Tycel Phillips, MD, discusses sonrotoclax’s FDA approval for mantle cell lymphoma and why the BCL2 inhibitor opens more possibilities.
As the first approved BCL2 inhibitor for the treatment of mantle cell lymphoma (MCL), sonrotoclax (Beqalzi) introduces a new option that opens up more possibilities for combination regimens and patients who have progressed or are not good candidates for pirtobrutinib (Jayprica), according to Tycel Phillips, MD.1
In an exclusive interview with OncLive®, Phillips overviewed how these data translate to clinical practice and highlighted where and when turning to sonrotoclax is appropriate for patients with relapsed/refractory MCL. Phillips also discussed multiple ongoing notable clinical trials evaluating sonrotoclax in combination with other common treatments for MCL.
Phillips is an associate professor in the Department of Hematology and Hematopoietic Cell Transplantation in the Division of Lymphoma at City of Hope in Duarte, California.
Phillips: [The approval of sonrotoclax is] a big thing for the relapsed/refractory MCL space, given the limited options in the post-BTK inhibitor space. While we've had quite a few approvals lately [the post-BTK inhibitor space, this] is still an area where more drugs are needed, and sonrotoclax slotting in there provides another option for patients where you would consider pirtobrutinib or in patients who may progress on pirtobrutinib and still not be able to get to CAR T-cell therapy. An oral option is always beneficial. [Considering] the shorter half-life compared with venetoclax [(Venclexta) vs sonrotoclax] and what appears to be an efficacy profile that mirrors what we see on pirtobrutinib, I’ll be very excited for patients who are, in some cases, limited on options in this space. Given the limited number of patients with MCL and how difficult it is to conduct clinical trials, it's very important at least to have early access to this agent while the confirmatory trial is in process.
If we look at the dataset, the ORR looked very similar to what we saw with pirtobrutinib in this space, with an ORR of 52%. The CR rate was slightly lower than [other data reported for] pirtobrutinib, with a CR rate of 16%. In those who responded, there was some durability of response, with the median duration of response a little over a year. We'll wait for a longer follow-up just to see the maturation of the data, but one of the important things for patients with MCL is time to response [with sonrotoclax] is quite short. In this study, [time to response] was around 2 months, which, vs other agents, compares very favorably and potentially could be used as an option before or after pirtobrutinib or, in a similar vein, can be used as something as a bridge to CAR T-cell therapy.
Another aspect of this approval is that it will eventually open up this agent to be used in combination with other drugs in this space. You could potentially start seeing some novel combinations revolving around sonrotoclax in this space, which will be quite helpful overall as we look forward to making further progress in MCL.
There’s one that's already ongoing, which is the phase 3 CELESTIAL-RRMCL study [NCT06742996], which will look at the combination of sonrotoclax plus zanubrutinib [Brukinsa] vs zanubrutinib alone.2 This trial is very much like what we saw with the phase 3 SYMPATICO study [NCT03112174], and likely will be the confirmatory study for this molecule.3 [Sonrotoclax plus zanubrutinib] is just the easiest transition given that the combination of BCL2 inhibitors and BTK inhibitors is something that's being explored across the board, like you have the phase 2 BOVen study [NCT03824483] in the frontline setting, and then [sonrotoclax plus zanubrutinib] will potentially be a relapsed/refractory option for this patient population.
Ideally, given what we've seen with venetoclax, these medications can potentially be combined with CD20 antibodies. CD19 antibodies such as tafasitamab-cxix [Monjuvi], or other drugs like bispecific antibodies. There is some data about BCL2 inhibitors improving T-cell fitness; you could possibly look at this prior to what we see with patients who receive CAR-T cell therapy. There are a couple of different ways where you can start to see this molecule having an evolving role. The biggest thing is that even though we've used venetoclax quite a bit, venetoclax does not have any approval in the MCL space. The fact that sonrotoclax has accelerated approval will make it easier for even some investigator-initiated studies, as you could actually access this medication as a standard of care versus having to get medication from the sponsor, which sometimes can be a bit difficult if it doesn't align with their sort of agenda at that point in time.
Given what we know so far about the rationale for BTK inhibitor resistance and MCL, if you have a patient with an early progression on a BTK inhibitor, then maybe a situation where sonrotoclax would fit vs pirtobrutinib in that situation. Ideally, in this space with approved options, the goal should still be to get a patient to CAR T-cell therapy. If you can't get to CAR T-cell therapy, sonrotoclax could be an option, but pirtobrutinib is still probably a little bit easier as there's no ramp up. Ideally, whatever leads to the resistance to zanubrutinib or acalabrutinib [Calquence] is likely something that may also lead to some resistance for pirtobrutinib in that patient space, which is likely evident in the much higher response rate and durability of response in patients who are BTK-naive vs those who are BTK-exposed, especially in patients where BTK inhibitors was the first initial prior line of therapy. It just gives clinicians options in that space. If you have to choose between these two oral agents, you could be a bit more judicious about which one you would choose for a certain situation vs just having to depend on pirtobrutinib alone at this point.
