Transparency Submission

FDA Clearance: Use of ibrutinib with venetoclax (I+V) is not an FDA-approved combination

Rationale for Requested Change: Clinical Data: Phase 3 SYMPATICO Study Primary analysis results of the phase 3, international, randomized, double-blind SYMPATICO study showed that treatment with I+V resulted in significantly longer median progression-free survival (PFS) compared with ibrutinib + placebo (I+Pbo) in patients with relapsed/refractory (R/R) MCL and no new safety signals were observed.1 Results from the safety run-in phase of SYMPATICO were previously published.2 • In total, 267 patients were enrolled and randomized to receive I+V (ibrutinib 560 mg once daily + venetoclax with standard 5-week ramp-up) (n=134) or I+Pbo (n=133). Patients received the regimen for 2 years followed by single-agent ibrutinib 560 mg once daily until progressive disease (PD) or intolerable toxicity. o In the I+V arm, the median age was 69 years and 16% of patients had received =3 prior lines of therapy. Blastoid morphology was detected in 14% of the patients, 38% of patients were categorized as high risk sMIPI score, and 46% had bulky disease =5 cm • With median follow-up of 51.2 months (range, 0.1+-61.6): o Median PFS by investigator assessment (primary endpoint): 31.9 months vs 22.1 months for I+V vs I+Pbo, respectively (hazard ratio [HR] 0.65; 95% CI, 0.47-0.88; stratified log-rank P=0.0052). ? PFS benefit with I+V compared to I+Pbo was demonstrated across sensitivity analyses and prespecified subgroups, including, but not limited to mTP53 (HR 0.57; 95% CI, 0.33-0.97) and blastoid variant (HR 0.94; 95% CI, 0.50-1.75). o Median time to next treatment was not reached vs 35.4 months for I+V vs I+Pbo (HR 0.60; 95% CI, 0.40-0.89; P=0.0096). o Complete response rates were: 54% vs 32% for I+V vs I+Pbo (P=0.0004). o Median overall survival (OS, interim analysis) was 44.9 months with I+V vs 38.6 months with I+Pbo [HR 0.85 (95% CI, 0.62-1.19), P=0.3465]. • At median treatment duration of 22.2 months for the I+V arm and 17.7 months for the I+Pbo arm, the most common (=5% in either arm) grade =3 adverse events (AEs) for I+V vs I+Pbo were: neutropenia (31% vs 11%), pneumonia (13% vs 11%), thrombocytopenia (13% vs 8%), anemia (10% vs 3%), diarrhea (8% vs 2%), leukopenia (7% vs 0%), MCL (7% vs 12%), atrial fibrillation (5% vs 5%), COVID-19 (5% vs 1%), and hypertension (4% vs 9%). • AE (including MCL not meeting PD criteria) leading to discontinuation of any treatment occurred in 31% and 36% in the I+V vs I+Pbo cohorts, respectively. • AE leading to dose reduction of any treatment occurred in 36% and 22% of I+V and I+Pbo cohorts, respectively. • There were no reports of clinical tumor lysis syndrome (TLS); laboratory TLS occurred in 5% and 2% of I+V and I+Pbo arms, respectively. • 10 COVID-19 related-AEs leading to death in each arm had no meaningful impact on PFS or OS benefit with I+V as demonstrated by censoring patients with COVID-19 death before PD at last adequate disease assessment.