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Daratumumab (Darzalex) Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Clinical Advances in Immunotherapy in Myeloma Webinar 1, June 14, 2017 Monoclonal Antibodies Speakers Moderator: Mary DeRome Multiple Myeloma Research Foundation Norwalk, Connecticut Faculty: Tom Martin, MD University of California, San Francisco San Francisco, California Amy Marsala, MPH, MSN, NP University of California, San Francisco San Francisco, California Gary Rudman, CSP Myeloma Patient Advocate 1 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Topics for Discussion • Current and future monoclonal antibodies (what they are, how they work) • Management of side effects in the era of monoclonal antibodies • Patient experience on phase 2 clinical trial of Empliciti (elotuzumab) Tom Martin, MD 2 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Current Overall Survival for Newly Diagnosed Myeloma 1.0 89% vs 81% 0.9 Still losing 25% patients in first 3 years 75% vs 62% 0.8 0.7 2007–2011 0.6 0.5 0.4 0.3 Proportion Surviving 2001–2006 0.2 0.1 0.0 012345678910 Years From Diagnosis A good trend but we always need to improve!! Myeloma Treatment: It’s an Art 3 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug New Agents in Myeloma Therapy Oral Kinase HDAC Immuno- New IMiDs proteasomes inhibitors Novel MOA inhibitors therapies • Lenalidomide • Bortezomib • Vemurafenib • Venetoclax • Panobinostat • Monoclonal • Pomalidomide • Carfilzomib • Afuresertib • Selinexor antibodies – Daratumumab • Ixazomib • Dinaciclib • Filanesib • Ricolinostat • CC-122 – Elotuzumab • Ibrutinib • CC-220 • Oprozomib – Isatuximab • Marizomib • Trametinib – Idasanutlin • Dabrafenib • Immune • JNJ-42756493 checkpoint inhibitors • Sotatercept ̶ Pembro- • CB-5083 lizumab ̶ Durvalumab • Immune cell therapy ̶ CAR-T ̶ BiTEs ̶ Vaccines IMiD, immunomodulatory drug; HDAC, histone deacetylase inhibitor, MOA mechanism of action, BiTE, bispecific T-cell engager; CAR-T, chimeric antigen receptor (CAR) T cells Harnessing the Immune System to Fight Myeloma Types of Immunotherapy, Immuno-Oncology Passive Active Chimeric antigen Vaccines Monoclonal receptor (CAR) (therapeutic antibodies T cells not preventive) Direct effects Monoclonal antibody 1. Extract WBCs from patient 2. Modify and Antigen expand cells in lab ADCC Fc receptor CDC Myeloma cell C1q 3. Infuse MM-targeted cells back to Lysis NK cell MAC patient Cell death MAC, membrane attack complex; CDC, complement dependent cytotoxicity; ADCC, antibody directed cellular cytotoxicity 4 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Types of Monoclonal Antibodies Naked Drug conjugates Bispecific T cell CD3 PD-1 CD16 PD-1 BiTE Targets In MM Target Antigen (CD33, CD19, etc) Target BCMA Cell SLAMF7 CD38 • Nothing is attached • A toxin or radioactive isotope is attached Monoclonal Antibodies Can Kill Myeloma Cells in Multiple Ways DIRECT EFFECT INDIRECT EFFECTS Interferes with survival or Labels myeloma cells Activates T cells by delivers myeloma- for killing by Labels myeloma cells “taking the brakes killing substances complement for killing by NK cells off” Monoclonal antibody NK cell toxins Myeloma cell surface target Checkpoint inhibitor Complement Fc receptor 5 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Two Approved Monoclonal Antibodies: Elotuzumab and Daratumumab Elotuzumab Daratumumab • Received approval for • Received approval patients with following a phase 2 relapsed/refractory single-agent trial2 for myeloma from a large patients with randomized relapsed/refractory combination phase 3 myeloma trial1 1. Lonial S et al. N Engl J Med. 2015;373:621. 2. Lonial S et al. Lancet. 2016;387:1551. Elotuzumab (Empliciti) Anti-SLAMF7 mAb 1 SLAMF7 NK SLAMF7 expressed on both MM cell cells and NK cells 2 Elotuzumab Tags MM cells for ADCC via NK cells and activates NK cells via SLAMF7 EAT-2 for MM cell destruction Myeloma independent of ADCC cell death MM Activity in combination with lenalidomide led to ELOQUENT trial NK, natural killer; ADCC, antibody-dependent cellular cytotoxicity Lonial S et al. N Engl J Med. 2015;373:621. Dimopoulos MA et al. Blood. 2015;126: Abstract 28. 