Frontline Tamibarotene Plus Venetoclax and Azacitidine Induces 100% CR Rate in SELECT-AML-1 Trial

Thomas Cluzeau, MD, PhD

The addition of the oral, selective RARα agonist tamibarotene to venetoclax (Venclexta) and azacitidine produced a 100% complete response (CR; n = 7)/CR with incomplete hematologic recovery (CRi; n = 2) rate (n = 9) vs 70% (n = 7/10; CR, n = 3; CRi, n = 4) with venetoclax and azacitidine alone in response-evaluable patients with newly diagnosed, RARA-overexpressed acute myeloid leukemia (AML), meeting the primary end point of the phase 2 SELECT-AML-1 trial (NCT04905407).^1,2

“I am highly encouraged by the initial data from the randomized portion of SELECT-AML-1,” Thomas Cluzeau, MD, PhD, head of Hematology at Nice University Hospital, Côte d’Azur University in France, said in a news release. “Despite the recent advances in treatment for unfit AML patients, there remains a substantial need for options that offer higher response rates and improved overall survival, particularly for the one-third of patients who do not respond to existing standard-of-care. I believe tamibarotene may offer a significant therapeutic advance for the treatment of AML and I am eager to continue enrolling patients in the ongoing SELECT-AML-1 trial.”

SELECT-AML-1 is evaluating the safety and antitumor activity of the triplet regimen compared with venetoclax and zacytidine alone in approximately 80 patients with newly diagnosed AML unfit for standard intensive chemotherapy. Notably, patients in the control arm who do not respond to the combination will be allowed to receive the triplet regimen as salvage therapy.

In December 2022, results from the safety lead-in portion of the trial showed that 83% of evaluable patients (n = 5/6) achieved CR/Cri.

As of November 13, 2023, 23 patients had enrolled in the randomized portion of the trial, 19 of whom were evaluable for response. The median patient age was 77 years (range, 66-85) in the triplet arm vs 76 years (range, 69-84) in the combination arm.

The median duration of treatment was 66 days (range, 8-188) in the triplet arm vs 75 days (range, 7-277) in the combination arm.

Additional results from the trial indicated that the median CR/CRi response was 21 days (range, 14-28) with the triplet vs 25 days (range, 17-56) with the combination. All patients in the triplet arm achieved CR/CRi by the end of the first cycle of therapy vs 60% of patients in the combination arm.

“These data highlight the potential of tamibarotene to be a cornerstone therapy for newly diagnosed, unfit AML patients with RARA overexpression, further demonstrating its differentiated product profile and validating our biologically targeted approach,” David A. Roth, MD, chief medical officer of Syros, added. “These results––the first from a randomized, controlled study––demonstrate the potential impact of adding tamibarotene to the standard-of-care, venetoclax and azacitidine and, importantly, are consistent with prior experience.”

Regarding safety, the triplet was generally well tolerated, mirroring prior clinical data from the safety lead-in portion of the trial. Additionally, no new safety signals or evidence of increased myelosuppression with the triplet occurred. Most non-hematologic adverse effects (AEs) were low grade and reversible, and the rates of serious AEs were similar between arms.

“Across multiple clinical trials, we have observed tamibarotene’s ability to rapidly deliver clinically relevant activity, with a well-tolerated safety profile, including in a combination setting. We look forward to advancing our comprehensive clinical development program for tamibarotene, with additional data from SELECT-AML-1 and pivotal complete response data from our SELECT-MDS-1 trial in higher-risk myelodysplastic syndrome with RARA overexpression expected next year, as we work to deliver profound benefit to patients with hematologic malignancies,” Roth concluded.

SELECT-AML-1 remains open to enrollment. Updated data from the study, including duration of response, minimal residual disease negativity, and survival, are expected in 2024.

Tamibaroteneis also under evaluation in the phase 3 SELECT-MDS-1 trial (NCT04797780) in combination with azacitidine in patients with newly diagnosed, higher-risk myelodysplastic syndrome with RARA gene overexpression.¹ In January 2023, the FDA granted fast track designation to tamibarotene for the treatment of patients with higher-risk MDS.³

Syros plans to complete patient accrual in the first quarter of 2024 and to report CR data by the middle of the fourth quarter of 2024.¹

References

1. Syros announces encouraging initial data from randomized SELECT-AML-1 phase 2 clinical trial evaluating tamibarotene in combination with venetoclax and azacitidine. News release. Syros Pharmaceuticals. December 6, 2023. Accessed January 16, 2024. https://finance.yahoo.com/news/syros-announces-encouraging-initial-data120000333.htmlguccounter=1&guce_referrer=aHR0cHM6Ly9zdGF0aWNzLnRlYW1zLmNkbi5vZmZpY2UubmV0Lw&guce_referrer_sig=AQAAACw4oSAZVv5MSTnpw-aKAg96qB0wVfziF6ywForhfmMIoV56-wGVFUUkcUE_cbBTZaRCszVjvi9UOU2CHUOX3ZdjwTDFlqS756pDDyS3IspupjYIkKM4Lh6FB_hkX34KFx4Fpln3Ot8lnY8UZBmAIv3Oac7qsYff_zH-W7R9YrrO
2. Tamibarotene plus venetoclax/azacitidine in participants with newly diagnosed AML. ClinicalTrials.gov. Updated January 11, 2024. Accessed January 16, 2024. https://clinicaltrials.gov/study/NCT04905407
3. Syros receives fast track designation from the FDA for tamibarotene for the treatment of higher-risk myelodysplastic syndrome. News release. Syros Pharmaceuticals. January 26, 2023. Accessed January 16, 2024. https://www.businesswire.com/news/home/20230126005350/en/Syros-Receives-Fast-Track-Designation-from-the-FDA-for-Tamibarotene-for-the-Treatment-of-Higher-Risk-Myelodysplastic-Syndrome