Background
Two Phase 3 double-blind placebo-controlled RCTs (FIT1 and FIT2, analyzed together). 150 adults with persistent or chronic ITP (≥3 months), platelet count ≤30×10⁹/L, and ≥3 prior ITP therapies (including ≥1 prior TPO-RA failure in many). Fostamatinib (R788; Tavalisse/Resonate) is an oral spleen tyrosine kinase (SYK) inhibitor that targets both macrophage-mediated platelet phagocytosis (FcγR signaling) and B-cell signaling, providing a distinct non-TPO-RA mechanism for ITP. Fostamatinib is a prodrug converted to the active metabolite R406. Randomized 2:1 in each study. Target population: heavily pretreated chronic ITP with inadequate response to standard therapies.
Interventions and follow up
Arm A: Fostamatinib 100 mg orally twice daily, escalating to 150 mg BID at week 4 if platelet <50×10⁹/L
Arm B: Placebo orally twice daily
Primary endpoint: Stable response (platelet ≥50×10⁹/L for ≥4 of the last 6 weeks of 24 weeks, starting within first 12 weeks)
mFollow up: 24 week
Arm B: Placebo orally twice daily
Primary endpoint: Stable response (platelet ≥50×10⁹/L for ≥4 of the last 6 weeks of 24 weeks, starting within first 12 weeks)
mFollow up: 24 week
Results
Stable response: 18% (fostamatinib) vs 2% (placebo), P<.001
Overall response (any platelet ≥50×10⁹/L during study): 43% vs 14%, P<.001
Response in prior TPO-RA failures: ~17% stable response
Median time to response: 15 days in responders
Overall response (any platelet ≥50×10⁹/L during study): 43% vs 14%, P<.001
Response in prior TPO-RA failures: ~17% stable response
Median time to response: 15 days in responders
Adverse events
Main adverse events: Hypertension 28% (fostamatinib) vs 13% (placebo), grade ≥3 hypertension 6%. Diarrhea 31% vs 16% (mostly grade 1–2). Nausea 21% vs 11%. ALT elevation grade ≥3: 6% vs 0%. Discontinuation due to AEs: 15% vs 3%. Infections not increased. No thromboembolic events. No bone marrow fibrosis concerns.
Conclusions
Fostamatinib achieved stable platelet response in 18% of heavily pretreated chronic ITP patients including those who failed TPO-RAs, establishing SYK inhibition as a valid mechanistic approach in refractory ITP, though response rates are modest.
Key Limitations
Key Limitations: Stable response rate of only 18% — majority of patients did not achieve durable responses. Overall response (43%) declines significantly to 18% when durable response criteria applied. Hypertension is a relevant toxicity requiring monitoring. ALT elevation common. High discontinuation due to AEs (15%). Difficult to interpret 'refractory' population due to variable prior therapy requirements. No head-to-head comparison to TPO-RAs in this setting; positioned as 3rd/4th-line given modest response rates.
Clinical Context
FDA approved April 2018 (Tavalisse) for chronic ITP in adults after ≥1 prior therapy — first approved non-TPO-RA mechanism for ITP. Particularly useful in prior TPO-RA failures (~17% response). Mechanism is distinct: SYK inhibition blocks both Fcγ-receptor–mediated platelet destruction and B-cell activation. Requires BP monitoring throughout treatment. Real-world response rates appear consistent with clinical trial data. Novel BTKi approaches (rilzabrutinib, Phase 3 ongoing) target overlapping B-cell/FcγR pathways with potentially improved tolerability profiles.
References