For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
Richter’s transformation, a rare event
Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.
Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.
The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.
Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.
DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
Manageable adverse events
Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
Favorable responses
In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.
“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”
The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.
“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”
To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”
A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.
Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.
SOURCE: Mato AR et al. ASH 2020, Abstract 126.