Relapsed/Refractory MM: Safety and Efficacy Data From RedirecTT-1
Centering discussion on RedirecTT-1, expert hematologist-oncologists consider safety and efficacy data with the combination of teclistamab and talquetamab in patients with relapsed/refractory multiple myeloma.
Transcript:
Ajai Chari, MD, PhD: It’s my pleasure now to share with the audience the really exciting RedirecTT-1 study. These are the first results from RedirecTT-1 [NCT04586426], and this is basically a combination of 2 bispecifics, teclistamab and talquetamab, which target simultaneously BCMA [B-cell maturation antigen] and GPRC5D in patients with relapsed refractory myeloma. And these data were presented at ASCO [American Society of Clinical Oncology] and EHA European Hematology Association] by Dr Cohen. So we know that teclistamab and talquetamab have monotherapy efficacy, and the question is, what is the right dose and schedule of the combination? You can see in this dose escalation schema, the RP2D [recommended phase 2 dosing] was found to be teclistamab 3 mg/kg, and talquetamab 0.8 mg/kg given every 2 weeks.
Then that was expanded. The primary objective of this phase 1B study, of course, was really to look at safety and identify as recommended [for] phase 2. The secondary objectives are listed here. These were patients with relapsed/refractory myeloma that were triple-class exposed to a PI [proteasome inhibitor], IMiD [immunomodulatory agent], and CD38. So we know that teclistamab has a monotherapy response rate of 63% from MajesTEC-1 [NCT04557098]. And talquetamab, as we heard from Dr Schinke, was greater than 70% in MonumenTAL-1 [NCT04634552].
The thought is by targeting different antigens, could we potentially overcome resistance. And it’s the first time we’ve heard these results. This study was primarily accrued in Europe. The US did not participate. Here are the baseline characteristics. When we include all dose levels, the N was 93, but in the recommended phase 2, it was 34. Pretty typical prior baseline characteristics. The marrow greater than 60% is about 25% extramedullary, which is going to be interesting and important in this dataset, is about a third of patients. Similarly, high risk of about a third of patients; ISS [International Scoring System] 3, about 20%. This is a little bit less heavily treated than MonumenTAL-1 and MajesTEC-1, with 4 lines of therapy over about 6 years.
We can see that when we look at exposure, there was about 60% penta drug exposure. Also, some ide-cel [idecabtagene vicleucel] bispecific exposure. But looking at refractoriness, about 75%, 80% were triple-class refractory and about a quarter of patients were penta drug refractory, and nearly all patients, approximately 90%, were progressing on their last line of therapy. In spite of this significantly prior-treated patient population, the overall response rate at all dose levels was 86%. I just pause for a second because we’re—it’s shocking to me that we keep talking about efficacy in a phase 1 study, but that’s how impressive these data are with the T-cell redirections. When we look at the RP2D, it’s a 96% response rate, which is really remarkable for this population. I think many would argue [it] rivals CAR [chimeric antigen receptor T-cell therapy] data. And when we look at VGPR and better, we’re looking at about 40%. The median follow-up was 13 and 8 months in the overall group as well as the RP2D patient population, the median duration of response [was] not even reached with this follow-up. Rapid responses within 1 and a half to 2 months. Median time to best response within 3 to 4 months. Median PFS [progression-free survival], is a very impressive 20.9-month PFS for all dose levels, and not even reached for the RP2D. But we know it’s going to be more than 9 months because over 70% of patients are progression-free even in the RP2D, which has slightly shorter follow-up. So these are really remarkable efficacy results.
When we look at extramedullary disease, which we know is an unmet need across all myeloma therapies, including T-cell redirection, including CAR T, we’re seeing a response in all cohorts of 72%, and in the recommended phase 2 it is 86%. Importantly, the study took pains to make sure these are not paramedullary, but truly extramedullary soft-tissue plasmacytomas. And this is a median follow-up of 7.2 months. The median PFS was about 10 months for the RP2D, and not reached for the median duration of response. So [it’s] exciting data for a truly unmet need in relapsed/refractory myeloma. And, of course, safety is important. We see, as Dr Schinke mentioned, all bispecifics have grade 1 CRS [cytokine release syndrome] on the order of up to 70% and very few grade 3 and higher [adverse effects; AEs]. And that’s what we saw here as well.
The remainder of AEs really fit with each drug, with the dysgeusia, skin, and nails for the talquetamab and the neutropenia coming more from the teclistamab. We’ll look at infections in a second as well. There were 5 ICANS [immune effector cell–associated neurotoxicity syndrome] events, which was in 3 patients; the maximum severity was grade 3. In general, this was very well tolerated. Febrile neutropenia was seen in about 13%, but there were no discontinuations due to [hematological] AEs. When we look at infections, which I alluded to, we do see infections because of the nature of the population as well as the therapy. All infections, grade 3 and higher are in the whole cohort, 53%; in the RP2D, 38%. Again, caution with the RP2D because of a lot of short follow-ups. Most of the infections were grade 1 and 2. Of course, we saw significant [hypogammaglobulinemia] with about 82% getting IgGs [immunoglobulins] less than 400. There was one grade 5 septic shock. Something obviously, again we need to keep an eye on. IVIG [intravenous immunoglobulin] was given to 37 patients, including about half the patients at the RP2D.
Of course, one other question is when you combine different bispecifics and T-cell redirections, do you exacerbate the CRS? It looks like the answer is no. In the RP2D, 73% [were] primarily grade 1 and 2. And these occur during step-up dosing or cycle 1. All of these are resolved. The timing and duration are pretty typical. And about a quarter of patients received tocilizumab. So pretty typical for the bispecific space. So I think what’s exciting about this is the first dual bispecific combination strategy that we’ve heard. And the response rate was a very impressive 96% in triple-class exposed patients competing with, as I alluded to, CAR T therapies. A very impressive 86% with those with extramedullary disease and median DOR [duration of response] not even reached. Safety was consistent with monotherapy, no additional additive toxicities. The extramedullary data is so interesting that there’s actually an extension cohort specifically targeting this.
Transcript edited for clarity.
