Cirmtuzumab/Ibrutinib Shows Encouraging Clinical Activity, Safety in MCL and CLL

Cirmtuzumab (UC-961), when used in combination with ibrutinib (Imbruvica), showed encouraging activity with favorable tolerability in patients with relapsed/refractory mantle cell lymophoma (MCL), as well as in patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from a phase 1/2 study (NCT03088878) presented during the 2020 ASH Annual Meeting & Exposition.

Among 12 evaluable patients with MCL in part 1 of the trial, the objective response rate (ORR) achieved with the combination was 83%, which included a complete response/complete metabolic response (CR/CMR) rate of 58% (n = 7) and a partial response (PR) rate of 25% (n = 3). Two patients achieved stable disease with the approach. 

The CR/CMR in this subgroup was achieved at a median of 3.8 months in heavily pretreated patients who had relapsed after ibrutinib, autologous or allogeneic stem cell transplant, and CAR T-cell therapy. Notably, the CR rate in high-risk patients was 50% with cirmtuzumab/ibrutinib versus 17% with historical ibrutinib plus rituximab (Rituxan).

“In terms of MCL, the CR rates were much higher than [what has been seen historically with] single-agent ibrutinib,” lead study author Hun Ju Lee, MD, said. “[Additionally], the combination [did not] increase any toxicity, [which makes] it even better for many patients who need something gentle, so that they can maintain their quality of life.”

Among 34 patients with CLL in parts 1 and 2 of the trial, the ORR was 88% with the cirmtuzumab doublet, which included a CR rate of 3% (n = 1) and a PR rate of 85% (n = 25); 4 patients achieved disease stability. In those who were treatment naïve, the ORR was even higher, at 92% (n = 11/12), while it was 86% in those with relapsed/refractory disease (n = 19/22). At a median follow-up of 12.8 months, 100% of these patients were free of disease progression.

In an interview with OncLive, Lee, an assistant professor of Medicine in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, discussed the trial and its key findings.

OncLive: What set the stage for this research? 

Lee: Thomas Kipps, MD, of the University of California, San Diego, was the first to recognize neoantigens that were expressed in lymphoma cells and leukemia cells, and they were able to do the preclinical studies to validate that these neoantigens that are expressed will be a favorable target that's only expressed on neoplastic cells. 

[There was also] the observation that there may be some synergy between RR1 and the B-cell receptor signaling pathway. There was the question of why, if we were able to use ibrutinib to shut down the B-cell receptor signaling pathway, we were not getting 100% CRs? There is a mechanism by which these cells [operate that] they're able to overcome these inhibitors that we [use].

One of the mechanisms we are hypothesizing is that the RR1 pathway may be contributing to the escape mechanism. Hence, blocking both sides may be a very interesting therapeutic [approach] for many of our patients.

What were the objectives of the study and what end points were evaluated?

Cirmtuzumab is a new antibody, and in part 1 [of the study] we were able to enroll both [patients with] CLL and [those with] MCL. We had rapid enrollment for this trial, and for patients who received cirmtuzumab plus ibrutinib, we saw fairly exciting preliminary data. We were able to achieve an overall response rates north of 80%, and a CR rate of 58%, which was really [impressive] compared [with] the historical [data we saw with] ibrutinib alone. 

On top of that, [the combination] was very well tolerated. In many patients with MCL, they are diagnosed in their seventh decade of life; these patients are 65 years of age or older, with a lot of comorbidity, and they tolerated [this approach] very well. We also did not see any additive toxicity with the combination. 

Are the response rates durable?

Median PFS was [had not yet been] reached in the cirmtuzumab arm, so we are very pleased [about that]. With further follow-up, we will be able to show that, compared with historical ibrutinib, [this approach] was superior. We are pleased with durability. Our first patient [has been] on the trial for more than 2 years, and he [had previously received an] allogenic transplant. 

Could you expand on the safety profile of the combination? Were any toxicities of special interest?

We did not see any signals of increased atrial fibrillation, or other [effects] like diarrhea and skin rashes. We were expecting [those toxicities], but we did not see them. With the higher number of patients that we expect [to include] in part 2 [of the trial], I’m sure we'll see [those effects]; however, thus far, we have been very fortunate.

Reference

1. Lee HJ, Choi MY, Siddiqi T, et al. Cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: clinical activity in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) from a phase 1/2 study. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-141917