6 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Phase 3 Trial of Elotuzumab ELOQUENT-2 • Compared to Revlimid and dexamethasone alone, the Relapsed/refractory addition of elotuzumab myeloma patients significantly increased: – Progression-free survival – Overall response rates n = 321 n = 325 R • The triple combination resulted in a 30% reduction in the risk of disease progression or death • Another phase 3 trial comparing Elo + Rev + Rev + dex the same combinations is dex underway in patients with newly diagnosed disease PFS benefit seen with elotuzumab in all predefined subgroups Lonial S. et al. N Engl J Med. 2015;373:621. Monoclonal Antibody: Empliciti (elotuzumab) What are the How is Empliciti possible side Current Indications administered? effects? • In combination with •IV • Fatigue Revlimid and • Once a week for the • Diarrhea dexamethasone for first 8 weeks then every • Fever patients with 2 weeks • Constipation relapsed/refractory • Pre-medication in • Cough myeloma (who have anticipation of infusion • Peripheral neuropathy received one to three reactions • Infusion reactions prior therapies [2015]) • Nasopharyngitis • Upper respiratory tract infection • Decreased appetite • Pneumonia • Small chance of second new cancer 7 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Daratumumab (Darzalex) Naked monoclonal that binds to CD38 on myeloma cells Active as single agent and in combination with lenalidomide1-3 First mAb approved for treatment of myeloma patients who have received at least three prior lines of therapy (including a PI and an IMiD) or who are double refractory to a PI and an IMiD Infusion reactions main side effect4 Potential impact on both standard- and high-risk disease mAb, monoclonal antibody; PI, proteasome inhibitor; IMiD, immunomodulatory drug 1. Lokhorst HM et al. N Engl J Med. 2015;373:1207. 2. Lonial S et al. Lancet. 2016;387:1551. 3. Plesner T et al. Blood. 2015;126: Abstract 507. 4. Voorhees PM et al. Blood. 2015;126: Abstract 1829. Phase 3 Trials of Daratumumab CASTOR and POLLUX CASTOR1 POLLUX2 Relapsed/refractory Relapsed/refractory myeloma patients myeloma patients n = 251 n = 247 n = 286 n = 283 R R Dara + Rev + Dara + Vel + dex Vel + dex Rev + dex dex 61% reduction in risk of disease 63% reduction in risk of disease progression or death for DVd vs Vd. progression or death for DRd vs Rd 1. Palumbo A et al. N Engl J Med. 2016;375:754. 2. Dimopoulos M et al. N Engl J Med. 2016;375:1319. 8 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Monoclonal Antibody: Darzalex (daratumumab) How is Darzalex What are the possible Current indications administered? side effects? • In combination with •IV • Infusion reactions Revlimid and • Once a week for the first 8 • Fatigue dexamethasone, or weeks, then every 2 weeks • Nausea Velcade and for 4 months, then monthly • Back pain dexamethasone, for • Pre- and post-medication • Fever patients who have received for infusion reactions at least one prior therapy • Cough (2016) • Upper respiratory tract • As monotherapy, for infection patients who have received at least three prior lines of therapy including a PI and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent (2015) Immune Checkpoint Inhibitors in Multiple Myeloma Target PD-1, PDL-1 Allow T cells to function Current agents under investigation in myeloma: nivolumab and pembrolizumab Activity only in combination with other myeloma agents Liu J et al, Blood. 2007;110:296. Tamura H et al. Leukemia. 2013;27:464. Paiva B et al. Leukemia. 2015. 2015;29:2110. Keir ME et al. Annu Rev Immunol. 2008;26:677. Hallett WH et al. Biol Blood Marrow Transplant. 2011;17:1133. Homet Moreno B, Ribas A. Br J Cancer. 2015;112:1421. Görgün G et al. Clin Cancer Res. 2015;21:4607. 9 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Phase 1 Trial of Pembrolizumab: Keynote 023 • Patients had heavily pretreated RRMM (median four prior Patients did not respond to at therapies); 86% had received a least two prior regimens, including a PI and an IMiD stem cell transplant and 75% were refractory to lenalidomide • 49% were unresponsive to two, n = 51 three, or four medications • Acceptable safety profile, with adverse events similar to those seen in patients using Pembrolizumab + Rev + pembrolizumab in solid tumors low-dose dex • Overall response rate was 50% and disease control rate (CR, PR, or SD) was 98% Conclusion: results are promising; phase 3 studies of pembrolizumab are now under way. PI, proteasome inhibitor; IMiD, immunomodulatory drug Mateos MV et al. J Clin Oncol. 2016;34: Abstract 8010. Monoclonal Antibodies in Development: Phase 3 Trials Drug Administration Type Trials Side Effects RR MM • Fatigue, nausea, cough, dyspnea • Pomalyst* + dex ± • Anemia, thrombocytopenia, Isatuximab† IV mAb Isatuximab† neutropenia
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