Belamaf, an antibody-drug conjugate targeting B-cell maturation antigen, induced deep and durable responses in patients with RRMM in the DREAMM-2 trial (NCT03525678).
To evaluate single-agent belamaf ...vs the doublet Pd in adults with RRMM (second relapse or later) in the phase III, open-label, randomized, multicenter DREAMM-3 trial (NCT04162210).
Patients were randomized (2:1) to belamaf 2.5 mg/kg intravenously every 3 weeks or Pd (pomalidomide 4 mg/day orally on days 1–21 of each 28-day cycle; dexamethasone 40 mg orally 20 mg if >75 years once weekly). Primary endpoint was progression-free survival (PFS).
Overall, 325 patients were enrolled (belamaf, n=218; Pd, n=107). Median age was 68 years. Median duration of exposure was 4.1 months for belamaf and 5.3 months for Pd. Median follow up was 11.5 months and 10.8 months. Median PFS was 11.2 months for belamaf and 7.0 months for Pd, but the HR (1.03) was not statistically significant (P=0.558). Overall response rates were similar (belamaf, 41%; Pd, 36%); however, rates of very good partial response or better were 25% and 8%. Median (range) duration of response for belamaf was more durable: not reached (NR) (17.9–NR) for belamaf and 8.5 (7.6–NR) months for Pd. At 12 months, the probability of maintaining a response was 77% (belamaf) and 50% (Pd). Median PFS from randomization to progression on subsequent line of therapy (PFS2) was 18.7 months for belamaf and 12.7 months for Pd. Overall survival (OS) data were immature (37.5% overall maturity at primary analysis; median OS, 21.2 months for belamaf and 21.1 for Pd HR=1.14; P=0.746). No new safety signals were reported; ocular toxicity was successfully managed with dose modifications.
While PFS superiority was not demonstrated, single-agent belamaf induced deeper and more durable responses than the Pd doublet. No new safety signals were observed. Patient-reported outcomes will be presented. Belamaf continues to be investigated in combination with established and novel agents.
The International Staging System (ISS) underwent revision to include high-risk chromosomal abnormalities (R-ISS), and recently, to assign a score for each risk feature, including 1q21+ (R2-ISS), ...providing better discrimination in patients (pts) with intermediate-risk multiple myeloma (MM).
To validate the R2-ISS in pts with relapsed/refractory MM (RRMM) and in pts treated with anti-CD38 monoclonal antibodies (mAb), using Phase 3 ICARIA-MM and IKEMA study data.
Pts from the treatment (triplet) and control (doublet) arms were pooled for both the ICARIA-MM (isatuximab–pomalidomide–dexamethasone; Isa-Pd vs Pd) and IKEMA (Isa–carfilzomib–d; Isa-Kd vs Kd) studies. Pts were classified based on R2-ISS (score of 0 = Stage I; 0.5–1.0 = Stage 2; 1.5–2.5 is Stage 3; and >3.0 = Stage 4).
Hazard ratios (HR) and corresponding confidence intervals (CI) were estimated using the Cox proportional hazards model.
Of 609 pts, 68 were classified as Stage 1; 136, Stage 2; 204, Stage 3; 55, Stage 4; and 146 were not classified. Progression-free survival (PFS) decreased with increasing stage (Stage 2, median mPFS 21.2 months HR 1.52; 95% CI: 0.979–2.358; Stage 3, mPFS 12.2 months HR 2.59; 95% CI: 1.709–3.923; and Stage 4, mPFS 7.0 months HR 3.51; 95% CI, 2.124–5.784 vs Stage 1, mPFS 38.8 months). Pts receiving Isa-based triplet therapy had longer PFS vs those receiving doublet therapy (mPFS 23.9 vs 11.8 months HR 0.544; 95% CI, 0.436–0.680), which was seen for all R2-ISS stages. In an exploratory overall survival (OS) analysis including final ICARIA-MM and immature IKEMA data, OS also decreased with increasing stage (Stage 2, mOS not reached NR; HR 1.3; 95% CI 0.78–2.18; Stage 3, mOS 27.5 months HR 2.77; 95% CI, 1.730–4.450; and Stage 4, mOS 11.3 months HR 4.25; 95% CI, 2.480–7.269 vs Stage 1, mOS NR).
For the first time, these data independently validate the prognostic value of the R2-ISS staging system in pts with RRMM, and in pts treated with anti-CD38 mAb. Isa-based triplet therapy led to improved PFS regardless of R2-ISS stage vs the doublet.
Abstract
Introduction: Rituximab (R)-based therapies are standard for patients (pts) with relapsed advanced iNHL. Copanlisib (C) is a PI3K inhibitor approved as monotherapy for relapsed follicular ...lymphoma (FL) in pts who have had ≥2 prior systemic therapies. We report primary data from the Phase III CHRONOS-3 study of treatment with C+R vs placebo (P)+R in relapsed iNHL (NCT02367040).
Methods: Pts with relapsed iNHL who were progression-free and treatment-free for ≥12 months (mo) after last R-based therapy or unwilling/unfit to receive chemotherapy were randomized 2:1 to receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15 (28-day cycle); R 375 mg/m2 was given i.v. on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint: centrally assessed progression-free survival (PFS). Secondary endpoints: objective response rate (ORR), duration of response, complete response rate (CRR), overall survival (OS), and treatment-emergent adverse events (TEAEs). The data cut-off date was August 31, 2020.
Results: 307 pts were randomized to C+R and 151 to P+R. FL was the most common lymphoma histology subtype (60.0%), followed by marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM, 8.3%). Median age was 63 years (range 28-91). With a median follow-up of 19.2 mo, the primary study endpoint was met: C+R significantly reduced the risk of disease progression/death vs P+R (hazard ratio HR 0.52 95% CI 0.39, 0.69; 1-sided p=0.000002); median PFS was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5), respectively. Reductions in risk of progression/death were seen across all histology subtypes (HR 95% CI): FL 0.580 0.404, 0.833; MZL 0.475 0.245, 0.923; SLL 0.243 0.111, 0.530; LPL/WM 0.443 0.160, 1.231. ORRs were 80.8% (CRR 33.9%) for C+R and 47.7% (CRR 14.6%) for P+R. Higher ORRs and CRRs were seen across all iNHL subtypes with C+R treatment. Median OS was not estimable. Most common TEAEs (all grades G/G3+) in pts receiving C+R were hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% all G3), and diarrhea (33.6%/4.9% all G3). For pts receiving P+R, hyperglycemia (23.3%/8.2% all G3), hypertension (19.2%/8.9% all G3), neutropenia (16.4%/12.3%), and upper respiratory tract infection (16.4%/0%) were the most common TEAEs. Serious adverse events were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in 6 pts (2.0%) receiving C+R (1 0.3% deemed treatment-related; pneumonitis) and 1 (0.7%) receiving P+R.
Conclusions: C+R demonstrated broad and superior efficacy vs P+R in pts with relapsed iNHL. The safety profile of C+R was manageable and consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed iNHL, representing a potential new therapy option for relapsed iNHL across all subtypes.
Citation Format: Matthew J. Matasar, Marcelo Capra, Muhit Özcan, Fangfang Lv, Wei Li, Eduardo Yañez, Katya Sapunarova, Tongyu Lin, Jie Jin, Wojciech Jurczak, Aryan Hamed, Ming-Chung Wang, Ross Baker, Igor Bondarenko, Qingyuan Zhang, Jifeng Feng, Klaus Geissler, Mihaela Lazaroiu, Guray Saydam, Árpád Szomor, Krimo Bouabdallah, Rinat Galiulin, Toshiki Uchida, Lidia Mongay Soler, Anjun Cao, Florian Hiemeyer, Aruna Mehra, Barrett H. Childs, Yuankai Shi, Pier Luigi Zinzani. CHRONOS-3: Randomized Phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT001.
