphomas includes CD20-targeting antibodies such as Rituxan. However, patients may develop resistance to Rituxan, which severely worsens their prognosis.

Forty Seven’s macrophage checkpoint inhibitor Hu5F9-G4 — or simply 5F9 — is an antibody that targets the CD47 factor, blocking the “don’t eat me” signal used by cancer cells to avoid being ingested by macrophages, a kind of immune cell that engulfs invaders.

The investigational therapy works much like other immune checkpoint inhibitors, but instead of activating T-cells, it improves the ability of macrophages to identify cancer cells and eliminate them.

Adding Genentech’s PD-L1 inhibitor Tecentriq to the mix may result in even better anti-tumor responses in DLBCL patients, as most macrophages in their tumors produce the PD-L1 factor to suppress other immune cells from eliminating the cancer cells.

“True to our mission, while we continue to vigorously pursue the combination of 5F9 plus rituximab in [non-Hodgkin’s lymphoma] patients, we are eager to explore additional opportunities to even further optimize treatment for patients with the most aggressive forms of disease and look forward to working with Genentech to evaluate the potential of a triplet regimen,” Takimoto said.

“We are excited to evaluate this novel triplet combination in collaboration with a global leader in [non-Hodgkin’s lymphoma]. An analysis of biomarkers revealed the presence of a high level of PD-L1-expressing macrophages in the tumors of DLBCL patients enrolled in two large Phase 3 trials … and provides a strong rationale for this new trial,” said Mark Chao, MD, PhD, co-founder and vice president of clinical research at Forty Seven.

The new trial is an extension of an agreement established in 2018, under which Forty Seven and Genentech are already testing a combination of 5F9 plus Tecentriq in acute myeloid leukemia and bladder cancer.

In May 2018, the U.S. Food and Drug Administration granted fast track status to 5F9 for the treatment of relapsed or refractory DLBCL and follicular lymphoma, another form of non-Hodgkin’s lymphoma.