Phase 1b Results for Subcutaneous Talquetamab Plus Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma

Autor:	Thomas J. Prior, Donna E. Reece, Paula Rodriguez-Otero, Amrita Krishnan, Maria-Victoria Mateos, Bhagirathbhai Dholaria, Parameswaran Hari, Daniel Morillo Giles, Niels W.C.J. van de Donk, Jesús F. San-Miguel, Mark Wade, Ajai Chari, Hartmut Goldschmidt, Alfred L. Garfall, Elham Askari, K. Martin Kortuem, Jenna D. Goldberg, Saad Z. Usmani, Cesar Rodriguez, Raluca Verona, Brendan M. Weiss, Nizar J. Bahlis, Albert Oriol, Shun Xin Wang Lin, Thomas Martin
Rok vydání:	2021
Předmět:	Oncology medicine.medical_specialty business.industry Immunology Daratumumab Cell Biology Hematology medicine.disease Biochemistry Internal medicine Relapsed refractory medicine In patient business Multiple myeloma
Zdroj:	Blood. 138:161-161
ISSN:	1528-0020 0006-4971
DOI:	10.1182/blood-2021-148813
Popis:	Introduction: Novel agents are needed for multiple myeloma (MM), which remains incurable with most patients (pts) relapsing or becoming refractory to standard therapies. Talquetamab (Tal) is a bispecific antibody that binds to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on plasma cells with limited expression in healthy tissue, and CD3 to redirect T cells to GPRC5D-expressing MM cells. Tal monotherapy at the recommended phase 2 dose (RP2D) was well tolerated and yielded an overall response rate of 70% after 6.3 months of follow-up in pts with relapsed/refractory MM (RRMM) in the phase 1 MonumenTAL-1 study; responses were durable and continued to deepen over time. Daratumumab (Dara) is a monoclonal antibody approved for MM treatment that targets CD38 on MM cells, resulting in direct cytotoxicity of MM cells. Dara also impacts immune cell populations, ie, increasing helper and cytotoxic T cells and decreasing suppressive CD38+ immunoregulatory cells. Preclinical studies showed addition of Dara enhanced Tal-mediated lysis of MM cells, suggesting the combination may also increase clinical activity in pts with RRMM. We report initial findings for pts with RRMM who received Tal + Dara in a phase 1b multicohort study (TRIMM-2; NCT04108195). Methods: Eligible pts (aged ≥18 years) were diagnosed with MM and had received ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and an IMiD. Pts were excluded if they had received an anti-CD38 therapy ≤90 days. Subcutaneous (SC) Tal and Dara were administered in 28-day cycles in different dosing cohorts (with step-up dosing for Tal). The primary objectives were to identify the RP2D of Tal in combination with Dara and to characterize the safety of Tal + Dara at the RP2D. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] graded per ASTCT guidelines). Results: As of Jul 23, 2021, 23 pts were administered SC Tal + Dara in separate cohorts: Dara 1800 mg + Tal 400 µg/kg weekly (n=8), + Tal 400 µg/kg biweekly (n=5), and + Tal 800 µg/kg biweekly (n=10). Median follow-up across the Tal + Dara cohorts was 2.9 months (range 0.3-11.2). Median age of pts treated with Tal + Dara was 68 years (range 44-81), and 52.2% were male. Pts had received a median of 6 prior lines of therapy (range 3-18); 82.6% were triple-class exposed (82.6% received prior Dara and 8.7% received prior isatuximab) and 73.9% were penta-drug exposed. Any grade AEs were reported in 95.7% of pts and grade 3/4 AEs in 78.3%. The most frequently reported AEs (≥30% across Tal + Dara cohorts) were dysgeusia (52.2%; all grade 1/2), neutropenia (39.1%; grade 3/4 30.4%), thrombocytopenia (39.1%; grade 3/4 21.7%), anemia (34.8%; grade 3/4 21.7%), CRS (34.8%; all grade 1/2), and skin exfoliation (30.4%; all grade 1/2). The median time to CRS onset was 2.5 days (range 2-4), and the median duration was 2 days (range 1-3). Infections occurred in 34.8% of pts (grade 3/4 17.4%). Skin disorders were reported in 65.2% of pts (grade 3/4 13.0%), including nail disorders in 17.4% (all grade 1/2); these events were manageable and did not lead to treatment discontinuation. Two events of ICANS were reported (a grade 1 event [concurrent with CRS] and a grade 3 event), both of which resolved and did not recur. One pt in the Dara 1800 mg + Tal 400 μg/kg biweekly cohort died due to disease progression. Responses in different dosing cohorts are shown in the Table. The median time to first response across Tal + Dara cohorts was 1.0 month (range 0.9-2.4), and median duration of response was not reached. The pharmacokinetic profile of Tal was similar to that observed in the phase 1 monotherapy study. Tal + Dara treatment resulted in proinflammatory cytokine production and T-cell activation, evidenced by interferon-γ and tumor necrosis factor-α induction and PD-1 and CD38 upregulation on peripheral T cells, respectively. Updated data with longer follow-up will be presented at the congress. Conclusions: Tal in combination with Dara was well tolerated, with a safety profile comparable to the monotherapies, and showed promising efficacy in pts with RRMM. These findings support further clinical development of Tal + Dara combination therapy. Figure 1 Figure 1. Disclosures Chari: BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hari: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Bahlis: Janssen: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos: Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. van de Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding. Dholaria: Janssen: Research Funding; Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau; Pfizer: Research Funding. Garfall: Janssen: Honoraria, Research Funding; GSK: Honoraria; Novartis: Research Funding; Tmunity Therapeutics: Research Funding; Amgen: Honoraria. Goldschmidt: Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grant; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Krishnan: City of Hope Cancer Center: Current Employment; JANSSEN: Consultancy, Research Funding; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; MAGENTA: Consultancy; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Martin: Janssen: Research Funding; Amgen: Research Funding; Oncopeptides: Consultancy; Sanofi: Research Funding; GlaxoSmithKline: Consultancy. Morillo Giles: Janssen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Reece: BMS: Honoraria, Research Funding; GSK: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria. Rodriguez: Takeda: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; BMS: Consultancy, Speakers Bureau. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Usmani: Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; Merck: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding. Verona: Janssen: Current Employment. Wang Lin: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Prior: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Wade: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Weiss: Janssen: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Askari: Janssen: Research Funding.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::e21e6992e7bb9ac4a3e021c2ee7cda56 https://doi.org/10.1182/blood-2021-148813 Zobrazit plný text záznamu