The combination of Hu5F9-G4 and rituximab demonstrated promising activity among patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study published in The New England Journal of Medicine.
The regimen — which also appeared safe — now is being evaluated in an ongoing phase 2 trial.
Hu5F9-G4 (Forty Seven Inc.) is an anti-CD47 monoclonal antibody that inhibits a key macrophage checkpoint and contributes to macrophage destruction of lymphoma cells, according to study background.
“When the drug is administered with a tumor-targeting antibody such as rituximab, a synergistic enhancement of ‘eat me’ signals promotes disease elimination,” Ranjana Advani, MD, Saul Rosenberg professor of lymphoma and physician leader of the lymphoma clinical care program at Stanford University, and colleagues wrote.
Advani and colleagues sought to assess the safety of Hu5F9-G4 plus rituximab (Rituxan; Genentech, Biogen), as well as to identify a dose for phase 2 evaluation. Secondary objectives included evaluations of efficacy as well as the pharmacokinetic and immunogenicity profiles of Hu5F9-G4.
The study included 22 patients, 15 of whom had diffuse large B-cell lymphoma and 7 of whom had follicular lymphoma. Patients had received a median four prior treatments (range, 2-10), and 95% of them had rituximab-refractory disease.
All patients received a 1 mg/kg priming dose of Hu5F9-G4, followed a week later by escalating weekly maintenance doses of 10 mg/kg (3 patients), 20 mg/kg (6 patients) or 30 mg/kg (13 patients). Patients who received the 30 mg/kg dose received an additional 30 mg/kg dose on day 11.
Treatment continued until disease progression, unacceptable toxicity or lack of clinical benefit.
Rituximab was administered to all patients at 375 mg/m2 weekly starting in the second week of the first cycle, and then monthly in the second through sixth cycles.
Median treatment duration was 22 weeks (range, 1.7-70.7).
Three patients (13.6%) died due to disease progression.
Three dose-limiting toxic effects occurred. These included one case of grade 3 pulmonary embolism, which resolved after anticoagulation, and one case of grade 4 neutropenia, which resolved after receipt of granulocyte colony-stimulating factor. One patient who developed grade 3 idiopathic thrombocytopenia purpura discontinued treatment and received glucocorticoid and IV immune globulin treatment that resolved the thrombocytopenia.
Most treatment-related adverse events occurred within the first few weeks, and the majority were grade 1 or grade 2. The most common were chills, headache and anemia (41% each), and infusion-related reactions (36%). Dose modifications mitigated anemia.
Researchers did not identify a maximum-tolerated dose.
However, they identified 30 mg/kg as the ideal phase 2 dose of Hu5F9-G4. In the phase 1b study, that dose led to nearly 100% CD47 receptor occupancy on circulating white and red cells.
In the entire cohort, 50% of patients achieved objective response and 36% achieved complete response.
In the DLBCL subgroup, 40% achieved objective response and 33% achieved complete response.
In the follicular lymphoma subgroup, 71% achieved objective response and 43% achieved complete response.
At median follow-up — 6.2 months for those with DLBCL and 8.1 months for those with follicular lymphoma — 91% of responses remained ongoing.
The study by Advani and colleagues builds upon solid evidence that antibody-dependent cellular phagocytosis — released by blocking the CD47-signal regulatory protein alpha checkpoint — can fight tumors and work with anti-CD20 treatment to kill lymphoma cells, Alberto Mantovani, MD, professor of pathology at Humanitas University in Milan and scientific director of Istituto Clinico Humanitas, and Dan L. Longo, MD, professor in the department of medicine at Harvard Medical School, wrote in an accompanying editorial.
“The results ... are remarkable not only because of their own clinical merit ... but also because they have broader implications for cancer immunotherapy,” Mantovani and Longo wrote.
“If confirmed and extended, the results ... pave the way to macrophage checkpoint blockade as a new immunotherapy strategy,” they added. “The development of macrophage checkpoint strategies goes back to the very roots of cancer immunology and immunotherapy. In applying macrophage activation in cancer treatment, we are in a sense going back to the future.” – by John DeRosier
Advani R, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1807315.
Disclosures: Forty Seven and Leukemia & Lymphoma Society supported this study. Advani reports institutional research support from Forty Seven, as well as grants or personal fees from Agensys, AstraZeneca, Autolus, Bayer, Bristol-Myers Squibb, Celgene, Gilead/Kite, Janssen, Juno, Kura, Kyowa, Merck, Millennium, Nano String, Pharmacyclics, Regeneron, Roche/Genentech, Seattle Genetics, Spectrum, Sutro and Takeda. Please the study for all other authors’ relevant financial disclosures.