| | | |  | Hello from the land of parades, potholes, and ordering drinks to-go! Adam Feuerstein, Angus Chen, and Damian Garde here with all the news from day 2 of the annual meeting of the American Society of Hematology, live from New Orleans. | | |  For any distressed England fans considering a change of allegiance. (Damian Garde/STAT) Center stage for a rare, platelet-destroying disease At today’s plenary session, ASH organizers chose to highlight an encouraging, new treatment for primary immune thrombocytopenia — a rare, autoimmune condition that typically doesn’t receive all that much attention, despite its debilitating impact on patients.
The antibody treatment called efgartigimod, developed by Belgian drugmaker Argenx, raised platelet counts and stopped bleeding episodes compared to a placebo, achieving the primary and secondary goals of a large Phase 3 clinical trial. The study results represent a potentially new and more effective way of treating adults with primary immune thrombocytopenia, which causes the body to attack and destroy its own blood-clotting proteins. When severe and uncontrolled, the disease can force patients to have their spleen removed.
“Immune thrombocytopenia can be very difficult to treat, especially in patients who have an insufficient response to previous therapies,” said Catherine Broome, a physician and associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center. “There is no clear standard of care and many patients continue to experience significant symptoms and decreased quality of life.”
Read more. | ‘ASH has been taken by bispecifics’ The next evolution in immunotherapy for blood cancer is the bispecific antibody, a molecule that handcuffs tumors to T cells with the aim of eradicating malignancies. Data presented at ASH suggest the new crop of medicines will win FDA approval, but it remains to be seen which will get the most use — and whether any can supplant CAR-T therapy in earlier lines of treatment.
Today, Regeneron Pharmaceuticals presented data on odronextamab, a bispecific antibody, in patients with diffuse large B-cell lymphoma that persisted despite two or more attempts at treatment. The drug had a 49% response rate, and 31% of patients had a complete response, meaning they had no detectable disease. At the median, those complete responses lasted for 18 months.
In NEJM, Roche published data from a similar study of glofitamab, which, like odronextamab, binds to a molecule called CD20 on the surface of cancer cells and the protein CD3 found on T cells. Glofitamab had a response rate of 52% and a complete response rate of 39%. The median duration of complete response was about 20 months.
The promise of these therapies, as Washington University oncologist Nancy Bartlett wrote in an accompanying editorial, is that they seem to have efficacy on par with CAR-T but with a lower rate of cytokine release syndrome, or CRS, a severe immune reaction common with therapies targeting T cells. The question now is whether, once approved, CD20xCD3 bispecifics should be used before CAR-T. That will require longer follow-up and more studies, Bartlett wrote.
It’s also unclear whether the treatments have identical safety profiles. Regeneron had modified the dosing regimen of odronextamab to limit side effects, but its study observed five treatment-related deaths: three from pneumonia, one from Covid-19, and one from sepsis. Neither epcoritamab, a CD20xCD3 bispecific up for FDA approval next year, nor glofitamab had treatment-related fatalities in their pivotal studies.
In the meantime, the news about odronextamab, glofitamab, and Johnson & Johnson’s talquetamab made ASH 2022 something of a benediction for bispecifics. After early promise, the field ran into safety concerns that led some companies to rethink dosing. Years later, the class is emerging as a viable treatment option.
“ASH has been taken by bispecifics,” said Andres Sirulnik, senior vice president for hematology at Regeneron. “These are exciting times.” | Investigating real-world evidence in the evolving treatment landscape In the fight against cancer, why is real-world evidence so important to patients and clinicians? A multiple myeloma patient advocate, Cindy Chmielewski, interviews Imran Khan, MD, PhD, US Vice President of Hematology Medical Affairs at Janssen Oncology, to discuss the value of real-world evidence to advance our understanding of cancer and the latest data that will be presented at ASH. Learn more about the value of real-world evidence and Janssen Oncology’s data that will be presented at ASH. | A new immunotherapy target for multiple myeloma meets success The approved bispecific and CAR-T cell therapies for multiple myeloma have all targeted BCMA. That’s offered many patients the chance at long-lasting remission but myeloma patients still often relapse. So, researchers have been looking for a new target for immunotherapies in multiple myeloma, and they’ve found one in a protein called GPRC5D.
Researchers working with Janssen, a unit of Johnson & Johnson, presented data on a new bispecific antibody targeting GPRC5D called talquetamab that showed an impressive over 70% response rate in patients that had relapsed or refractory multiple myeloma. Some of those patients had already failed BCMA-targeted therapy, either a CAR-T or bispecific.
“To me, this is the biggest thing to come out of ASH this year. It’s amazing,” said Faith Davies, the director of the clinical myeloma program at NYU Langone's Perlmutter Cancer Center, who was not involved in the trial. “It’s actually huge that we’ve got a new target.”
The work is the first that “really validated” GPRC5D as a target that can direct immunotherapies for relapsed or refractory multiple myeloma patients, said Amrita Krishnan, one of the authors of the study and director of the City of Hope Judy and Bernard Briskin Center for Multiple Myeloma Research. That might open the door to a new group of treatments that can offer myeloma patients another chance at beating back their cancer after all other treatments have failed.
Read more. | Bluebird works to dispel a lingering concern The future of Bluebird Bio, a gene therapy pioneer pushed to the brink of financial insolvency, depends in part on convincing the FDA that its one-time treatment for sickle cell disease doesn’t put patients at risk for developing cancer. At ASH, the company presented a detailed analysis of two case reports, concluding that there were no signs of an emerging malignancy.
Two patients treated with Bluebird’s gene therapy, called lovo-cel, were initially diagnosed with myelodysplastic syndrome, a form of cancer, but were later determined to have persistent anemia. That worrisome signal led the FDA to impose a partial clinical hold in late 2021, preventing the company from enrolling patients under 18.
Presenting an analysis of the two cases at ASH, Bluebird concluded that the anemia stemmed from both patients having a rare genetic mutation, not a treatment-related precursor to developing cancer. The company added that genetic mutation to its exclusion criteria for ongoing studies.
Whether that analysis will persuade the FDA to lift its clinical hold remains to be seen. But Bluebird plans to file lovo-cel for approval in early 2023, submitting data showing that 96% of sickle cell patients were free of painful flare-ups two years after receiving the treatment. | CAR-T rapid manufacturing shows early promise CAR-T takes a while to make, and patients often have to wait weeks after having their T cells extracted to actually get the therapy. In some cases, patients with extremely aggressive cancers have died while waiting to receive an infusion. Drugmakers have been trying to accelerate the manufacturing time, and Novartis presented new Phase 1 clinical data at ASH today on a CAR-T product — rapcabtagene autoleucel or rap-cel — made with a rapid manufacturing process called T-charge.
That shortens the manufacturing time from a standard 10 days to less than two days. The Phase 1 data presented suggested that rap-cel’s rapid manufacturing process may also have made it a more effective CAR-T cell, experts said.
“It’s an example of work trying to overcome some of the limitations of CAR-T,” said Jakub Svoboda, a cell therapy researcher at the University of Pennsylvania who did not work on the trial. “What’s really interesting is that it may allow the product to be different — an improvement of the cell product itself.”
Although, Svoboda added, the true test of whether rap-cel is actually better than past CAR-T products won’t come until Phase 3 randomized trials are done.
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