FDA Approval of GPRC5D-Targeting Bispecific Antibody Talquetamab for Patients With R/R MM

Ajai Chari, MD, University of California, San Francisco, California, discusses the significance of the accelerated approval of talquetamab and the data that led to the approval, as well as provides commentary on the current treatment landscape and offers advice for practicing oncologists regarding using this therapy for the treatment of patients with R/R multiple myeloma. 

Transcript:

Hi, my name is Ajai Chari. I'm a professor of clinical medicine at the University of California, San Francisco, where I'm also the director of the myeloma program here. 

Oncology Learning Network: What is talquetamab? What data led to this approval?

Talquetamab is a first in class bispecific antibody, which means it's off the shelf, and it's targeting CD3 and GPRC5D. The data that led to this accelerated approval are from the MonumenTAL-1 study, which include patients from the phase 1 dose escalation portion of the study, but also the phase 2 portion and those patients who got 1 of the 2 approved doses of 0.4 milligrams per kilogram weekly or 0.8 milligrams per kilogram every 2 weeks. This was essentially in an unmet need population—patients had to have at least 3 or more lines of therapy with a [proteasome inhibitor, an immunomodulatory agent, and an anti-] CD38 monoclonal antibody.

What is the current treatment landscape for patients with multiple myeloma? 

We're in a really revolutionary period in myeloma. Historically, when I was a fellow, we had steroids and conventional chemo, and in the last few decades we've added proteasome inhibitors, IMiDs, immunotherapies like naked antibodies such as CD38-targeting daratumumab, cetuximab, and XPO1 inhibitor. And historically, to get a new drug approved in a patient population that had exhausted available therapies, the response rate was 20% to 30%, PFS of 3 to 4 months. And now we're looking at these products that are generating unprecedented responses and outcomes in patients who've exhausted even more therapy. Right now, I think the best treatment for a patient who's exhausted all of those would be a T-cell redirection antibody or CAR T, and fortunately we have more options than ever for those patients.

What is the safety profile of talquetamab?

Talquetamab is a GPRC5D-targeting antibody, so the cytokine release syndrome (CRS) is the primary side effect of this agent. As with all bispecifics, in terms of the most common, it occurs in 70% to 80% of patients. Typically, though, it's grade 1 to 2, so quite manageable. To mitigate that there are step-up doses required, either 3 to 4 depending on the dose you're using, and the label does require a 48-hour admission for the CRS monitoring and management with this agent. And premeds are also given, including dexamethasone, acetaminophen, and antihistamines to mitigate some of those side effects. 

The remaining AEs [adverse events] of this agent are related to the GPRC5D target. This target is over-expressed on myeloma cells, particularly neoplastic myeloma cell, and that comes back to be relevant later, but other tissues that express GPRC5D are heavily keratinized. So we do see, for example, nail changes. The nail becomes a little bit more [ ] and discolored, but it's generally not uncomfortable, more of a cosmetic problem. We also do see rashes, skin rashes, dryness, redness. Typically, it's early on in the treatment, and it's quite manageable with emollients and topical steroids. Rarely, for high-grade rashes, an oral steroid course may be indicated.

And third, and perhaps the most challenging is because it's new to us, is the oral toxicity basket, which includes primarily dysgeusia, loss of taste, dry mouth, maybe even difficulty swallowing, because of the dryness. It's quite common, 70% or so have some kind of oral toxicity. Our approach to this has been oral saliva substitutes, hydration, encouraging patients to do that, even some caloric supplementation like shakes, high-protein caloric shakes. But the main thing that has worked so far, I think, is really dose intensity modulation.

So fortunately, the median time to response with this agent is 1 month. And then for those patients where we are having these AEs that are not responding to supportive care, I just tell the patients we're going to hold a dose, and then we can revisit the dose and the schedule. So either lower the dose or the frequency. And that seems to help with this. 

At my prior institution, we treated patients on either monotherapy or combination, about 100 patients, and only 1 patient came off for non-progression, or related to an adverse event. So that's what's great about this agent, that it's manageable. And I would add that because it's manageable, it's also combinable, and these AEs are not overlapping with other myeloma drugs. So that's nice.

And one final point I'd like to make regarding AEs is actually relating to the infections and deaths. The rates of deaths in this are very low compared to some of the other studies in this space. The rates of high-grade infections are quite manageable, 15% to 20% instead of some of the other agents that can be as high as 45%, grade 3 and higher. And we've shown in the laboratory that you can have good COVID antibody production to the vaccines. We did not have as many COVID-related deaths with this. In fact, no COVID-related deaths. And so I think its infection profile is unique and again, speaks to the combinability. And then the lack of a significant death signal bodes well for randomized phase 3, and we're not going to be as concerned about any OS signal there either, so a quite manageable AE profile.

What advice do you have for practicing oncologists that are interested in using talquetamab for their patients?

The first thing I would tell community doctors is that bispecifics are here to stay. I think the naked monoclonal antibodies…there's a famous line from a Fergie song, “2000-and-late.” So, we had naked antibodies over 30 years ago, but we now are in a new era of immunotherapy of these bispecific drugs. Cytokine release syndrome is an important AE to learn how to manage, and it's not just the physician. Physicians may do the training and the REMS program that are being required, but we need to educate the infusion nurses, the floor nurses that are monitoring these patients in the hospital, the pharmacists who might be mixing drugs like tocilizumab to treat CRS, our infectious disease colleagues, our neurology colleagues, ICU and emergency room, it's the healthcare system.

But it's worth it to do that because you're seeing responses of over 70%. And the PFS and the 0.8 milligram per kilogram was updated at EHA; it’s actually 14 months. So for an off-the-shelf product to be working in the vast majority of patients for so long is really remarkable. And I think it is just another reminder that myeloma may be leading the way, but there's already 2 bispecifics for myeloma, one for lymphoma. I think it's imperative that we all learn and get on this bispecific wave so that our patients can benefit.

What are the next steps for investigating talquetamab in this or other populations?

This was an accelerated approval and obviously this is the first indication and will require confirmatory phase 3. So confirmatory phase 3 studies are ongoing, but also, really, I'm excited about the combination studies that are going on. There are already data that had been presented with the combination of daratumumab and talquetamab that showed a PFS of 19 months. Talquetamab plus the sister drug teclistamab showing another impressive PFS of 20 months, and also very encouraging data in extramedullary disease there. So those are really exciting. There's also studies going on with checkpoint, other myeloma backbone drugs, also moving this into earlier lines of therapy. So, lots of research on this agent and it'll be really exciting to see the data mature on all of those studies.

What is the overall significance of this approval?

This agent, it's a long time coming to have an off-the-shelf product targeting something other than DCMA, and to a provide response rate of over 70%, a PFS of 14 months in a heavily treated population. In particular, even patients with prior T-cell redirection therapy, which is a really unmet need, had a response rate of 63%. So it's a really exciting option for patients, and I'm glad that it's available now to patients through the accelerated approval strategy.

Source:

FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. US Food and Drug Administration; Published online August 10, 2023. Accessed August 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma