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Novel Drug Targets Lymphoma Cells’ ‘Don’t Eat Me’ Signal

AMSTERDAM — A novel drug that targets the so-called ‘do not eat me’ signal that protects malignant tumor cells in lymphoma has shown potentially long-lasting effects in relapsed and/or refractory lymphoma patients.

The drug, Hu5F9, (or 5F9), is a first-in-class anti-CD47 product, being developed by Forty Seven Inc, a spinout from Stanford University. It is a humanized, IgG4 isotype monoclonal antibody that is considered to be a macrophage immune checkpoint inhibitor.

New clinical data with 5F9 were presented here at the 24th Congress of the European Hematology Association.

“The most exciting part of this is that 5F9 is a novel form of immunotherapy that can induce durable remissions in lymphoma patients who were refractory to previous therapy,” first author Mark Roschewski, MD, associate research clinician and clinical director of the Lymphoid Malignancies Branch (LYMB) of the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, told Medscape Medical News.

“That fact, coupled with the very tolerable safety profile and lack of cumulative toxicities, means that this can be given to nearly all patients,” he said.

Patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) can have particularly poor prognoses, with a median overall survival of just 6.3 months, according to one recent study, and other refractory lymphomas can also have poor prognoses.

Such evidence underscores that “well-tolerated, chemo-free regimens that induce durable responses in late-line patients are needed,” Roschewski commented.

Phase 1b data on the drug, published last year in the New England Journal of Medicine, showed encouraging efficacy and safety when combined with rituximab (an anti-CD20 monoclonal antibody) in patients with r/r DLBCL and patients with follicular lymphoma when combined with rituximab.

The two agents appear to work together in overcoming the problem with CD47 as a target: this protein is  overexpressed in most cancers, but it also appears on normal cells. While 5F9 targets the CD47 signal, rituximab importantly steers it to only lymphoma cells for sensitization, sparing the normal cells. 

“CD47 blockade (with 5F9) takes the foot off the brakes, while rituximab puts the foot on the accelerator, leading to maximal tumor phagocytosis,” Roschewski explained.

In presenting the latest findings from both phase 1b and phase 2 studies at the meeting, Roschewski reported data on a total of 70 patients with DLBCL and 45 patients with indolent lymphoma, including 41 patients with follicular lymphoma and 4 patients with marginal zone lymphoma.

Overall, the patients had a median age of 66 (range 21 to 88) and were refractory, with a median of 3 prior therapies (range 1-10).

Most of these patients (85%) were refractory to a prior rituximab regimen, and most patients were also ineligible for CAR-T cell therapy.

The new drug was administered in doses up to 45 mg/kg, in combination with rituximab, and was found to be well tolerated, with most adverse events classified as Grade 1 or 2. The most common adverse events were, as expected, on-target anemia, infusion reactions and related symptoms, including fever, chills, and headache.

Roschewski noted that on-target anemia, an effect of CD47 blockade, can be mitigated with 5F9 priming and maintenance dosing, and in the studies that he was reporting, this anemia was transient.

Eight of the 115 patients (7%) discontinued treatment due to adverse events.

Response rates on 97 patients with data available from phase 1 and 2 studies have been encouraging, showing an overall response rate, according to Lugano criteria, of 45% in the studies combined, with a rate of 36% among 59 patients with DLBCL and 61% among 38 patients with indolent lymphoma.

The corresponding complete response rates were 19% for the overall patient population, 15% in DLBCL, and 24% in indolent lymphoma. Similar responses were observed across multiple DLBCL subtypes and patients with primary refractory lymphoma.

The median time to response in the phase 1b and phase 2 cohorts was rapid, occurring in just 1.8 months (range 1.6–7.3 months).

“An important aspect of these patients were that most of them were refractory to prior therapy,” Roschewski said. “In fact, 80% of the patients in the indolent arm were refractory to rituximab. This highlights how the 5F9-rituximab combination is able to overcome rituximab resistance.”

The duration of response to the 5F9-rituxumab regimen has been encouraging, with no median duration of response met in patients who were treated in the phase 1b trial.

The median follow-up among those with DLBCL has been 13.8 months (range 3.6–23.8 months), and in those with follicular lymphoma, 21 months (range 6.2–27.6 months).

Roschewski noted that a 30 mg/kg dose of 5F9 has been selected as the dose moving forward and, in future studies, combinations with other drugs in addition to rituxumab are likely.

Approached for comment, Anton Hagenbeek, MD, PhD, professor of hematology in the Academic Medical Center at the University of Amsterdam, the Netherlands, agreed that the data on the drug, so far, does seem notable.

“This is interesting first data with this macrophage immune checkpoint inhibitor,” he told Medscape Medical News.

“An overall response rate of 39% in relapse /refractory DLBCL patients, quite a number of whom were rituximab-resistant, is not bad, as this is one of the highest unmet needs in hemato-oncology.”

The findings furthermore suggest the exciting possibility of moving some patients toward stem cell transplant eligibility, he added.

“This might make patients who did not undergo an autologous stem cell transplant [ASCT] beforehand eligible for this high dose ASCT treatment with curative intent,” Hagenbeek said. “I would love to see results of ASCT in patients responding to 5F9.”

Hagenbeek also cautioned that these are still early days for this novel drug: “The series is still rather small,” he noted.

The study was funded by Forty Seven, Inc and the Leukemia and Lymphoma Society. Roschewski has disclosed no relevant financial relationships. Hagenbeek is a consultant for Takeda USA.

European Hematology Association (EHA) 2019 Annual Meeting: Abstract S867. Presented June 14, 2019.

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