Addition of Rigosertib Improves Azacitidine Benefit in Patients With Higher-Risk MDS

Shyamala C. Navada, MD

The combination of rigosertib and azacitidine (Vidaza) demonstrated improved response rates over single-agent azacitidine in patients with higher-risk myelodysplastic syndrome (MDS), including patients naïve to a hypomethylating agent (HMA) and those who were refractory to HMAs, according to findings presented at the at the 2019 European Hematology Association (EHA) Congress.¹ The responses following combination treatment were both rapid and durable.

“In HMA-naïve patients, oral rigosertib at doses of 840 mg or more per day, administered with azacitidine, was associated with an overall response rate of 90% and, importantly, a complete response rate of 34%,” commented Shyamala C. Navada, MD, assistant professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai in New York.

Azacitidine represents the current standard first-line therapy in higher-risk MDS where an overall response rate (ORR) of up to 50% has been observed. Since most patients ultimately relapse with successful treatment, different drug combinations have been tested; so far, none have shown a superior response or outcome over azacitidine monotherapy. The lack of efficacy may be explained by limited treatment exposure due to the toxicity that accompanies these combinations.

“Novel combinations that are better tolerated are required to improve the clinical outcome in patients with MDS,” she said.

Rigosertib is a Ras-mimetic that binds the Ras-binding domain in Ras effector proteins thereby inhibiting the PI3K and PLK cellular signaling pathways. In vitro, the combination of rigosertib and azacitidine inhibits growth and induces apoptosis of leukemic cells. Extensive in vitro analysis was done to determine the sequence of administration that provided optimal synergy, which resulted in a schema of 4-week cycles of sole rigosertib administered twice daily prior to the combination followed by single-agent rigosertib and 1 week of no treatment.²

Navada noted that oral rigosertib added to standard-dose azacitidine was well-tolerated by both HMA-naïve and HMA-failure patients with MDS. The combination provided improved efficacy in a phase I/II study with daily doses of rigosertib at 560 mg (morning) and 280 mg (evening). The ORR was 77%, which improved to 88% in HMA-naive patients, and was lowered to 60% in the HMA-failure group. However, an increase in genitourinary (GU) adverse events (AEs) was noted.

Based on the observation that rigosertib at a higher dose of 1120 mg/day provided improved ORR in patients with lower-risk MDS,³ this dose level was investigated in expanded cohorts,⁴ and subsequent studies using risk-mitigation strategies to reduce GU AEs were done.⁵

In this phase II trial, patients with MDS were treated with rigosertib at 840 mg or 1120 mg plus standard-dose parenteral azacitidine at 75 mg/m²/day for 7 days starting on day 8. Both cohorts included patients with HMA-naïve and HMA-refractory MDS. The median age of the patients was 69 years (ranges, 42-90) and 59% of patients were male. The IPSS classification was intermediate-1, intermediate-2, high, and unknown in 32%, 35%, 28%, and 4% of patients, respectively. Thirty-five patients had received prior HMA therapy, which consisted of azacitidine in 35%, decitabine in 8%, and both in 4% of patients.

Of 55 patients treated with ≥840 mg rigosertib, 29 received 1120 mg, and 26 received 860 mg (morning/evening split doses). Both cohorts included HMA-naive and HMA-failed patients. Regarding patients with HMA-naïve MDS who received rigosertib ≥840 mg/day, 29 were evaluable for response. Of these, 26 patients demonstrated response, providing an ORR of 90%. Among responding patients, 10 patients (34%) achieved a complete response (CR), 5 (17%) showed marrow CR with hematologic improvement, 3 (10%) showed only hematologic improvement, and 8 (28%) showed only marrow improvement. Three additional patients (10%) had stable disease (SD); importantly, no disease progression (PD) was observed. The median duration of treatment was 7.8 months (range, 7.0-25.2+) and median duration of response (DoR) was 12.2 months (range, 0.1-24.2+).

Among patients with HMA-refractory MDS who received rigosertib ≥840 mg daily, 26 patients were evaluated for response. The ORR was 54%, including 1 patient (4%) each who achieved CR or partial response (PR); 5 patients (19%) had marrow CR and hematologic improvement, 2 (8%) with only hematologic, and 5 (19%) with marrow improvement. SD was observed in 7 patients (27%) and 5 (19%) experienced PD. The median duration of treatment was 4.9 months (range, 1.1-20.8+) and DoR was 10.8 months (range, 0.1-11.8+).

Navada pointed out: “The median duration of response in patients failing HMA was approximately 11 months, which is important since the historic median overall survival is approximately 4 to 6 months.”

In the HMA-naive and HMA-failed cohorts, the median time to initial response was 1 and 2 cycles and the median time to best response was 4 and 5 cycles, respectively, which was quicker than observed with single-agent azacitidine.

Responses were observed at all levels of cytogenics that ranged from 73% in patients with very poor to 76% in patients with good cytogenetics; notably, the response was 100% in 4 HMA-naïve patients having poor cytogenetics.

In 46 transfusion-dependent patients, 30% of HMA-naïve and 15% of HMA-failed patients achieved transfusion independence.

“The combination regimen was well-tolerated and was given in continuing cycles for >2 years, even in those who did not respond to HMA therapy,” said Navada.

“Safety management guidelines for genitourinary toxicities work and allowed patients to continue on combination therapy,” she added. These guidelines included split rigosertib doses, hydration, mandatory pre-bedtime bladder emptying, and adjustment of urine PH with sodium bicarbonate when needed. Adherence to these guidelines provided successful management in 70% of patients with grade ≥2 hematuria.

Safety was evaluated in 79 patients receiving rigosertib at all dose levels; 100% of patients had an adverse event (AE) of any grade. The most commonly reported AEs of grade ≥3 were hematuria, and dysuria in 10% of patients receiving ≥840 mg rigosertib.

“Based on the safety and efficacy profile of the combination in MDS, a pivotal phase II trial is planned in an HMA-naïve population,” commented Navada.

References

1. Navada SC, Garcia-Manero G, Atallah E, et al. Phase II study of oral rigosertib combined with azacitidine in patients with higher-risk myelodysplastic syndromes (MDS). Presented at 2019 EHA Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract S839.
2. Navada S, Garcia-Manero G, Hearn K, et al. Oral rigosertib combined with azacitidine in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS): effects in treatment naïve and relapsed/refractory patients. Presented at 2017 EHA Congress; June 22-25, 2017; Madrid, Spain. Abstract S488.
3. Sekeres MA, Othus M, List AF, et al. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017;35(24):2745-2753. doi: 10.1200/JCO.2015.66.2510.
4. Raza A, Yalçin C, Cimist M, et al. Long term responses to rigosertib in lower-risk myelodysplastic syndromes (MDS) patients. Blood. 2017;130(suppl 1):5316.
5. Navada SC, Garcia-Manero G, Atallah E, et al. Phase 2 expansion study of oral rigosertib combined with azacitidine (AZA) in patients (Pts) with higher-risk (HR) myelodysplastic syndromes (MDS): efficacy and safety results in HMA treatment naïve & relapsed (Rel)/refractory (Ref) patients. Blood. 2018;132(suppl 1):230.

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