Efficacy and safety of first-line ibrutinib plus venetoclax in patients with mantle cell lymphoma (MCL) who were older or had <i>TP53</i> mutations in the SYMPATICO study.

7017 Background: The phase 3 SYMPATICO study evaluated ibrutinib (Ibr) combined with venetoclax (Ven) in 3 cohorts of patients (pts) with MCL: an open-label safety run-in phase to evaluate concurrent initiation of Ibr+Ven in relapsed/refractory (R/R) MCL; a randomized phase to evaluate Ibr+Ven vs Ibr+placebo (Pbo) in R/R MCL; and an open-label cohort to evaluate first-line Ibr+Ven in treatment-naive (TN) MCL. Primary analysis of the randomized phase showed superior PFS with Ibr+Ven vs Ibr+Pbo in pts with R/R MCL (Wang M et al, Lancet Oncol , in press). Here, we report efficacy and safety of Ibr+Ven in pts with TN MCL in older pts (≥65 y) or younger pts with a TP53 mutation ( TP53 mut) (≥18 y) who are in need of novel and better tolerated treatment options. Methods: Older pts (≥65 y) or pts with a TP53 mut with TN MCL received oral Ibr 560 mg once daily and Ven (5-wk ramp-up to 400 mg once daily) for 2 y, then single-agent Ibr 560 mg until PD or unacceptable toxicity. Primary endpoint was complete response (CR) rate assessed by investigator per Lugano. Key secondary endpoints included overall response rate (ORR), duration of response (DOR), PFS, OS, and time to next treatment. Subgroup analyses were performed according to TP53 mut status and age. Results: In total, 78 TN MCL pts were enrolled. At baseline, 83% of pts were ≥65 y, 97% had ECOG PS of 0–1, 45% had high-risk simplified MIPI score, 31% had bulky disease (≥5 cm), 78% had bone marrow involvement, 46% had splenomegaly, and 37% had TP53 mut. Median time on study was 40.5 mo (range, 0.6+–46.9). CR rate was 69% (95% CI, 58–79), and ORR was 95% (95% CI, 87–99). Median DOR was 37.1 mo (95% CI, 30.3–NE). Median PFS was 40.2 mo, and 3-y OS was 79%. CR rate was 76% in pts ≥65 y without TP53 mut, 44% in pts ≥65 y with TP53 mut, and 73% in pts &lt;65 y with TP53 mut; median PFS was 40.2, 22.0, and 15.4 mo, and 3-y OS was 85%, 66%, and 73%, respectively (Table). Median duration of treatment was 24.0 mo (range, 0.3–46.9). Most common AEs were diarrhea (49%), fatigue (37%), neutropenia (35%), and COVID-19 (32%). Most common grade ≥3 AE was neutropenia (29%). Conclusions: First-line Ibr+Ven showed promising efficacy with high CR rates and durable remissions in pts with TN MCL with and without TP53 mut. Safety was acceptable and trended better in younger pts. Ibr+Ven may be an option for older pts with TN MCL or pts of any age with TP53 mut. Clinical trial information: NCT03112174 . Outcomes (95% CI) Without TP53 mutn=44 With TP53 mut n=29 ≥65 y without TP53 mutn=42 ≥65 y with TP53 mutn=18 &lt;65 y without TP53 mutn=2 &lt;65 y with TP53 mutn=11 TotalN=78 CR rate, % 77(62–89) 55(36–74) 76(61–88) 44(22–69) 100(16–100) 73(39–94) 69(58–79) ORR, % 98(88–100) 90(73–98) 98(87–100) 89(65–99) 100(16–100) 91(59–100) 95(87–99) Median PFS, mo 40.2 (37.2–NE) 22.0(9.2–NE) 40.2(37.2–NE) 22.0(11.3–NE) NR(11.1–NE) 15.4(8.2–NE) 40.2(29.4–NE) 3-y OS, % 86(71–93) 68(47–82) 85(70–93) 66(39–83) 100(100–100) 73(37–90) 79(68–86)