Ajai Chari, MD, PhD, of Mount Sinai Medical Center in New York, NY, discusses findings from a phase I study of the novel agent talquetamab, a first-in-class bispecific antibody that binds to GPRC5D and CD3, for the treatment of relapsed/refractory multiple myeloma.
DocWire News: Can you give an overview of the study design of the phase I trial assessing talquetamab and highlight its findings?
Dr. Chari: We’ve made a lot of progress in myeloma, but there remains unmet need of patients who’ve exhausted particularly proteasome inhibitors, monoclonal antibodies, and CD38 antibodies, so-called triple-class refractory. There’s really a search for ongoing new agents in this space. And talquetamab is an agent that I think meets that criteria. It’s a completely novel compound. It’s the first time we’re targeting GPRC5D, which is an orphan receptor. We don’t know the signaling, but what we do know about is it’s overexpressed in plasma cells and pretty much other than that, some hair follicles, but very little of the normal body or other cells express this, making it an ideal target for monoclonal antibody. And in this bispecific antibody that we did this first-in-human study, while the expectation of a phase I study is primarily safety and dose finding, we saw very encouraging efficacy results for this population and a tolerable profile. I think that’s why this is a really exciting presentation, and I think it will be great for patients and providers.
DocWire News: Why is GPRC5D a target of interest for multiple myeloma?
Dr. Chari: There’s already a lot of interest in this triple-class refractory space, but BCMA is an exciting option. For example, there’s targets of BCMA using antibody drug conjugates, bispecifics, CAR-Ts, it’s a very crowded space, but what happens when a patient exhausts BCMA-based therapy, and they also have their own issues with, for example, there’s an infection signal. So there’s a need for other targets. And GPRC5D meets that I think because it’s a different target [that is] overexpressed on plasma cells, not expressed in other tissues. And now we’re seeing efficacy results on the same order of the bispecifics targeting BCMA. We’re seeing 70% [responses]. Albeit, these are small numbers in early data, but 70% response rate in this population and also durable responses, I think this is really exciting.
DocWire News: What should hematologist/oncologists know about talquetamab as a potential treatment for multiple myeloma?
Dr. Chari: The drug is really exciting. We’re seeing responses and the safety profile, which is also of importance to practicing physicians and clinicians primarily from a hematologic perspective. We saw some neutropenia, although the neutrophil count for inclusion was only 1,000 for eligibility, very few infections, in fact, grade 3 and higher infections was only 8% across the entire study, none so far at the recommended phase II dose. So that’s really encouraging. Cytokine release syndrome were low grade events, and we saw some dysgeusia and grade 1 and 2 skin toxicities, but overall, [it’s] a tolerable drug with activity in a triple-class and penta-refractory patient population that’s durable. This is a really exciting option for patients and their caregivers in the future.
DocWire News: What other clinical trials are planned for talquetamab?
Dr. Chari: The efficacy data needs to be expanded, so the phase II study is ongoing. There’s also combinatorial approaches. We know that from preclinical data, bispecifics combined well with daratumumab, which is a CD38 antibody. But when we treat patients with CD38, there is a clonal expansion of T-cells, which is thought to naturally synergize with these bispecific approaches. Basically, a combinatorial approach with dexamethasone and daratumumab and another one with the additional pomalidomide, so triplet and quadruplet combinations strategies are being studied. And obviously the other question is once we have more data, how much earlier can we move this based on its safety profile and really encouraging efficacy? I think there’s great interest in seeing this move up early. There’s a lot of unmet needs in early diagnosis. For example, a question would be high-risk myeloma, extramedullary disease, renal failure, frail/elderly—a lot of populations where they don’t necessarily make it to the umpteenth line of therapy, so we need potent drugs earlier in the disease course.