Activity of Ceralasertib With BTK Inhibition in High-Risk R/R CLL Calls to Further Investigation

Wojciech Jurczak, MD, PhD

Treatment options are limited for patients with chronic lymphocytic leukemia (CLL) who relapse on agents that target B-cell receptor signaling pathways. In preclinical research, ATR inhibition demonstrated the ability to induce synthetic lethality and overcome chemoresistance in TP53-mutated and ATM-defective CLL cells, and a proof-of-concept phase 1/2 study was conducted.

In the multicenter, nonrandomized, open-label study (NCT03328273), 11 patients with a median age of 64 years who received a median of 3 prior lines of therapy were treated. Eight of the patients received the novel ATR inhibitor, ceralasertib, in arm A, and 3 patients received the ceralasertib combined with acalabrutinib (Calquence) in arm B.

The coprimary end points of the study were safety and pharmacokinetics, and the secondary end points were overall response rate (ORR), complete response rate, duration of response (DOR), progression-free survival (PFS), and overall survival.

Limited clinical benefit was observed with ceralasertib in patients with high-risk relapsed or refractory (R/R) CLL. There were no responses in the single-agent arm. At a median follow-up of 15.1 months, the median PFS in arm A was 3.8 months (95% CI, 0.7-4.6). The median OS in arm A was 16.9 months (95% CI 6.6-not reached [NR]).

In arm B, the ORR observed was 100%, with all responses being partial responses to acalabrutinib plus ceralasertib, and the median DOR was NR. At a median follow-up of 15.9 months, the median PFS and OS were NR in arm B.

Safety findings showed that ceralasertib led to dose-limiting toxicities (DLTs) and 1 grade 3 or higher adverse event of anemia. In comparison, there were no grade 3 or DLTs in the combination arm.

In an interview with Targeted Oncology™, Wojciech Jurczak, MD, PhD, head of the Department of Oncology at Maria Sklodowska-Curie National Research Institute of Oncology, discussed the clinical trial investigation of ceralasertib with or without acalabrutinib in patients with high-risk R/R CLL.

TARGETED ONCOLOGY: What treatment options are there for patients with CLL who have relapsed on B-cell receptor pathway signaling therapies?

Jurczak: Patients with chronic lymphocytic leukemia have a variety of treatment options and this does vary depending on which side of the Atlantic [Ocean] they come from, because NCCN guidelines are entirely different from the European guidelines.

In the United States, there is a tendency to offer the targeted therapy, namely the BTK inhibitors or venetoclax to everyone. While in Europe, we are more conservative. The European guidelines make it compulsory to offer targeted therapy to all patients with 17p deletion or p53 mutation. For others, including 11q deletion, we don't have to, but it is just a possibility. Still, some of the patients get chemoimmunotherapy, whereas some get targeted chemo or targeted agents.

The key question is whether we want to go for BTK inhibitor monotherapy, or a time-limited therapy, which is offered by BCL-2 inhibitors. We're talking just about the things which don't register because in clinical studies, we are now investigating combinations, and even triplet combinations of molecular targeted drugs where both BCL-2 inhibitors and BTK inhibitors and in fact given together.

Can you discuss the mechanism of action of the novel targeted agent, ceralasertib, and what is the rationale for using this drug in CLL?

Ceralasertib is a drug with a very interesting mode of action. In fact, it's the first inhibitor of RET-free related protein or an RTR inhibitor, which is specifically important in the patients with 11q deletion. Now, patients with an 11q deletion are not the worst of the worst, because they are regarded an intermediate risk with rationale of giving them the targeted therapy instead of chemoimmunotherapy.

There was hope that addition of either ATR inhibitor or ATR inhibitor in combination with BTK inhibitor would give a substantial benefit in terms of efficacy and the population treated. This unfortunately was not achieved, partly due to toxicity where we could not keep the patients on therapy long enough, and partly due to inefficiency of this particular population. Therefore, in a way, it's always safe to say that negative studies should be published as well, but this is what it is. The combination of an ATR inhibitor and BCL-2 inhibitor is evidently not something which we could recommend to the vast majority of the patients.

Can you discuss the design of the phase 1/2 study of ceralasertib with or without acalabrutinib for the treatment of high-risk R/R/ CLL?

This was a phase 1 and 2 with 2 arms. For inclusion criteria, we took all the patients with relapsed/refractory CLL requiring therapy, and those patients had high-risk genomic features. In arm A, they had deletions 17p, tp53 mutation, or deletion 11q. In arm B, we concentrated only on those with the deletion of 11q. They had to have adequate human biological functions and a reasonable ECOG status.

For exclusion criteria, we had the diagnosis of ataxia-telangiectasia, the prior exposure to ATR inhibitors, which was very rare, and some conditions were cardiovascular or other procedures that made it difficult to treat the patients per the study protocol.

In arm A, we gave ceralasertib 160 milligrams bi-daily continuously. But as we faced severe hematological toxicity, it was later changed to 2 weeks on the drug and 2 weeks off the drug. In arm B, where we move on to those with 11q deletion, therefore only those who should be most responsive, we had acalabrutinib bi-daily, and this was in cycle 1. From cycle 2 onwards, we had acalabrutinib plus ceralasertib.

Now in both cases, hematological toxicity was dose- and effect-limiting. We can say that ceralasertib monotherapy in BTK-exposed, high-risk CLL patients showed limited if any benefit. Ceralasertib plus acalabrutinib was tolerable with preliminary clinical activity with patients with 11q deletion but the study faced problems and did not find enough eligible patients.

What was interesting about the study results?

Throughout this study, we could not achieve any complete response. The only partial responses we observed were in arm B, where it was acalabrutinib plus ceralasertib with 11q deletion. All the other patients either progressed, or we could observe just stabilization of the process. In conclusion, ceralasertib monotherapy was not recommended, and a combination therapy was potentially effective and the patients with 11q deletion, although the study didn't recruit well enough to make the results meaningful.

Based on the signals with the combination, how do you think ceralasertib can be applied to high-risk R/R CLL treatment in the future?

It is difficult to say because the mechanism of action is unique and it could be further explored in patients with 11q deletion, although I would rather not recommend it in the first 2 lines of therapy. In those with 11q deletion who are failing on a more dedicated therapy like BTK inhibitors, or BCL-2 inhibitors, it could be a reasonable option, and it could be further investigated in this cohort.

_REFERENCES:

_{Jurczak W, Elmusharaf, N, Fox CP, et al. CT532 - Phase 1/2 results of ceralasertib (Cerala) as monotherapy or in combination with acalabrutinib (Acala) in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: American Association for Cancer Research 2022 Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT532.}