Background: Isatuximab (ISA) targets CD38-expressing tumor cells through a combination of activities, including antibody-dependent cellular cytotoxicity, direct pro-apoptotic activity, and ...complement-dependent cytotoxicity. A phase I study evaluating ISA monotherapy demonstrated promising clinical activity in 35 patients with relapsed/refractory multiple myeloma (RRMM) (Martin T et al, J Clin Oncol 2014; 32:8532). This is an ongoing phase II study (NCT01084252) with 2 stages: stage 1 to select the dose for stage 2 of the study, and stage 2 to assess efficacy and safety of ISA monotherapy or in combination with dexamethasone in RRMM. In stage 1, patients were randomized to 1 of 3 dose groups: ISA 3 mg/kg Q2W, 10 mg/kg Q2W × 2 cycles then Q4W, or 10 mg/kg Q2W. Based on pharmacokinetic data, a fourth dose of 20 mg/kg QW × 4 doses then Q2W was added. The overall response rates (ORRs) for the 4 dosing schemes were 4% (1/23), 20% (5/25), 29% (7/24), and 24% (6/25), respectively. Based on these results, a dose of 20 mg/kg QW for cycle 1 followed by 20 mg/kg Q2W in subsequent cycles was chosen for stage 2 of the study (Richter J et al, J Clin Oncol 2016;34:8005). Here, we report the baseline characteristics and demographic data from stage 2 at the selected dosing scheme from stage 1. Full safety and efficacy data will be presented at the meeting.
Methods: This study enrolled patients with MM who had previously received an immunomodulatory drug and a proteasome inhibitor. Patients received ISA monotherapy (20 mg/kg on Day 1, 8, 15, and 22 QW of cycle 1 followed by 20 mg/kg on Day 1 and 15 Q2W of subsequent cycles) or ISA in combination with dexamethasone (40 mg/day 20 mg/day in patients ≥75 years old). The primary objective was to evaluate the activity of ISA as monotherapy and in combination with dexamethasone in patients with RRMM in terms of ORR.
Results: A total of 165 patients received at least 1 cycle of treatment. Median age was 67 (37-85) years. Median time from diagnosis to first dose was 5.35 (0.7-23.0) years. Median number of prior lines was 4 (2-11) and median number of prior regimens was 6 (2-17). Patients received a median of 5 (1-17) cycles of treatment, with a median duration of exposure of 22 (1-69) weeks. Discontinuation occurred in 106 (64.2%) patients due to adverse events (15 patients, 9.1%), disease progression (85 patients, 51.5%), or patient decision (6 patients, 3.6%).
Conclusion: The full efficacy and safety data for this heavily pre-treated RRMM population will be available for presentation at the meeting.
Funding: Sanofi
Dimopoulos:Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Capra:Janssen: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria. Hungria:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Jenner:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vorobyev:Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Biocad: Consultancy; Takeda: Speakers Bureau; BMS: Speakers Bureau; Astellas: Speakers Bureau. Yanez Ruiz:Universidad de la Frontera: Employment. Yin:Sanofi: Employment. Hamlett:BDM Consulting Inc.: Employment; Sanofi: Consultancy. Vij:Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Background: EBV-positive (EBV+) cells are detectable in a variable but significant fraction of lymphomas of all lineages and histologic type by in situ hybridization for EBV-encoded RNA (EBER-ISH). ...EBV positivity generally confers a worse prognosis in lymphoma but, with the exception of adoptive T-cell therapies, no EBV-targeting mechanism-based anti-lymphoma therapeutics are in development. EBV's DNA genome encodes a viral thymidine kinase (vTK, BXLF1) and a serine/threonine protein kinase (PK, BGLF4), which are expressed only during lytic cycle, and can activate anti-viral nucleoside analogues via mono-phosphorylation, leading to inhibition of EBV DNA synthesis. Nstat is able to induce the expression of PK/BGLF4 and vTK/BXLF1. This effect supports the mechanism-based strategy of leveraging EBV's presence in lymphoma by combining Nstat with VGCV, the oral prodrug for ganciclovir (GCV). EBV's PK phosphorylates GCV, which inhibits both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells (bystander effect). Based on this targeted approach, a phase 1b/2a trial was launched to determine the safety and activity of this combination in R/R EBV+ lymphomas of various lineages and histology. Here we report the phase 1b results.
