Early Promise for Experimental Antibody-Drug Conjugate in Multiple Myeloma

GSK2857916, an investigational antibody-drug conjugate that targets a key B-cell maturation antigen (BCMA), offers “deep and durable” responses to some patients with relapsed/refractory multiple myeloma, suggest preliminary findings from the second, expansion part of the phase I DREAMM-1 trial (abstract 741; NCT02064387). The findings were presented at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9–12 in Atlanta.

Despite anticipated corneal toxicity, the drug-antibody conjugate was well-tolerated with manageable toxicities, reported Suzanne Trudel, MD, of the University of Toronto, Princess Margaret Cancer Centre, in Toronto, Ontario, Canada.

“GSK2857916 resulted in an overall response rate of 60% in heavily pretreated patients with multiple myeloma,” Dr. Trudel said. “Median progression-free survival was 7.9 months.”

Patients were not selected for expression of BCMA, the agent’s target, she noted. The duration of response cannot yet be quantified.

The BCMA-targeting and mechanisms of action set GSK2857916 apart from currently approved antimyeloma drugs and open the door to the development of combination therapies, Dr. Trudel said.

Expression of the tumor necrosis factor superfamily cell surface receptor BCMA is restricted to B-lineage cells, including healthy plasma cells and myeloma cells. GSK2857916 is a humanized IgG1 antibody with a microtubule-disrupting payload that targets BCMA. When this agent encounters a BCMA-bearing cell, it attaches and rapidly delivers the payload drug into the cell interior. It is believed to also be capable of inducing antibody-dependent immunogenic cell death.

The authors reported findings from the second part of a two-cohort, phase I expansion study that enrolled patients with heavily pretreated multiple myeloma. Patients received 3.4 mg/kg, 1-hour infusions of GSK2857916 every 3 weeks, for up to 12 months.

The data cutoff for the reported analyses was June 26, 2017. As of that date, of 35 patients in the first cohort, treatment was ongoing for 17 (49%) and 18 (51%) had discontinued treatment, in most cases (n = 15) because of disease progression. Two patients discontinued treatment because of adverse events and another withdrew from the study because of patient choice.

The overall response rate (60%, 21 of 35 patients; 95% CI, 42.1%–76.1%) included 2 complete responses and 18 partial responses, 15 of which were very good partial responses. The overall response rate was 43% among patients with prior daratumumab treatment (n = 14) and 42% for patients with prior daratumumab who were refractory to immunomodulatory agents and proteasome inhibitors.

Corneal toxicity and thrombocytopenia were frequent adverse events and led to dose modifications. Corneal adverse events of any grade included blurred vision, dry eye, photophobia, increasing tear production, keratitis, eye pain, eye pruritus, keratopathy, and night blindness. Grade 3 corneal toxicity included dry eye (one patient, 3%), keratitis (two patients, 6%), and eye pain (one patient). Median time to onset was 23 days, and the median duration was 30 days.

Infusion-related reactions affected 23% of patients, but no reactions occurred on subsequent infusions.

Monotherapy and combination therapy clinical trials are planned. The study was funded by GlaxoSmithKline.