The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

Summary Daratumumab is a CD38‐targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard‐of‐care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D‐VRd) for transplant‐eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D‐VMP) for transplant‐ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D‐Rd) for relapsed/refractory MM. In total, 199 patients were treated (D‐VRd, n = 67; D‐VMP, n = 67; D‐Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21‐day induction cycles for D‐VRd was 71·6% [90% confidence interval (CI) 61·2–80·6%], and the overall response rates (ORRs) for D‐VMP and D‐Rd were 88·1% (90% CI 79·5–93·9%) and 90·8% (90% CI 82·6–95·9%). With longer median follow‐up for D‐VMP and D‐Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease–negativity (10‒5) rates were 16·4% and 15·4%. Infusion‐related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard‐of‐care regimens demonstrated comparable clinical activity to DARA IV–containing regimens, with low infusion‐related reaction rates and reduced administration time.

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10574 Introduction: Activation of Notch signaling occurs in ∼40% of human BCs and high Notch expression is associated with poor outcome. Inhibition of Notch inhibits BC cell proliferation in vitro. Notch signaling requires gamma secretase (GS), which cleaves Notch, releasing the Notch intracellular domain (NICD) to activate transcription of target genes. MK-0752 is a potent GS inhibitor. Methods: In Part 1 of the study, pts with advanced solid tumors were enrolled using an accelerated dose escalation with 1 pt/dose level until the occurrence of ≥Grade 2 toxicity, then 3–6 pts/dose level. MK-0752 was administered by once-daily oral dosing in 28-day cycles. Once a maximum tolerated dose (MTD) was established, an additional 22 pts with advanced BC were to be enrolled in Part 2. Six-point PK plasma profiles were collected over 24 hours on Days 1 and 28 and assayed by LC/MS/MS. PD measurement of plasma Abeta40 peptide (another gamma secretase substrate) was performed pre/post dose on Days 1 and 28. Tumor biopsies on Days 1 and 28 were obtained from a subset of pts to assess changes in Notch activity by immunohistochemical analysis of NICD. Results: In Part 1, two pts were enrolled at 450mg daily, and five pts at 600mg daily. Dose-limiting toxicities (DLTs) were Grade 3 diarrhea, constipation, nausea, and abdominal cramping at 600 mg. In Part 2, an additional 14 pts with BC were enrolled at 450mg daily. In this cohort, Grade 2/3 fatigue requiring dose reduction occurred in 6 pts. Grade 3 diarrhea (1pt), nausea (1 pt) and elevated liver transaminases (2 pt) were also observed. Mean PK parameters (at 450mg, 600 mg) on Day 1 were AUC0–24hr = 1036, 1065μM·hr, Cmax = 72, 61μM, C24hr = 25, 32μM, and tmax = 3, 7 hr. PD measurements of GS inhibition showed a 12–78% (mean 46%) decrease in plasma Abeta40 at 4 hours on Day 1 compared to predose. Conclusion: Continuous dosing of MK-0752 at 450mg daily in pts with BC was associated with significant toxicity, predominantly fatigue, and cannot be considered a MTD. An intermittent dosing schedule is being explored. MK-0752 at all doses inhibited GS, as demonstrated by decreases in plasma Abeta40. Analysis of efficacy and intratumoral Notch inhibition will be reported at the meeting. [Table: see text]

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Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved as monotherapy or in combination with standard-of-care regimens for the treatment of relapsed or refractory multiple myeloma (RRMM). In the primary analysis (median follow-up, 16.9 months) of the phase 3 APOLLO study (NCT03180736), the addition of DARA to pomalidomide and dexamethasone (D-Pd) showed a significant progression-free survival (PFS) improvement over pomalidomide and dexamethasone (Pd) alone in patients (pts) with RRMM (Dimopoulos MA, et al. Lancet Oncol. 