Methods: Eligible patients had biopsy-proven R/R EBV+ lymphoma by EBER-ISH (any positive cell) and had failed ≥1 prior systemic therapy. Phase 1b followed a 3+3 design over 5 dose ranging cohorts. The phase 1b primary objectives were safety/tolerability of Nstat/VGCV and recommended phase 2 dose (RP2D). In cohorts 1-4, variable doses of Nstat and VGCV were administered orally continuously on 28-day cycles. In cohort 5 Nstat was administered for the first 4 days of each week with daily VGCV. Toxicity was assessed by CTCAE 5.0. Efficacy was assessed by local and central radiology every 2 cycles by PET/CT (Lugano 2014 Classification). Correlative studies for phase 1b include PK/PD and other exploratory biomarkers.
Results: Phase 1b enrolled 25 patients. The median age was 58 (19-84) with 72% males. Thirteen patients had either EBV+ T/NK-cell lymphoma (N=8; 5 TCL, 3 NKL), or Hodgkin lymphoma (HL) (N=5). Twelve patients had EBV+ B-cell lymphoma (BCL) (Table 1), of which 4 were HIV+ and 3 had a history of PTLD. Median number of prior therapies was 2 (1-9). Two patients with TCL had failed prior HDACi therapy. In cohorts 1-4, the most frequent treatment related hematologic grade 3-4 (G3-4) adverse events (AE) were thrombocytopenia (35%), neutropenia (25%), and lymphopenia (15%), none of which occurred at G3-4 in cohort 5. No non-hematologic G3-G4 AE were observed in >10% of patients in any cohort and no patient discontinued therapy due to AE. The RP2D was declared to be Nstat 20 mg days 1-4 each week and VGCV 900 mg daily on a 28-day cycle. At the RP2D there have been no G3-4AE.
Seventeen patients are evaluable for response (8 BCL 5 T/NK, 4 HL). ORR was 53% (9/17), with 29% CRR (5/17). The Clinical Benefit Rate (CBR; CR/PR/Stable Disease) was 76% (13/17). Responses were seen across histologic subtypes and in heavily pre-treated patients. Durable responses were observed (one >12 months and one >10 months). For the 14 evaluable HIV-negative patients (5 BCL, 5 T/NK, 4 HL) ORR, CRR, and CBR were 64%, 36%, and 93%, respectively, with CRs and PRs in all histologic subtypes. The ORR was 3/5 for BCL (2 CR, 1 PR); 5/5 for T/NK (2 CR, 3 PR); and 1/4 in HL (1 CR). One BCL patient with combined variable immunodeficiency (CVID) achieved a CR. Only 1 of 3 BCL patients with a history of PTLD was evaluable and achieved a CR. All three evaluable HIV+ BCL patients progressed. Of 8 patients with detectable baseline plasma EBV DNA, 7 demonstrated a reduction (-17% to -83%). Other biomarker studies are in progress.
Conclusion: In this phase 1b study, the combination of oral Nstat and VGCV was well tolerated in patients with EBV+ lymphomas, with no unexpected G3-G4 AE, and showed a very encouraging signal of efficacy, especially in HIV-negative patients, with CRs in BCL, TCL, and HL. The combination of Nstat and VGCV is a compelling targeted oral therapy for R/R EBV+ lymphomas of different lineage and histologic type and should be explored in other EBV+ malignancies. The phase 2a portion of this study is actively recruiting (NCT03397706).
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Porcu:Viracta: Honoraria, Other: Scientific Board, Research Funding; Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Feldman:Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brem:Celgene: Honoraria, Speakers Bureau; BMS/Pfizer: Honoraria; Janssen: Honoraria, Speakers Bureau; Bayer: Honoraria; Genetech: Honoraria; Pharmacyclics: Honoraria, Speakers Bureau. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Barta:Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Trauger:Viracta: Employment. Gutheil:Viracta Therapeutics: Consultancy. Katkov:Viracta: Employment. McRae:Viracta: Employment. Royston:Viracta: Employment.
Introduction
Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population ...pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes.
Methods
Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (
n
= 3), 4 mg/kg (
n
= 3), 8 mg/kg (
n
= 4), and 16 mg/kg (
n
= 34). A total of 650 patients in EQUULEUS (
n
= 128), POLLUX (
n
= 282), and CASTOR (
n
= 240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively.
Results
Pharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events.
Conclusion
These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies.
Funding
Janssen Research & Development.
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