FDA Grants Pevonedistat Breakthrough Status for Higher-Risk MDS

The FDA has granted breakthrough therapy designation to pevonedistat for the treatment of patients with higher-risk myelodysplastic syndromes.

The FDA has granted breakthrough therapy designation to pevonedistat for the treatment of patients with higher-risk myelodysplastic syndromes (HR-MDS), according to an announcement from Takeda Pharmaceutical Company Limited.1

“Higher-risk MDS is associated with poor prognosis, diminished quality of life and a higher chance of transformation to acute myeloid leukemia, another aggressive cancer. The combination of pevonedistat and azacitidine is a promising therapeutic approach with the potential to be the first novel treatment advancement for higher-risk MDS in more than 10 years,” Christopher Arendt, head of the Oncology Therapeutic Area Unit at Takeda, stated in a press release.

The designation was based on findings from the phase 2 Pevonedistat-2001 trial (NCT02610777) which were presented during the 2020 ASCO Virtual Scientific Program and showed that pevonedistat plus azacitidine resulted in a trend toward improved event-free survival (EFS) and a numerical improvement in overall survival (OS) in patients with higher-risk MDS/chronic myelomonocytic leukemia (CMML), and low-blast acute myelogenous leukemia (LB AML).2

A median EFS of 21.0 months was reported in the pevonedistat/azacitidine arm compared with 16.6 months in the azacitidine-alone arm in the intent-to-treat (ITT) population; this translated to about a 34% reduction in the risk of death or transformation to AML (HR, 0.665; 95% CI, 0.423-1.047; P = .076). Moreover, the median OS in the investigative and control arms was 21.8 months and 19.0 months, respectively (HR, 0.802; 95% CI, 0.512-1.256; P = .334).

In the global, open-label, multicenter, proof-of-concept study, patients with higher-risk MDS/CMML or LB AML were randomized to receive either 20 mg/m2 of pevonedistat administered intravenously (IV) on days 1, 3, and 5 in combination with 75 mg/m2 of IV or subcutaneous (SC) azacitidine (n = 58) on days 1 to 5, 8, and 9, or the same schedule of azacitidine alone (n = 62) in 28-day treatment cycles. To be eligible to participate, patients could not be candidates for allogeneic stem cell transplant, and they could not have received previous treatment with hypomethylating agents.

The co-primary end points of the trial were EFS, defined as time to death or transformation to AML in higher-risk MDS/CMML or death in LB AML, and OS. Notably, the study was not powered to identify a difference in OS per its statistical design. The secondary end point of the trial was objective response rate (ORR).

In the trial, patients in the combination arm received a median of 13 cycles of treatment versus just 8.5 cycles in the control arm. Moreover, the median dose intensity of azacitidine was maintained at 96.9% in the combination group versus 98.2% in the control group.

Results from a prespecified subgroup analysis of the ITT population revealed that all patients benefitted from the pevonedistat combination except 29 patients with intermediate-risk disease (HR, 1.890; 95% CI, 0.552-6.467) and 5 patients with an ECOG performance status of 2 (HR, 3.348; 95% CI, 0.336-33.362).

In the patients with higher-risk MDS, the median EFS was found to be significantly prolonged with the pevonedistat combination versus azacitidine monotherapy, at 20.2 months versus 14.8 months, respectively (HR, 0.539; 95% CI, 0.292-0.995; P =.045). Median OS was also reported to be numerically longer in the investigative arm versus the control arm, at 23.9 months versus 19.1 months, respectively (HR, 0.701; 95% CI, 0.386-1.273; P = .240).

In the subgroup of patients with LB AML, a trend toward improvement in OS was observed with the combination versus the monotherapy, at 23.6 months versus 16.0 months, respectively (HR, 0.494; 95% CI, 0.220-1.109; P = .081). However, an improvement in EFS or OS was not observed in the higher-risk CMML patient subgroup with the combination. The median EFS in this group was 21.0 with the pevonedistat combination and not estimable (NE) with azacitidine alone (HR, 4.302; 95% CI, 0.791-23.407), and the median OS was 21.7 months versus NE, respectively (HR, 7.519; 95% CI, 1.362-41.510; P = .010).

Among a total of 108 patients determined to be evaluable for response, the ORR was 70.9% with the pevonedistat combination, which was comprised of a 40.0% complete response (CR) rate, a 5.5% CR rate with incomplete bone marrow recovery (CRi), a 5.5% partial response (PR) rate and a 20% hematologic improvement (HI) rate. With the azacitidine monotherapy, the ORR was 60.4%, which was comprised of a 30.2% CR rate, a 7.5% CRi rate, a 7.5% PR rate, and a 15.1% HI rate.

Furthermore, the median duration of response was 20.6 months with the combination versus 13.1 months with the monotherapy.

Regarding safety, the most common, any-grade adverse effects (AEs) that occurred in at least 25% of patients on either arm were in line with prior data with pevonedistat and the known toxicity profile of azacitidine. Toxicities include pyrexia, cough, constipation, nausea, neutropenia, diarrhea, anemia, febrile neutropenia, and fatigue.

“We thank the FDA for recognizing pevonedistat, and the urgency to develop innovative therapies that address critical treatment needs for higher-risk MDS, a patient population with few options,” Arendt added.


  1. Takeda announces US FDA breakthrough therapy designation granted for pevonedistat for the treatment of patients with higher-risk myelodysplastic syndromes (HR-MDS). News release. Takeda Pharmaceutical Company Limited. July 30, 2020. Accessed July 30, 2020. https://bit.ly/39IYsDS.
  2. Ades L, Watts JM, Radinoff A, et al. Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777). J Clin Oncol. 2020;38(suppl 15; abstr 7506). doi:10.1200/JCO/2020.38.15_suppl.7506