Type: Oral
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological III
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Clinical Research, Combination therapy, drug development, Therapies, Monoclonal Antibody Therapy
Methods: Patients (Pts) with relapsed or refractory (RR) MCL with ≥1 prior line of therapy (LOT) or treatment-naïve (TN) or RR CLL with ≥1 prior LOT were enrolled. In Part 1 (Dose Escalation in MCL, CLL), multiple doses were evaluated. As a result, Zilo 600 mg IV starting q2wks x3 then q4wks + Ibr 420mg (CLL/SLL) or 560 mg (MCL/MZL) daily dosing was selected as the recommended dosing regimen for use in Part 2 (Dose Expansion) and Part 3 (CLL only; pts randomized 2:1 to receive Zilo+Ibr vs. Ibr alone). The study opened to RR MZL pts with ≥1 prior anti-CD20 based therapy as of June 2022.
Results: Sixty-seven pts (33 MCL and 34 CLL) were treated in Parts 1&2 and 28 pts (CLL) were treated in Part 3 of the study. In Parts 1 and 2, there were 27 RR MCL and 34 CLL (12 TN and 22 RR) efficacy evaluable pts. In Part 3, there were 23 efficacy-evaluable CLL pts randomized to receive either Zilo+Ibr (16) or Ibr (7).
Safety in MCL and CLL: The most frequent (≥30%) treatment emergent adverse events (TEAEs), regardless of causality for all pts treated with Zilo+Ibr (N=85), were fatigue (42.4%), contusion (36.5%), and diarrhea (37.6%). The most frequent (≥5%) Grade ≥3 TEAEs, regardless of causality, were hypertension (10.6%), pneumonia (7.1%), neutropenia (5.9%), atrial fibrillation (5.9%), and fatigue (5.9%). In Parts 1 and 2, grade ≥3 hematologic laboratory abnormalities observed in pts with MCL and CLL, respectively, were neutrophils decrease (9.1% and 17.6%), platelets decrease (12.1% and 2.9%), and hemoglobin decrease (9.1% and 0%).
Efficacy in MCL: The objective response rate (ORR) was 85.2% (40.7% CR, 44.4% PR) with a median duration of response (mDOR) of 34.1 months (mos) (95% CI:13.67, NE). The CR rate was 29.6%, 37% and 40.7% at 6, 12 and 26 mos, respectively. Median PFS (mPFS) was 35.9 mos (95% CI: 17.3, NE) with median follow-up (mf/u) of 15.1 mos and landmark PFS (LPFS) at 30 mos was ~70%. For 6 pts with P53 mutations, the ORR was 83.3% (1 CR, 4 PRs), mDOR was 13.84 mos (11.93, NE), mPFS was 17.3 (95% CI: 2.85, NE) and LPFS at 12 mos was >80%. In patients with Ki67≥30% (14), the ORR was 85.7% (5CRs, 7PRs) with mDOR NR (13.67, NE), for intermediate sMIPI (9) ORR was 88.9% (5 CRs, 3 PRs) with mDOR of 34.13 mos, and for high sMIPI (3) ORR was 66.7% (1 CR, 1PR) with mDOR NR (13.84, NE). Overall survival was not reached (NR; 95% CI: 18.9, NE) and landmark OS at 12 mos was ~90%.
Efficacy in CLL: In Parts 1 and 2, the mPFS had not been reached for all pts with CLL with mf/u of 32.9 mos. The LPFS at 36 mos was 100% for pts with 1-2 prior LOT, ~70% for pts with >2 LOT. From pooled analysis of all Parts, the LPFS at 30 mos was 100% for the 9 pts with P53 alterations. In Part 3, mPFS had not been reached in either group (Zilo+Ibr or Ibr) with mf/u of 24.1 mos
Conclusions: In this study, Zilo+Ibr is well-tolerated with a safety profile that is very similar compared with Ibr alone. With respect to grade ≥3 neutropenia in RR MCL, the rate observed with Zilo+Ibr was 9.1%, which is lower than the 29% reported for Ibr alone in its Phase 3 study. The combination is very promising in pts with RR MCL (ORR 85.2%, CR 40.7%, mPFS 35.9 mos), compared with historical results for Ibr alone (ORR 66%, CR 20%, mPFS 12.8 mos; Rule 2017). For CLL pts with p53 alterations, overall efficacy with Zilo+Ibr is also very promising with LPFS at 30 mos of 100% that almost doubles historic Ibr monotherapy LPFS of ~55% (Byrd 2019). This encouraging exploratory study is ongoing, with the addition of MZL pts, and has provided the impetus for a Phase 3 registrational study evaluating Zilo+Ibr in MCL (ZILO-301).
