Background
Phase 3, open-label, randomized controlled trial (ONTIME). N=299 patients with higher-risk MDS (IPSS Intermediate-2 or High) who had failed or were refractory to prior hypomethylating agent (HMA) therapy (azacitidine or decitabine). HMA failure represents the highest unmet need in MDS — median OS after HMA failure is ~5–6 months, and no standard salvage therapy has been established. Rigosertib is a non-ATP-competitive inhibitor of the RAS-RAF-PLK1 signaling pathway. ONTIME used continuous 72-hour IV infusions. Randomized 2:1 to IV rigosertib vs best supportive care (BSC)/physician's choice. Published Lancet Oncology 2016.
Interventions and follow up
Arm A: Rigosertib 1800 mg/day continuous IV infusion over 72 hours (days 1–3) every 2 week
Arm B: Best supportive care or physician's choice (low-dose cytarabine, azacitidine re-challenge, or BSC)
Primary endpoint: OS
mFollow up: 18 month
Arm B: Best supportive care or physician's choice (low-dose cytarabine, azacitidine re-challenge, or BSC)
Primary endpoint: OS
mFollow up: 18 month
Results
mOS (rigosertib vs BSC): 6.1 vs 5.9 months, HR 0.87 (95% CI 0.67–1.12), P=.33 — NOT SIGNIFICANT
mOS (IPSS High-risk subgroup, pre-specified): 8.2 vs 5.9 months, HR 0.72 (exploratory)
ORR: 9% vs 2% (hematologic improvement or better)
Stable disease at 24 wks: 24% vs 10%
mOS (IPSS High-risk subgroup, pre-specified): 8.2 vs 5.9 months, HR 0.72 (exploratory)
ORR: 9% vs 2% (hematologic improvement or better)
Stable disease at 24 wks: 24% vs 10%
Adverse events
Overall: Grade ≥3 AEs 64% (rigosertib) vs 60% (BSC); discontinuation due to AEs 21%.
Genitourinary (class effect): Urinary symptoms (urgency, dysuria, hematuria from drug crystallization) 50% any grade, grade ≥3 11% — requires adequate hydration and urinalysis monitoring.
Hematologic: Anemia grade ≥3 40%, thrombocytopenia 29%.
Infectious: Febrile neutropenia grade ≥3 11%.
Constitutional/GI: Fatigue grade ≥3 12%; peripheral edema 27%; diarrhea grade ≥3 4%.
Genitourinary (class effect): Urinary symptoms (urgency, dysuria, hematuria from drug crystallization) 50% any grade, grade ≥3 11% — requires adequate hydration and urinalysis monitoring.
Hematologic: Anemia grade ≥3 40%, thrombocytopenia 29%.
Infectious: Febrile neutropenia grade ≥3 11%.
Constitutional/GI: Fatigue grade ≥3 12%; peripheral edema 27%; diarrhea grade ≥3 4%.
Conclusions
Rigosertib IV did not improve OS versus best supportive care in higher-risk MDS after HMA failure (mOS 6.1 vs 5.9 months, HR 0.87, P=.33). ONTIME is a key negative trial that defined the limits of PLK1/RAS pathway inhibition in MDS and confirmed the lack of an effective salvage standard in post-HMA higher-risk MDS — a major ongoing unmet need.
Key Limitations
Despite a pre-specified subgroup suggesting benefit in IPSS High-risk patients (HR 0.72), the primary intent-to-treat endpoint was negative, and subgroup analyses should be interpreted cautiously. IV infusion (72h continuous) is burdensome and practically challenging. Urinary toxicity is a significant quality-of-life concern. Rigosertib oral formulation was subsequently tested in a phase 3 trial (INSPIRE) but also showed no OS benefit. The MDS post-HMA failure space remains a major unmet need — current options include allo-SCT (eligible minority), clinical trials, or supportive care. Promising emerging agents (imetelstat, sabatolimab, APR-246) have not yet demonstrated clear survival benefit in this setting.
Clinical Context
ONTIME established that rigosertib IV is not an effective salvage therapy for post-HMA higher-risk MDS. No standard of care has been established for post-HMA higher-risk MDS; allo-SCT is the only potentially curative approach for eligible patients. Key options under investigation: venetoclax combinations (with aza or HMA), TP53-targeting agents (APR-246/eprenetapopt, magrolimab), sabatolimab (STIMULUS-MDS2 in progress), oral rigosertib (INSPIRE — also negative). MDS with TP53 mutations has particularly poor outcomes post-HMA, with a median OS of ~3–5 months. Clinical trial enrollment is the recommended approach for post-HMA higher-risk MDS. ESMO-MCBS: not assigned (negative trial).