Phase 1/2 Study of Polatuzumab in Combination with Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR-P) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Preliminary Safety, Efficacy, and Molecular Analysis

Background: Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) pts, especially those who are not cured with CAR-T, have poor outcome. Targeted agents can disrupt key survival pathways in DLBCL, but rarely induce durable responses as monotherapy. We previously showed combination targeted therapy (ViPOR) is safe and able to induce durable remission in R/R non-GCB DLBCL and HGBCL-DH-BCL2 (Melani. NEJM. 2024). Furthermore, we observed synergistic cytotoxicity with MMAE, the chemotherapy payload of Polatuzumab (POLA), and the ViPOR agents in DLBCL cell lines (Staudt lab, unpublished). We also noted differential sensitivity to POLA in ABC vs GCB DLBCL secondary to CD79B glycosylation and expression (Corcoran. Cancer Discov. 2024). We hypothesized that adding POLA to ViPOR will further improve efficacy, especially in non-GCB DLBCL, and time-limited, cyclic dosing will limit toxicity.

Methods: R/R DLBCL pts with adequate organ function are eligible. In Ph 1, a “3+3” design is used to determine the recommended phase 2 dose (RP2D) of POLA IV D2 and venetoclax (VEN) PO D2-14 at 3 dose levels (DLs) (DL1: 1.4 mg/kg + 600 mg, DL2: 1.8 mg/kg + 600 mg, and DL3: 1.8 mg/kg + 800 mg) with fixed-dose ibrutinib, prednisone, obinutuzumab, and lenalidomide as previously published. A Ph 2 expansion cohort, enriched for non-GCB DLBCL, is included at the RP2D. ViPOR-P q21d x 6C is given without maintenance or consolidation. All pts receive TLS, PCP, HSV, and G-CSF prophylaxis (ppx) with VTE ppx per PI discretion. Baseline CT, PET, BM, and tumor biopsy is performed with CT scans after C2, C4, and C6 and PET after C6. Surveillance CT is then performed q3m x 1y, q4m x 1y, q6m x 1y, then annually x 2y. Minimal residual disease (MRD) is assessed in plasma ctDNA using clonoSEQ at baseline, during treatment, and in f/u.

Results: 32 DLBCL pts (15 in Ph 1 & 17 in Ph 2) have been enrolled. Median age is 55y (range, 23-83) with 72% male pts. 17 (53%) pts had non-GCB DLBCL, 11 (34%) HGBCL-DH-BCL2, 2 (6%) HGBCL-DH-BCL6, and 1 (3%) pt each with GCB DLBCL and THRLBCL. 7 (22%) pts had transformed lymphoma. Stage III/IV disease was noted in 84% and 56% of pts had an IPI score >3. Median prior therapies was 2 (range, 1-6), with prior CAR-T in 44% and 56% of pts refractory per SCHOLAR-1 criteria.

One dose-limiting toxicity (DLT) of G4 thrombocytopenia >7d occurred at DL3 with no other DLTs observed, thus DL3 was identified as the RP2D. Hematologic AEs were most common and included G3-4 (% cycles) thrombocytopenia (27%), neutropenia (21%), and anemia (10%), with 2 events of febrile neutropenia among 126 total cycles. Non-hematologic AEs (% pts) of any grade included hypokalemia (94%), diarrhea (77%), nausea (48%), and elevated LFTs (48%), with the only G3-4 non-hematologic AE in >10% of pts being hypokalemia (26%). G1-2 neuropathy was seen in 9 (29%) pts with no G3-4 neuropathy observed. 1 TLS event occurred and resolved after temporary HD, and there was no treatment-related mortality. Dose reductions and delays occurred in 10% and 8% of cycles, respectively, and 3 pts prematurely stopped therapy due to toxicity or illness.

In 28 evaluable DLBCL pts off-treatment, overall response rate was 75% (21/28) with 50% (14/28) complete responses (CR). CR rate was 63% (10/16) in non-GCB and 33% (4/12) in GCB DLBCL by IHC, with GCB CRs only seen in HGBCL-DH-BCL2 (36%, 4/11) and HGBCL-DH-BCL6 (100%, 2/2). By RNA-seq, CR rate was 86% (6/7) in ABC, 45% (5/11) in GCB, and 100% (1/1) in unclassified DLBCL. In refractory and post-CAR-T pts, CR rate was 38% (6/16) and 33% (4/12), respectively. With a median f/u of 22.6m, 57% of CRs are ongoing with a 2y (95% CI) progression-free survival (PFS) and overall survival of 36% (18-54) and 53% (32-71), respectively. 2y PFS was 45% in non-GCB and 25% in GCB DLBCL by IHC, and 71% in ABC and 27% in GCB DLBCL by RNA-seq. In post-CAR-T and refractory pts, 2y PFS was 27% and 22%, respectively.

Conclusion: ViPOR-P is safe without notable additional toxicity, especially neutropenia and neuropathy, compared to ViPOR, and DL3 was identified as the RP2D. Most AEs were hematologic and manageable with G-CSF with rare febrile neutropenia observed. Fixed-duration ViPOR-P x 6C without maintenance resulted in durable CRs, especially in pts with non-GCB DLBCL by IHC and ABC DLBCL by RNA-seq, including refractory and post-CAR-T pts. Molecular and MRD analyses are ongoing, and enrollment continues to assess whether ViPOR-P improves CR rate compared to ViPOR alone in R/R non-GCB DLBCL.