In an interview with Pharmacy Occasions, Omar Nadeem, MD, medical director of the Myeloma Immune Effector Cell Remedy Program on the Dana Farber Most cancers Institute, and assistant professor of drugs at Harvard Medical Faculty, shared compelling information and constructive outcomes linked to GPRC5D-targeted CAR T-cell remedy. He introduced the findings from the CC-95266-MM-001 (NCT04674813) examine on the European Hematology Affiliation (EHA) 2024 Hybrid Congress.
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Pharmacy Occasions: Are you able to elaborate on the precise mechanisms by way of which CAR (chimeric antigen receptor) T-cell remedy targets GPRC5D and its potential implications for the therapy of relapsed/refractory a number of myeloma (MM)?
Omar Nadeem, MD: GPRC5D is a brand new goal that is been found on the [MM] cells. We now have a number of brokers which can be both in growth or already authorized for concentrating on GPRC5D which have led to fairly spectacular outcomes. We now have a bispecific antibody referred to as talquetamab [Talvey; Janssen Biotech, Inc] that’s at present authorized for prior strains of remedy in relapsed/refractory [R/R] [MM] that makes use of a T-cell mechanism to redirect the T-cells in the direction of [MM] cells utilizing this antigen. Then CAR T-cell remedy—which we even have 2 authorized merchandise that at present goal BCMA [B-cell maturation antigen]—we now have CAR T-cell merchandise which can be additionally concentrating on GPRC5D utilizing the mechanism of CAR T-cell directed killing in sufferers with [R/R MM].
Pharmacy Occasions: Given the excessive response charges noticed in sufferers with 1 to three prior regimens, how do you envision GPRC5D CAR T-cell remedy becoming into the present therapy panorama for [MM], notably compared to present therapies?
Nadeem: In our trial that we introduced at EHA, this was the cohort C replace of the part 1 examine wanting on the GPRC5D CAR T-cell product in [R/R MM]. In that individual examine, we checked out a cohort of 1 to three prior strains of remedy. As you talked about, the median prior strains of remedy in that cohort have been 2 and the vast majority of sufferers had triple class publicity and all of them have been at the very least refractory to immunomodulatory brokers and a proteasome inhibitor. In that early line inhabitants, the general response price was 96%, with a whole response price that was 42%. These numbers look in step with what we had seen within the closely pretreated cohort. On this part one examine the place sufferers had 3 or extra strains of remedy. So, responses do appear to be fairly excessive in each early and late line remedy on this part 3 trial. What we additionally know is that we now have now a number of approvals of mixture therapies for sufferers with 1 or extra prior strains of remedy. We lately had an approval of CAR T-cell remedy, cilta-cel [ciltacabtagene autoleucel (Carvykti; Janssen Biotech, Inc)] in 1 prior line of remedy for sufferers which can be lenalidomide (Revlimid; Celgene Company) refractory. So, placing this into context, these numbers do match up fairly effectively in opposition to what we have seen with the sooner line cohorts for cilta-cel, which is a BCMA-targeted CAR T-cell product. And having this selection obtainable sooner or later will permit sufferers to have the selection of selecting between both a conventional mixture routine or selecting between certainly one of a number of CAR T-cell remedy choices which have completely different targets and mechanisms. Every of those CAR T-cell merchandise have distinctive toxicities and concerns by way of security. So, I do suppose that is going to be good to have an choice for sufferers which can be selecting between CAR T-cell therapies and earlier strains.
Pharmacy Occasions:How do you intend to include patient-reported outcomes and high quality of life assessments to judge the holistic affect of GPRC5D CAR T-cell remedy on sufferers with relapsed/refractory (MM)?
Nadeem: GPRC5D has very distinctive toxicities related to it. We see very excessive charges of dysgeusia, particularly, and weight reduction in sufferers which can be receiving talquetamab, which is the bispecific antibody that targets GPRC5D. That has been fairly a limiting issue by way of its widespread use within the clinic and has important quality-of-life implications when sufferers do have these tastes adjustments that then results in weight reduction, and, regularly within the clinic, we now have to both dose scale back these sufferers, maintain remedy, or modify their schedule over time. The advantage of this CAR T-cell product is that it’s a 1-time remedy and maybe due to that, we’re seeing extra transient on-target off-tumor results with this explicit product. We can be taking a look at affected person reported outcomes and trying to see what affect these toxicities have on sufferers; however had an early look of the information, we do see decrease incidence of this. So, what we’re hoping for over time is that, while you evaluate it to the already authorized product, we will see higher quality-of-life experiences from sufferers, notably as they get additional and additional out from their CAR T-cell remedy.
