Positive results for Darzalex, Jakavi to be reported at ASH

The American Society of Hematology (ASH) will present its annual meeting and exposition virtually Dec. 5-8. Even though the meeting is not happening in person, attendees will still have the opportunity to review thousands of scientific abstracts dealing with the buzziest news and most talked-about topics in hematology today.

Robert A. Brodsky, M.D., ASH secretary and director of hematology at Johns Hopkins University School of Medicine in Baltimore, says the topics will include advances in areas including gene therapy, genome editing, bone marrow transplantation and hematologic malignancies, and a lot of basic research involving stem cells, leukemia progression and immunology.

As for the latest in drug treatments in the pipeline, Brodsky believes two large phase 3 trials will likely garner the most interest.

“The first is the APOLLO trial, a phase 3 randomized study of subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone,” he says, referring to a closely watched trial of treatments for multiple myeloma. “There is also the REACH3, a phase 3 randomized study of ruxolitinib versus best-available-therapy,” says Brodsky, referring to a chronic graft-versus-host-disease (GvHD) trial.

Breakthroughs of REACH3

David Feltquate, M.D., Ph.D., global head of Novartis’ hematology disease unit, notes that chronic graft-versus-host disease is a common and very serious complication of allogeneic (from one person to another ) stem cell transplantation, and patients frequently become resistant or dependent on steroids. GvHD occurs when the new T cells generated by the stem cell transplant recognize the recipient’s cells as “foreign” and mount an immunological attack. The skin, gut and liver are most commonly affected. Estimates of how common GvHD occurs vary greatly, and the risk of occurrence depends, in part, on the degree of tissue compatibility between the donor and the recipient. GvHD is conventionally divided into the acute form, which occurs within 100 days of the stem cell transplant, and the chronic one that occurs afterward. The condition can have major effect on people’s quality of life and serious cases can be deadly.

“This is why we are so excited about the results of REACH3, a phase 3 study that looked at Jakavi (ruxolitinib) in patients with steroid-refractory or steroid-dependent chronic GvHD,” he says. “What we know now is that Jakavi met the primary endpoint of the study, defined as superior overall response rate after 24 weeks, compared to best available therapy. We also know that Jakavi met two very important secondary endpoints, which were improvements in failure-free survival and also patient-reported symptoms.”

Jakavi is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases approved in Europe as a treatment for adult patients with polycythemia vera (PV) who are resistant to, or intolerant of, hydroxyurea, and for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (MF), post-polycythemia vera MF or post-essential thrombocythemia MF. Novartis licensed ruxolitinib from Incyte Corp. for development and commercialization outside the United States. The drug is marketed in the United States by Incyte as Jakafi.

The REACH3 trial has forerunner, REACH2, which was designed to study Jakavi in people with the acute form of GvHD. The REACH2 results were published in the May 7, 2020, issue of The New England Journal of Medicine. The investigators randomized 309 acute GvHD patients for whom glucocorticoids were not effective (“glucocorticoid-refractory”), 154 to Jakavi and 155 to a control group that was treated with a therapy chosen by the investigator from list of nine options (the large number of choices is indicative of just how unsettled treatment of GvHD is). The primary endpoint was overall response 28 days after the treatment started. The results showed that 62% of the patients in the Jakavi group met that end point compared with 39% of those in control group. The patients on Jakavi also fared better on various other endpoints.

“This is a major improvement in outcomes for acute GvHD patients and taken together with the results seen in chronic GvHD, could mean a change to standard of care for a very difficult-to-treat disease,” Feltquate says. “Based on these data, we plan to file for marketing authorization in GvHD in Europe and other countries.”

The full data from the REACH3 study is expected to be presented at a medical meeting in early 2021.

“Jakavi is now the first treatment to demonstrate efficacy in a large-scale randomized clinical trial in steroid-refractory or steroid-dependent chronic GvHD,” Feltquate says. “This is potentially practice-changing news in a disease area where unmet need and patient impact are very high.”

APOLLO taking off

In the phase 3 APOLLO randomized study comparing subcutaneous Darzalex (daratumumab) in combination with (Pomalyst) pomalidomide and dexamethasone compared with Pomalyst and dexamethasone alone in relapsed or refractory multiple myeloma, the daratumumab combination met the primary endpoint of improving progression-free survival.

“We are pleased with these positive results for daratumumab, administered as a subcutaneous formulation, in combination with pomalidomide and dexamethasone,” Jan van de Winkel, Ph.D., CEO of Genmab, said in a company press release issued in late July. Janssen bought the development and marketing rights to Darzalex in 2012.

As a phase 3 trial of treatment of a blood cancer with an increasing incidence in some populations, the APOLLO trial is noteworthy, but the results won’t break new ground. The FDA approved the Darzalex-Pomalyst-dexamethasone combination three years ago based on favorable results from a single-arm, phase 1 study. And in August of this year, the FDA approved another “triplet therapy” for relapsed or refractory multiple myeloma that includes Darzalex, Kyprolis (carfilzomib) and dexamethasone.

Other ASH news

In addition to the APOLLO and REACH3 trial results, Brodsky says the ASH schedule includes presentation of results from a multicenter trial comparing reduced-intensity allogeneic hematopoietic cell transplantation to hypomethylating therapy or best supportive care.

“It shows an important survival advantage in older patients with advanced myelodysplastic syndrome,” he says. “This will be the new standard of care.”

Another notable area of research is bone marrow transplant, including markedly expanded access to this potentially curative therapy with haploidentical donors, says Brodsky, who also foresees discussion about new research into sickle cell disease during the ASH meeting.

“There are exciting data in curative intent therapies,” he says. “Haploidentical bone marrow transplant results continue to be outstanding. Cure rates are approaching 90%. There are gene therapy and editing approaches showing encouraging early data in small numbers of patients. And there is exciting data for fixed-dose hydroxyurea in Africa.”

Keith Loria, a regular contributor to Managed Healthcare Executive®, is freelance writer in the Washington, D.C., area.