DREAMM-5 Study: Investigating the Synergetic Effects of Belantamab Mafodotin Plus Inducible T-Cell Co-Stimulator Agonist (aICOS) Combination Therapy in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Callander Natalie S. , Ribrag Vincent , Richardson Paul G. , Nooka Ajay K. , Song Kevin , Uttervall Katarina , Minnema Monique C. , Weisel Katja , Quach Hang , Min Chang-Ki , Ballas Marc S. , Li Xiaofang , Ratia Nirav , Kaisermann Morrys , Holkova Beata , Trudel Suzanne 
Published: November 2021

Introduction: Single-agent belantamab mafodotin (belamaf), a B-cell maturation antigen-targeting antibody-drug conjugate, achieved durable responses with a manageable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) in the Phase 2 DREAMM-2 trial (NCT03525678). The DREAMM-5 platform trial (208887; NCT04126200) is evaluating belamaf as combination therapy with other anticancer agents to determine if belamaf's unique multimodal mechanism of action (MoA) is synergistic with MoAs of selected agents to further augment efficacy in RRMM. In this substudy, belamaf is combined with feladilimab (GSK3359609), an inducible co-stimulatory T-cell molecule (ICOS, CD278) agonist (aICOS).

Methods: DREAMM-5 is an ongoing Phase 1/2 platform trial. Each platform substudy consists of a dose-exploration (DE) phase to identify effective belamaf combinations followed by a cohort-expansion (CE) phase to compare the combination with a shared single-agent belamaf control arm. The primary and secondary objectives of the DE phase are to determine the safety/tolerability and preliminary efficacy, respectively, of the combination therapy as well as to establish the recommended Phase 2 dose (RP2D) for the CE phase based on these data. A preliminary analysis of safety, pharmacokinetic, biomarker, and efficacy data performed at the end of the DE phase will determine if it should move forward to the CE phase. This is a preliminary analysis of data from patients in the DE phase of the DREAMM-5 belantamab mafodotin and aICOS substudy.

Patients are assigned to one of 3 belamaf + aICOS DE cohorts by a predetermined algorithm (N≤10 per cohort): belamaf (1.9 mg/kg or 2.5 mg/kg) + aICOS (8 mg) or belamaf (2.5 mg/kg) plus aICOS (24 mg). In cohort A, the starting dose of belamaf (1.9 mg/kg) and aICOS (8 mg) is administered to 3 patients, starting with a sentinel patient and expanding to the second and third patient consecutively over the course of at least 10 days. Cohort B (belamaf 2.5 mg/kg and aICOS 8 mg) and cohort C (belamaf 2.5 mg/kg and aICOS 24 mg) are only evaluated after the lower doses for each treatment clear the dose-limiting criteria for the first 3 patients.

Results: A total of 23 patients treated with belamaf + aICOS were included in this preliminary analysis. The median (range) of prior lines of therapy was 5 (3-10). The majority of patients (21 [91%]) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 and the remainder (2 [9%]) had an ECOG PS of 2. Thirty percent of patients (n=7) had high-risk cytogenetics, and no patients had extramedullary disease.

The preliminary overall clinical response rate for the total population was 48% (n=11; 95% CI: 26.8-69.4), with 26% of patients (n=6) achieving a very good partial response or better (Table).

Nineteen patients (83%) of the total population experienced an adverse event (AE) related to study treatment and 12 patients (52%) experienced Grade ≥3 AEs related to study treatment. A total of 16 patients (70%) in the total population experienced any grade ocular AEs while 9 patients (39%) had Grade ≥3 ocular AEs related to study treatment. Only 2 patients (1 each from cohorts A and B) permanently discontinued study treatment due to AEs. Dose reductions and delays were used to manage AEs in several patients (Table).

Conclusion: In this preliminary analysis, belamaf combined with aICOS showed encouraging clinical activity along with a safety profile that was manageable through dose modifications in heavily pretreated patients with RRMM. Evaluating the efficacy and safety of belamaf + aICOS combination therapy as well as establishing the RP2D for the CE phase is ongoing in this substudy.

Funding: GSK (Study 208887); belamaf drug linker technology licensed from Seagen; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Figure 1 Figure 1.

Disclosures

Ribrag: Nanostring: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Epizyme: Honoraria, Research Funding. Richardson: Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Secura Bio: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Nooka: Amgen: Consultancy, Research Funding; Adaptive technologies: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Oncology: Consultancy, Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Other: Travel expenses; Oncopeptides: Consultancy. Song: GlaxoSmithKline: Honoraria; Kite, a Gilead Company: Honoraria; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Minnema: BMS: Honoraria; Jansen-Cilag: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy; Celgene: Other: Hospitality. Weisel: Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, 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, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Quach: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, 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, Research Funding. Ballas: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Li: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ratia: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Kaisermann: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Holkova: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Trudel: Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Genentech: Research Funding; Amgen Canada: Honoraria; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.