Pharmacy Occasions: How does GPRC5D CAR T-cell remedy deal with the challenges posed by high-risk illness options, and what methods are in place to optimize outcomes for these sufferers particularly?
Nadeem: So, high-risk [MM], each within the newly recognized and the relapse setting, does stay an unmet want. We now have had large progress with [MM] therapies, over the previous 10 plus years or so. However sadly, sufferers with excessive threat [MM] nonetheless have, considerably inferior outcomes in comparison with these with out high-risk illness. So, this explicit product does have exercise in opposition to high-risk sufferers. These embrace sufferers, about 1/3 of sufferers in cohort C had extramedullary illness [when (MM) cells form tumors outside of the bone marrow (EMD)]. So, regardless of this being an earlier line cohort about 1/3 of sufferers had EMD, and about 1/4 of sufferers had excessive threat cytogenetics, highlighting the high-risk nature of this explicit inhabitants on this cohort. Together with that, regardless of that using CD38 monoclonal antibodies was not mandated for enrollment into this cohort, 3/4 of sufferers had prior CD38 directed remedy, and a bit over 1/2 of the sufferers have been triple-class refractory. Once more, highlighting the refractory nature of this affected person inhabitants. And regardless of that, we noticed excessive response price and see a fairly excessive full response price that we’ll see hopefully deepened over time. So, the exercise of this explicit product appears to be in sufferers each with normal and high-risk illness, whether or not that is measured by high-risk cytogenetics, prior strains of remedy, refractoriness, or presence of any of the [EMD] parts.
Pharmacy Occasions: The summary highlights the speedy mobile enlargement and deep tumor clearance post-infusion with GPRC5D CAR T-cell remedy. How do these findings affect your understanding of the therapy’s mechanism of motion and long-term effectiveness?
Nadeem: We all know the effectiveness of CAR T-cell therapies extremely depending on the enlargement of the CAR T-cell product in vivo. What we see with this explicit CAR product is similar to what we have seen with different CAR merchandise, is that you’ve this form of speedy enlargement after which it is clearance over time. And that’s very a lot seen with this product. We had studied within the part 1 element of this a number of completely different dose ranges and the 150 million dose, which is what’s been studied on this cohort, has been chosen because the part 2 dose. And with that, we do see very, excellent ranges of strong mobile enlargement. After which we usually see peak enlargement ranges about 2 weeks out, and that’s precisely the place we see the enlargement in lots of different CAR merchandise which can be recognized to be fairly efficient. And to date, that appears to be taking part in out very properly on this explicit CAR T-cell product as effectively. So what that tells me is that it is a very energetic CAR product that appears to be resulting in excessive response charges, after which it does have the kinetics that mirror among the different authorized merchandise which have already proven fairly large efficacy and good security within the [R/R] [MM] inhabitants.
Pharmacy Occasions: Because the trial continues, what further information or endpoints are you notably eager about exploring to additional elucidate the potential of this CAR T-cell remedy within the administration of (MM)?
Nadeem: Up to now, we have enrolled 31 sufferers into cohort C of this trial in 1 to three prior strains of remedy. With that, the median follow-up period is simply about 5 months, to date. With that being mentioned, what we’re hoping for is that these full response charges will deepen or enhance additional over time, as lots of the sufferers on the time of this information reduce off had simply obtained remedy. So, among the responses hopefully will deepen. The opposite factor we want to see, with extra time, is what the precise development free survival is by utilizing CAR T-cell remedy on this earlier line cohort. And hopefully we’ll yield good outcomes there together with increased charges of [minimal residual disease] negativity, which we’re hoping to seize at a number of time factors as sufferers transcend receiving their cell infusion. After all, you need to have a look at each early and late toxicities. Up to now, the information appears fairly promising, the place we’re seeing anticipated toxicities with this CAR T-cell product. We see [cytokine release syndrome (CRS) ] charges of about 80%, and no high-grade CRS occasions have been reported. And to date, we have seen a decrease incidence of among the on-target off-tumor results that we see with GPRC5D-targeted remedy equivalent to dysgeusia [a condition that alters taste perception], nail and pores and skin adjustments. We noticed fairly low charges of that, the place about 30 sufferers or much less had dysgeusia and it was all low grade and largely self-limiting. So, we’re hoping to see that we have no recurrence of that with longer observe up or another toxicities that haven’t but been recognized with this explicit product.
