BET Inhibitor Shows Promise in Advanced Solid Tumors, Relapsed/Refractory NHL

Victor Moreno Garcia, PhD

The reversible BET inhibitor CC-90010 was found to have preliminary antitumor activity in patients with heavily pretreated, advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma, according to the updated results of a phase 1 study (NCT03220347) presented during the 2020 ESMO Virtual Congress.¹

In patients enrolled on part A of the study (n = 69), the agent elicited a clinical benefit rate (CBR) of 17.4% was reported (n = 12; 95% CI, 9.3-28.4) along with an objective response rate (ORR) of 2.9% (n = 2; 0.4-10.1).

During treatment, 1 patient (1.4%) with diffuse astrocytoma achieved a complete response (CR) and continued on the treatment for 18 cycles until before experiencing disease progression. An additional patient with endometrial carcinoma achieved a partial response (PR) and was able to complete 8 cycles of treatment. Ten patients were able to maintain stable disease (SD) for at least 4 months; 3 patients had prolonged SD for 24 cycles, 1 patient had SD for 16 cycles, and 2 patients had SD for 15 cycles. Two patients with stable disease are still receiving treatment at cycles 28 and 24.

In part B of the study (n = 14), CC-90010 induced a CBR of 21.4% (n = 3; 95% CI, 4.7-50.8) along with an ORR of 14.3% (95% CI, 1.8-42.8). One patient with diffuse large B-cell lymphoma (DLBCL) experienced a CR and finished 5 cycles of treatment, while another patient with the same disease achieved a PR and completed 3 cycles. Two patients achieved SD (14.3%), 1 (7.1%) of whom maintained stability for 4 months or longer.

“CC-90010 was well-tolerated and showed preliminary antitumor activity in heavily pretreated patients with advanced solid tumors and relapsed DLBCL,” Victor Moreno Garcia, PhD, director of Clinical Research at the Phase 1 Trials Unit START at University Hospital Fundación Jiménez Díaz, said in a presentation during the meeting. “Treatment-related adverse effects [TRAEs] were mostly mild and manageable with dose interruptions and reductions.”

A potent and reversible small-molecule BET inhibitor, CC-90010 preferentially binds to bromodomain-containing proteins. The agent was found to lead to tumor reduction when evaluated in xenograft models and encouraging activity in patients with advanced malignancies.2 Because BET proteins are key players in the regulation of MYC oncogene expression, investigators hypothesized that CC-90010 may represent a potential effective option for patients with high-grade B-cell lymphoma, particularly those who have MYC rearrangements.^3,4

The multicenter, open-label, first-in-human phase 1 trial was comprised of 2 parts; part A focused was the dose-escalation phase of the trial, while the ongoing part B portion is evaluating the safety and efficacy of the agent in an expansion cohort.

To be eligible for the dose-escalation portion of the study, patients needed to be 18 years of age or older with either advanced unresectable solid tumors (n = 67) or relapsed/refractory DLBCL (n = 2). Additionally, patients needed to have an ECOG performance status of 0-1 and have progressed on or were unable to tolerate a standard anticancer treatment.

Numerous doses of CC-90010 were evaluated in part A, although the 45-mg dose, delivered 4 days on and 24 days off, was selected as the recommended phase 2 dose; the 30-mg dose, delivered 3 days on and 11 days off, was selected as an alternative dosing regimen. Dose escalation was completed on December 10, 2018 and the primary objectives of part A were reached.

Two cohorts of patients received the 45-mg dose of CC-90010: cohort 1 was comprised of 14 patients with relapsed/refractory DLBCL and cohort 2 was comprised of 1 patient with advanced basal cell carcinoma and 1 patient with NUT midline carcinomas. Cohort 1 is ongoing and cohort 2 has stopped. The recently-opened third cohort is comprised of patients with relapsed/refractory DLBCL who are receiving the agent at the 30-mg dose.

Patients enrolled on the dose-escalation portion of the trial had a median age of 57 years and were primarily male (n = 38; 55%). Meanwhile, those included in the safety and efficacy portion of the study had a median age of 63.5 years and 57% were male (n = 8). In part A, 48% (n = 33) of patients had an ECOG performance status of 0, while 52% (n = 36) had a status of 1; in part B, these percentages were 21% and 79%, respectively. The median number of previous systemic cancer therapies received was 4 in both parts of the trial.

Moreover, the majority of the patients, of 97% (n = 67) in part A had solid tumors, while 3% (n = 2) had DLBCL. Eighty-six percent (n = 12) of the patients included in part B had DLBCL, while 14% (n = 2) had solid tumors. Notably, at the time of enrollment, stage IV cancer was observed in the majority of patients who had solid tumors.

The median treatment duration was 8 weeks, and the majority of patients were able to receive their planned dose. During the dose-escalation portion of the trial, the monthly dosing schedule of 4 days on and 24 days off was found to have the lowest number of dose modifications compared with other schedules examined. Additionally, the monthly schedule of 4 days on and 24 days off and the biweekly dosing schedules of 3 days on and 11 days off were found to have safety profiles that were more favorable than that of the weekly dosing schedule.

“Adverse effects [AEs] were the most common reason for dose reduction—12% in part A and 14% in part B—and interruption—45% in part A and 43% in part B,” noted Moreno. “One patient in part A discontinued [treatment] due to an AE that was not treatment related.”

In total, 32 patients in part A had progressive disease (46.4%) and 12 were not evaluable (17.4%). Patients on dose escalation portion of the study were additionally reported to have had a median overall survival (OS) of 180 days (95% CI, 161-254) and a median progression-free survival (PFS) of 57 days (95% CI, 52-81). Four patients in part B experienced progressive disease (7.1%) while another 6 were not evaluable (42.9%). Patients enrolled on part B portion reportedly had a median OS of 102 days (95% CI, 92-NE) and a median PFS of 60 days (95% CI, 12-126). One heavily pre-treated patient who had been diagnosed with relapsed/refractory DLBCL experienced a 57% regression of target lesions following treatment.

The majority of treatment-related AEs were found to be mild or moderate in severity, reversible, and easily managed through dose adjustments and/or supportive care. The high rate of thrombocytopenia reported in part B (any grade, 79%; n = 11; grade 3/4, 64%; n = 9) is reflective of the high number of patients with hematologic malignancies on the trial, according to Moreno. Other common AEs reported in part B included anemia (any grade, 43%; grade 3/4 28%), neutropenia (any grade, 29%; grade 3/4 21%), nausea (any grade, 29%), and asthenia (any grade 21%; grade 3/4 7%). No treatment-related deaths occurred.

“This study is ongoing in [patients with] relapsed/refractory DLBCL and advanced solid tumors at the recommended phase 2 doses and relapsed/refractory DLBCL at an alternative dosing regimen," Moreno concluded.

References

1. Moreno V, Braña Im Sepulveda JM, et al. CC-90010, a reversible, oral bromodomain and extra-terminal (BET) inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma: updated results of a phase 1 study. Presented at: 2020 ESMO Virtual Congress; Virtual. September 19-21, 2020. Accessed September 28, 2020. Abstract 5270.

2. Moreno V, Sepulveda JM, Vieito M, et al. Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma. Ann of Oncol. 2020;S0923-7534(20):36381-X. doi:10.1016/j.annonc.2020.03.294

3. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Natl Acad Sci USA. 2011;108(40):16669-16674. doi:10.1073/pnas.1108190108.

Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917. doi:10.1016/j.cell.2011.08.017