2021;22[6]:801-812). Here, we report results from the APOLLO study, including outcomes of pts refractory to lenalidomide based on the last dose of lenalidomide received. Methods: Eligible pts were ≥18 years of age, had RRMM, had received ≥1 prior line of therapy (including both a proteosome inhibitor and lenalidomide), and had responded to prior treatment; pts with only 1 prior line of therapy were required to be refractory to lenalidomide. Pts were randomized 1:1 to Pd ± DARA, stratified via International Staging System disease stage (I vs II vs III) and number of lines of prior therapy (1 vs 2-3 vs ≥4). All pts received 28-day cycles of pomalidomide (4 mg PO daily on Days 1-21) and dexamethasone (40 mg [20 mg for pts ≥75 years of age], PO daily on Days 1, 8, 15, and 22). Pts in the D-Pd group received DARA subcutaneously (DARA SC; 1,800 mg; co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; ENHANZE ® drug delivery technology, Halozyme, Inc.]) or, prior to a protocol amendment, intravenously (DARA IV; 16 mg/kg; n=7) weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. Pts receiving DARA IV were allowed to switch to DARA SC starting on Day 1 of Cycle 3 or later. All pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Results: In total, 304 pts were randomized (D-Pd, n=151; Pd, n=153). At the time of randomization, 120 (79.5%) pts in the D-Pd group and 122 (79.7%) pts in the Pd group were refractory to lenalidomide. Among pts refractory to lenalidomide, the last dose of lenalidomide received was 5-10 mg in 30 (25.0%) pts in the D-Pd group and 31 (25.4%) pts in the Pd group and was 15-25 mg in 86 (71.7%) pts in the D-Pd group and 89 (73.0%) pts in the Pd group. With a median follow-up of 16.9 months, the median PFS in the overall population was 12.4 months in the D-Pd group versus 6.9 months in the Pd group (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.85; P=0.0018); the estimated 18-month PFS rate was 42.1% for the D-Pd group and 25.5% for the Pd group. Among pts refractory to lenalidomide, the median PFS was 9.9 months in the D-Pd group and 6.5 months in the Pd group (HR, 0.66; 95% CI, 0.49-0.90). For lenalidomide-refractory pts who last received a dose of 5-10 mg lenalidomide, the median PFS was 10.3 months for the D-Pd group and 8.5 months for the Pd group (HR, 0.75; 95% CI, 0.41-1.36); for lenalidomide-refractory pts who last received a dose of 15-25 mg lenalidomide, the median PFS was 10.7 months for the D-Pd group and 6.1 months for the Pd group (HR, 0.61; 95% CI, 0.42-0.88) (Figure). Grade 3/4 treatment-emergent adverse events occurred in 130 (87.3%) pts in the D-Pd group and 123 (82.0%) pts in the Pd group; the most frequently reported (≥15% in both groups) were neutropenia (67.8% vs 50.7%), thrombocytopenia (17.5% vs 18.0%), and anemia (16.8% vs 21.3%). Grade 3/4 pneumonia occurred in 20 (13.4%) pts in the D-Pd group and 10 (6.7%) of pts in the Pd group. Serious adverse events occurred in 75 (50.3%) pts in the D-Pd group and 59 (39.3%) pts in the Pd group. Conclusion: The addition of DARA to Pd provided a PFS benefit in the overall pt population and among pts refractory to lenalidomide. The safety profile observed in the APOLLO trial was consistent with previous reports for DARA SC and Pd. Additional analyses for lenalidomide-refractory pts, as well as efficacy and safety data for the overall population at longer follow up, will be presented. Figure 1 Figure 1. Disclosures Sonneveld: Celgene/BMS: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Terpos: Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Boccadoro: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Beksac: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Symeonidis: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Demo: Research Funding; WinMedica: Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bila: Janssen, Takeda, AMGEN: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Oriol: 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; 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. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Roche: 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; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: 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; Celgene - Bristol Myers Squibb: 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; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Orfanidis: Health Data Specialists: Current holder of individual stocks in a privately-held company. Kampfenkel: Janssen: Current Employment. Qiu: Janssen: Current Employment. Amin: Janssen: Current Employment, Current equity holder in publicly-traded company. Kosh: Janssen: Current Employment. Tran: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Dimopoulos: Beigene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; BMS: Honoraria. OffLabel Disclosure: The regimen is approved for patients who have received at least two prior therapies, whereas the APOLLO study included patients who have received at least 1 prior therapy.

