Background
Phase III open-label RCT. 280 patients with relapsed or refractory MCL after ≥1 prior line of therapy (median 2 prior lines). Designed to compare ibrutinib (irreversible covalent BTKi) against temsirolimus (mTOR inhibitor), the only then-approved agent for R/R MCL in Europe. Conducted by the European MCL Network. The RAY trial was pivotal in confirming the superiority of BTK inhibition over mTOR inhibition in R/R MCL.
Interventions and follow up
Arm A: Ibrutinib 560 mg PO daily until disease progression or unacceptable toxicity
Arm B: Temsirolimus 175 mg IV weekly × 3 weeks, then 75 mg IV weekly until disease progression or unacceptable toxicity
Primary endpoint: Progression-free survival (PFS) by independent radiological review committee (IRC) per Lugano criteria
Median follow-up: 20 months
Arm B: Temsirolimus 175 mg IV weekly × 3 weeks, then 75 mg IV weekly until disease progression or unacceptable toxicity
Primary endpoint: Progression-free survival (PFS) by independent radiological review committee (IRC) per Lugano criteria
Median follow-up: 20 months
Results
mPFS (IRC): 14.6 vs 6.2 months, HR 0.43, 95% CI 0.32–0.58, P<.0001
ORR: 72% (ibrutinib) vs 40% (temsirolimus)
CR rate: 19% vs 1%
mOS: NR vs 21.3 months (OS HR 0.76, not formally tested)
ORR: 72% (ibrutinib) vs 40% (temsirolimus)
CR rate: 19% vs 1%
mOS: NR vs 21.3 months (OS HR 0.76, not formally tested)
Adverse events
Overall (grade ≥3): 56% (ibrutinib) vs 68% (temsirolimus); discontinuation due to AEs 6% vs 12%
Ibrutinib-specific (grade ≥3): atrial fibrillation 5%, bleeding 2%, pneumonia 6%, hypertension 6%
Temsirolimus-specific (grade ≥3): thrombocytopenia 54%, neutropenia 25%, anemia 20%, infections 20%
Ibrutinib-specific (grade ≥3): atrial fibrillation 5%, bleeding 2%, pneumonia 6%, hypertension 6%
Temsirolimus-specific (grade ≥3): thrombocytopenia 54%, neutropenia 25%, anemia 20%, infections 20%
Conclusions
Ibrutinib significantly prolonged PFS and improved ORR compared with temsirolimus in R/R MCL, with a more favorable overall toxicity profile. This trial confirmed ibrutinib's superiority over mTOR inhibition and reinforced BTK inhibition as the dominant mechanism in R/R MCL.
Key Limitations
Open-label design; PFS by IRC could be subject to assessment bias, though IRC was used to mitigate this. Temsirolimus was a suboptimal comparator relative to bendamustine-rituximab or VR-CAP in BTKi-naive settings; a head-to-head vs BR would have been more informative. No assessment of TP53 or blastoid morphology outcomes separately. Atrial fibrillation and bleeding remain clinically important ibrutinib-specific risks. Subsequent data (SHINE trial) were needed to establish frontline benefit.
Clinical Context
RAY supported EU approval of ibrutinib for R/R MCL. Acalabrutinib (ACE-LY-004) and zanubrutinib (SEQUOIA/BGB-3111) subsequently showed similar or superior efficacy with better tolerability (less atrial fibrillation), and are ESMO-listed second-generation covalent BTKi options for R/R MCL. Pirtobrutinib (BRUIN, Mato NEJM 2023), a non-covalent BTKi, addresses the covalent BTKi-resistance population. RAY remains a key historical reference establishing the BTKi class in MCL.