Disclosures: Lee: Guidepoint Global: Honoraria; Pharmcyclics: Research Funding; Deloitte: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Briston-Myers Squibb: Research Funding; Janssen: Honoraria; Korean Society of Cardiology: Honoraria; Cancer Experts: Honoraria; Curio Science: Honoraria; Octernal Therapeutics: Research Funding; Seagen: Research Funding; Olson Research: Honoraria; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Honoraria. Choi: Abbvie, TG Therapeutics, Geron, Merck, Oncternal, Pharmacyclics: Research Funding. Siddiqi: Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PCYC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; Oncternal: Research Funding; TG Therapeutics: Research Funding. Rhodes: Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; SeaGen: Consultancy; Beigene: Consultancy; TG Therapeutics: Consultancy; Abbive: Consultancy; Genmab: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Oncternal: Research Funding; Morphosys: Consultancy; Loxo Oncology: Research Funding; Velosbios: Research Funding; Epizyme: Research Funding. Wierda: Loxo Oncology, Inc./Lilly: Research Funding; Karyopharm: Research Funding; Juno: Research Funding; Kite, a Gilead Company: Research Funding; Bristol Meyers Squibb (Juno and Celgene): Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Janssen: Research Funding; Genzyme: Consultancy; GSK/Novartis: Research Funding; Cyclacel: Research Funding; AstraZeneca/Acerta Pharma. Inc.: Research Funding; Gilead Sciences: Research Funding; Sanofi: Consultancy; Xencor: Research Funding; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; AbbVie: Research Funding. Isufi: BEAM Therapeutics: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite: Speakers Bureau. Tuscano: BMS: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Celgene: Research Funding; ADC therapeutics: Research Funding; Achrotech: Research Funding. Lamanna: AstraZenenca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo Oncology/Eli Lilly and Company: Research Funding; Mingsight: Research Funding; Octapharma: Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding. Koff: Atara BioTherapeutics: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Oncternal Therapeutics: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Viracta Therapeutics: Research Funding. Breitmeyer: Oncternal Therapeutics: Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Otonomy Inc: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Yazji: Oncternal Therapeutics: Current Employment. Wang: AbbVie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; BioInvent: Consultancy, Honoraria, Research Funding; CStone: Consultancy; BeiGene: Consultancy, Honoraria, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; Deciphera: Consultancy; Epizyme: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Leukemia & Lymphoma Society LLC: Consultancy, Honoraria; Lilly: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Oncternal: Consultancy, Research Funding; Pepromene Bio: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; VelosBio: Consultancy, Research Funding; Acerta Pharma: Honoraria, Research Funding; Celgene: Research Funding; Genmab: Research Funding; Molecular Templates: Research Funding; Vincerx: Research Funding; Anticancer Association: Honoraria; Clinical Care Options: Honoraria; Dava Oncology: Honoraria; Eastern Virginia Medical School: Honoraria; TS Oncology: Honoraria; Medscape: Honoraria; Meeting Minds Experts: Honoraria; Moffit Cancer Center: Honoraria; Mumbai Hematology Group: Honoraria; OMI: Honoraria; OncLive: Honoraria; Physicians Education Resources (PER): Honoraria; Practice Point Communications (PPC): Honoraria; First Hospital Zhejiang University: Honoraria; BGICS: Honoraria; CAHON: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Imedex: Honoraria; LLC TS Oncology: Honoraria. Jamieson: Aspera Biomedicines, Impact Biomedicines,: Consultancy, Other: co-founder of Aspera Biomedicines and Impact Biomedicines and has received royalties for intellectual property licensed by Forty Seven Inc, Patents & Royalties: Forty Seven Inc. Kipps: AbbVie: Consultancy, Research Funding; Genentech-Roch: Consultancy, Research Funding; Gilead: Consultancy; Pharmacyclics, LLC an AbbVie Company: Consultancy, Research Funding; Celgene: Consultancy; Oncternal: Research Funding.