Constantine S. Tam, MD from Peter MacCallum Cancer Centre and St. Vincent’s Hospital and the University of Melbourne discusses the ASH 2020 Abstract – 2938 Ibrutinib Plus Venetoclax in Patients With Relapsed/Refractory Mantle Cell Lymphoma: Results From the Safety Run-In Period of the Phase 3 Sympatico Study.
Context:
Ibrutinib (ibr) is an inhibitor of Bruton’s tyrosine kinase (BTK) that is approved in the United States once daily for patients (pts) with mantle cell lymphoma (MCL) who have undergone approximately 1 previous therapy. Venetoclax (ven) is approved for pts with CLL or previously untreated AML as a BCL-2 inhibitor. In early-phase trials, Ibr+ven demonstrated synergistic antitumor activity in preclinical models and complementary clinical activity (Zhao Br J Haematol 2015; Tam NEJM 2018; Jain NEJM 2019). The ongoing phase 3 SYMPATICO (PCYC-1143-CA, NCT03112174) research assesses the protection and effectiveness of ibr+ven in relapsed/refractory (R/R) MCL pts. A safety run-in (SRI) was performed to inform whether for the randomized portion of the study a 1-month (mo) ibr lead-in would be introduced; initial results from the SRI assessing tumor lysis syndrome (TLS) events and dose-limiting toxicities (DLTs) indicated that the study would continue with simultaneous ibr + ven, without ibr lead-in (Wang ICML 2019). Protection and efficacy reports from the SRI are given.Â
Protection and efficacy reports from the SRI are given. Â
Methods:Â
Pathologically verified MCL with detectable illness, 1-5 previous treatments, and no prior treatment with BTK or BCL inhibitors were the main eligibility requirements. In the SRI, pts are administered orally, 560 mg ibr + ven once daily in a 5-week ramp-up to 400 mg ven. Thereafter, ven is discontinued in all pts and ibr is continued until progressive disease (PD) or unacceptable toxicity. Ibr + ven is dosed simultaneously for 2 years. The primary SRI endpoint was the frequency of DLTs and TLS cases. Absolute response (CR) and partial response (PR) per the 2014 Lugano criteria, progression-free survival (PFS) and length of response were secondary endpoints (DOR). In bone marrow and peripheral blood, concentrations of undetectable minimum residual disease (MRD) have been measured. Efficacy and protection were assessed by TLS risk risk analysis (low or high). Next-generation sequencing determined the TP53 mutational status.
Outcomes:
The SRI included twenty-one pts, with a median study period of 22 (range, 2-31) mo. The median age was 68 (range, 53-84) years, and 2 (range, 1-4) were the median number of previous therapies; 6 pts were considered low TLS risk and 15 pts were considered high TLS risk. All pts had at least 1 lesion >2 cm at baseline; 11/21 (52 percent) had peripheral blood or bone marrow observable MRD at baseline. Of the 11 pts with TP53 mutation data available, 4 (36%) had TP53 mutated. The median therapy time was 18 (range, <1-28) mo. 3 pts had DLTs during the 5-week ven ramp-up, and 1 pt had a laboratory TLS (Wang ICML 2019) at high risk for TLS; no additional TLS events occurred during follow-up. Diarrhea (n=16 [76 percent]) and fatigue (n=11 [52 percent]) were the most common treatment-emergent adverse events (TEAEs). In 17 pts, Grade 3/4 TEAEs occurred (81 percent ). Thanks to TEAEs, four pts (19 per cent) discontinued research drugs. There were two treatment-emergent deaths: 1 from retroperitoneal hemorrhage unrelated to ibr or ven, consistent with progression of the disease, and 1 from COVID-19 at pt with CR. The overall response rate (ORR) for all pts was 81% (17/21), with an ORR of 83% (5/6) for the low-risk cohort for TLS and 80% (12/15) for the high-risk cohort for TLS (Figure). 62% (13/21) of pts had CR (low risk for TLS, 67% [4/6]; high risk for TLS, 60% [9/15]), 19% (4/21) of pts had PR (low risk for TLS, 17% [1/6]; high risk for TLS, 20% [3/15]); 5% (1/21) of all pts had stable disease, and 10% (2/21) had PD; 1 pt was invaluable. The median DOR (95 percent CI, 17.5 mo-NE) has not been achieved. The median PFS was not achieved per investigator evaluation (95 percent CI, 13.7 mo-NE); the estimated PFS was 75 percent (95 percent CI: 50 percent-89 percent) at 18 mo; (Figure). At baseline, all 11 pts with measurable MRD met undetectable MRD, including 7 pts that achieved CRs.
Findings: Conclusions:
Ibr + ven is an all-oral, once-daily, chemotherapy-free protocol being tested for R/R MCL pts treatment. No new safety signals were found with a median of 22 moon study; TLS events and DLTs were uncommon. Ibr + ven had sustained effectiveness, with an ORR of 81 percent, a 62 percent CR average, and no median PFS. Undetectable MRD was reached by all MRD-assessable pts. The ongoing randomized portion of the SYMPATICO study assesses the effectiveness and protection of ibr+ven compared to ibr+placebo in pts with R/R MCL; a single-arm open-label cohort is also ongoing in previously untreated pts, including pts with TP53 mutations.