Ibrutinib Plus Venetoclax in Patients With Relapsed/Refractory Mantle Cell Lymphoma: Results From the Safety Run-In Period of the Phase 3 Sympatico Study

Background: Ibrutinib (ibr) is a once-daily Bruton's tyrosine kinase (BTK) inhibitor approved in the US for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. Venetoclax (ven) is a BCL-2 inhibitor approved for pts with CLL or previously untreated AML. Ibr + ven have shown synergistic antitumor activity in preclinical models and complementary clinical activity in early phase studies (Zhao Br J Haematol 2015; Tam NEJM 2018; Jain NEJM 2019). The ongoing phase 3 SYMPATICO study (PCYC-1143-CA, NCT03112174) evaluates the safety and efficacy of ibr + ven in pts with relapsed/refractory (R/R) MCL. A safety run-in (SRI) was conducted to inform whether a 1-month (mo) ibr lead-in would be implemented for the randomized portion of the study; initial data from the SRI evaluating tumor lysis syndrome (TLS) events and dose-limiting toxicities (DLTs) concluded that the study would proceed with concurrent ibr + ven, with no ibr lead-in (Wang ICML 2019). Updated safety and efficacy from the SRI are presented.

Methods: The phase 3 SYMPATICO study is comprised of an open-label SRI and a double-blind randomized period. Key eligibility criteria were pathologically confirmed MCL with measurable disease, 1-5 prior therapies, and no prior treatment with BTK or BCL inhibitors. In the SRI, pts received oral, once-daily 560 mg ibr + ven in a 5-week ramp-up to 400 mg ven. Ibr + ven are dosed concurrently for 2 years; thereafter, ven is discontinued in all pts and ibr is continued until progressive disease (PD) or unacceptable toxicity. The primary endpoint of the SRI was occurrence of TLS events and DLTs. Secondary endpoints included complete response (CR) and partial response (PR) per the 2014 Lugano criteria, progression-free survival (PFS), and duration of response (DOR). Rates of undetectable minimal residual disease (MRD) were assessed in bone marrow and peripheral blood. Efficacy and safety were analyzed by TLS risk (low or high). TP53 mutational status was determined by next-generation sequencing.

Results: Twenty-one pts were enrolled in the SRI, with a median time on study of 22 (range, 2-31) mo. The median age was 68 (range, 53-84) years, and the median number of prior therapies was 2 (range, 1-4); 6 pts were considered at low risk for TLS and 15 pts were considered at high risk for TLS. All pts had at least 1 lesion >2 cm at baseline; 11/21 (52%) had baseline detectable MRD in peripheral blood or bone marrow. Of the 11 pts with available TP53 mutation data, 4 (36%) had mutated TP53. Median time on treatment was 18 (range, <1-28) mo. During the 5-week ven ramp-up, 3 pts had DLTs, and 1 pt at high risk for TLS had a laboratory TLS (Wang ICML 2019); no additional TLS events occurred during follow-up. The most common treatment-emergent adverse events (TEAEs) were diarrhea (n=16 [76%]) and fatigue (n=11 [52%]). Grade 3/4 TEAEs occurred in 17 pts (81%). Four pts (19%) discontinued study drugs because of TEAEs. Two treatment-emergent deaths occurred: 1 from a retroperitoneal hemorrhage unrelated to ibr or ven that was related to disease progression and 1 from COVID-19 in a pt with CR. The overall response rate (ORR) was 81% (17/21) in all pts, with an ORR of 83% (5/6) in the cohort at low risk for TLS and 80% (12/15) in the cohort at high risk for TLS (Figure). Sixty-two percent (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 unevaluable. The median DOR has not been reached (95% CI, 17.5 mo-NE). The median PFS per investigator assessment was not reached (95% CI, 13.7 mo-NE); estimated PFS at 18 mo was 75% (95% CI: 50%-89%) (Figure). All 11 pts with detectable MRD at baseline achieved undetectable MRD, including 7 pts who achieved CRs.

Conclusions: Ibr + ven is an all-oral, once-daily, chemotherapy-free regimen being studied for treatment of pts with R/R MCL. With a median of 22 mo on study, no new safety signals were observed; TLS events and DLTs were rare. Ibr + ven had sustained efficacy, with an ORR of 81%, CR rate of 62%, and the median PFS not reached. All MRD-assessable pts achieved undetectable MRD. The ongoing randomized portion of the SYMPATICO study is evaluating the efficacy and safety of ibr + ven compared with ibr + placebo in pts with R/R MCL; additionally, a single-arm, open-label cohort in previously untreated pts, including pts with TP53 mutations, is ongoing.

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