Introduction : Daratumumab (DARA) 16 mg/kg intravenous (IV) is approved as monotherapy for relapsed or refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma (NDMM). A subcutaneous (SC) co-formulation of DARA (DARA SC; 1,800 mg) with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) is under investigation in a number of ongoing studies. In the phase 3 COLUMBA study, DARA SC was shown to be noninferior to DARA IV, demonstrating similar efficacy and pharmacokinetics (PK), with a significantly decreased rate of infusion-related reactions (IRRs) and reduced administration time (median, 5 minutes; Mateos MV, et al. J Clin Oncol. 2019). This phase 2, open-label, multicenter study (PLEIADES) assessed the efficacy and safety of DARA SC combined with bortezomib, lenalidomide, and dexamethasone (D-VRd) and bortezomib, melphalan, and prednisone (D-VMP) in patients with NDMM, and combined with lenalidomide and dexamethasone (D-Rd) in patients with RRMM. The primary analysis of PLEIADES is to be presented at an upcoming meeting; here, we report updated results with longer follow-up. Methods: Transplant-ineligible NDMM patients received DARA SC (QW for Cycle 1 and Q3W for Cycles 2-9 in 42-day cycles, and Q4W for Cycles 10+ in 28-day cycles until disease progression) in combination with VMP for 9 cycles (V 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 for Cycle 1 and Days 1, 8, 22, and 29 for Cycles 2-9; M 9 mg/m2 orally [PO] Days 1-4 for Cycles 1-9; P 60 mg/m2 PO Days 2-4 for Cycles 1-9) and dexamethasone (20 mg PO QW for Cycle 1, Days 1 and 22 for Cycles 2-9, and Day 1 for Cycles 10+). RRMM patients with ≥1 prior line of therapy received DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, Q4W for Cycles 7+ until disease progression in 28-day cycles) in combination with Rd (R 25 mg PO Days 1-21 and d 40 mg IV or PO QW for each cycle until disease progression). Transplant-eligible NDMM patients received 4 cycles of DARA SC (QW for Cycles 1-3, Day 1 for Cycle 4 in 21-day cycles) in combination with VRd induction therapy for 4 cycles (V 1.3 mg/m2 SC Days 1, 4, 8, and 11 for each cycle; R 25 mg PO Days 1-14 for each cycle; d 20 mg IV or PO Days 1, 2, 8, 9, 15, and 16 for each cycle); subsequent therapy/autologous stem cell transplant were performed off study. Primary efficacy endpoints were overall response rate (ORR) for D-VMP and D-Rd and rate of very good partial response (VGPR) or better for D-VRd. Secondary endpoints included rate of VGPR or better for the D-VMP and D-Rd treatment cohorts and ORR for the D-VRd cohort. Secondary endpoints included rate of complete response or better, duration of response, minimal residual disease (MRD)-negativity rate, and DARA serum concentrations. Safety data included rates of treatment-emergent adverse events and IRRs. Results: 199 patients were enrolled (D-VMP, n = 67; D-Rd, n = 65; D-VRd, n = 67). At the clinical cutoff date (8 July 2019), median duration of follow up was 11.0 months for D-VMP, 11.2 months for D-Rd, and 7.1 months for D-VRd. ORR for D-VMP was 89.6% (90% confidence interval [CI], 81.3 - 95.0) and for D-Rd was 93.8% (90% CI, 86.5 - 97.9). Rate of VGPR or better for D-VRd was 70.1% (90% CI, 59.6 - 79.3). Response rates were comparable to published ORRs from the ALCYONE (Mateos MV, et al. N Engl J Med. 2018) and POLLUX (Dimopoulos MA, et al. N Engl J Med. 2016) studies of DARA IV plus VMP and Rd, respectively. The median duration of DARA SC administration was 5 minutes in all cohorts for the first, second, and all subsequent injections. The safety profiles in all cohorts were consistent with DARA IV in combination with various backbone standard-of-care regimens. Rates of IRRs and injection site reactions were consistent with those observed with DARA SC monotherapy in the COLUMBA study. The PK of DARA SC and each regimen was consistent with historical data and immunogenicity of DARA and rHuPH20 were comparable to previous reports. Updated efficacy data based on longer follow-up, including MRD-negativity rate, and updated safety data will be presented at the meeting. Conclusions: With longer follow-up, DARA SC in combination with standard-of-care regimens demonstrated comparable clinical activity and safety to corresponding DARA IV regimens, with considerably lower IRR rates and substantially shorter durations of administration. Disclosures Chari: Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Bristol Myers Squibb, Pharmacyclics, Karyopharm, Sanofi, Seattle Genetics, OncoPeptides, Millenium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. McCarthy:Janssen: Honoraria, Other: Educational grant to attend meetings . Suzuki:Celgene: Honoraria; Janssen: Honoraria; Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria. Hungria:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sureda:Sanofi: Honoraria; BMS: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Amgen: Membership on an entity's Board of Directors or advisory committees. Perrot:jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees; takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Hulin:Janssen, AbbVie, Celgene, Amgen: Honoraria; celgene: Consultancy, Honoraria. Iida:Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Abbvie: Research Funding; MSD: Research Funding; Sanofi: Research Funding; Teijin Pharma: Research Funding; Astellas: Research Funding; Gilead: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Maisnar:Janssen, Amgen, Celgene, Takeda, BMS: Consultancy, Honoraria. Karlin:Takeda: 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, Other: Travel Support; Celgene: 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, Other: Travel Support. Parasrampuria:Janssen: Employment, Equity Ownership. Masterson:Janssen: Employment, Equity Ownership. Kosh:Janssen: Employment, Equity Ownership. Yang:Janssen: Employment, Equity Ownership. Delioukina:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Carson:Janssen: Employment, Equity Ownership. OffLabel Disclosure: This abstract includes data from a phase 2 clinical trial of a subcutaneous formulation of daratumumab in combination with standard-or-care regimens. Subcutaneous daratumumab is currently under investigation in several clinical trials, but has not yet been approved. However, the intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of multiple myeloma.