Safety Findings From FORWARD II: A Phase Ib Study Evaluating the Folate Receptor Alpha (FR

Transcription

1 Safety Findings From FORWARD II: A Phase Ib Study Evaluating the Folate Receptor Alpha (FRα)-Targeting Antibody-Drug Conjugate (ADC) Mirvetuximab Soravtansine (IMGN853) in Combination With Bevacizumab, Carboplatin, Pegylated Liposomal Doxorubicin (PLD), or Pembrolizumab in Patients With Ovarian Cancer Abstract 5553 O Malley DM, Moore KN, Vergote I, Martin LP, Gilbert L, Gonzalez Martin A, Malek K, Birrer MJ, Matulonis UA

2 Patient Population and Objectives Primary Objective of Dose-Escalation Phase: Evaluate the safety and tolerability of mirvetuximab soravtansine when administered in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients with EOC, primary peritoneal cancer, or fallopian tube cancer Treatment schedule: Mirvetuximab soravtansine + bevacizumab administered on day 1 of a 3-week cycle (q3w) Mirvetuximab soravtansine + carboplatin administered on day 1 of a 3-week cycle (q3w) Mirvetuximab soravtansine + PLD administered on day 1 of a 4-week cycle (q4w) Mirvetuximab soravtansine + pembrolizumab administered on day 1 of a 3-week cycle (q3w) Eligibility: For the bevacizumab, PLD, and pembrolizumab regimens: platinum-resistant EOC, primary peritoneal, or fallopian tube cancer For the carboplatin arm: disease that is potentially platinum sensitive (did not progress within 6 months) At least one lesion that meets the definition of measurable disease according to RECIST 1.1 FRα positivity by IHC ( 25% of tumor cells with 2+ staining intensity)

3 FORWARD II Study Design

4 Patient Demographics & Baseline Characteristics Characteristic Bevacizumab Carboplatin PLD Pembrolizumab n = 14 n = 18 n = 16 n = 13 Age (range) 64 (50-81) 66 (47-82) 64 (47-73) 62 (47-78) No. of prior systemic therapies, n (%) (7) 9 (50) 9 (56) 1 (8) (93) 9 (50) 7 (44) 12 (93) Median (range) 6 (2-8) 3 (1-5) 2 (1-6) 5 (2-7) FRα expression, n (%) [n = 61] High 28 (48) 9 (64) 7 (39) 8 (50) 5 (38) Medium 14 (23) 3 (21) 4 (22) 5 (31) 2 (15) Low 18 (30) 2 (14) 7 (39) 3 (19) 6 (46) Prior exposure, n (%) Platinum compounds 14 (100) 18 (100) 16 (100) 13 (100) Taxanes 14 (100) 18 (100) 16 (100) 13 (100) Bevacizumab 9 (64) 5 (28) 9 (56) 6 (46) PARP inhibitor 6 (43) 9 (50) 4 (25) 4 (31)

5 Dose Level & Patient Allocation MIRV Q3W Bevacizumab Q3W No. MIRV Q3W Carbo Q3W No. MIRV Q4W PLD Q4W No. MIRV Q3W Pembro Q3W No. 5 mg/kg 15 mg/kg 3 5 mg/kg AUC4 4 5 mg/kg 30 mg/m mg/kg 200 mg 4 6 mg/kg 15 mg/kg 11 5 mg/kg AUC5 4 5 mg/kg 40 mg/m mg/kg 200 mg 9 6 mg/kg AUC mg/kg 40 mg/m 2 7 DLTs: Bevacizumab combination: Grade 2 neutropenia and thrombocytopenia (one patient; 6 mg/kg/15 mg/kg dose) Carboplatin combination: Grade 3 vasculitis (6 mg/kg/auc5 dose) Data cutoff 28 APR 2017

6 Treatment-Emergent Adverse Events: >20% (All Grades) Preferred Term BEV n = 14 Carboplatin n = 18 PLD n = 16 Pembrolizumab n = 13 Abdominal distension (%) 3 (21.4) 1 (5.6) 2 (12.5) 0 (0.0) Abdominal pain (%) 3 (21.4) 1 (5.6) 4 (25.0) 1 (7.7) ALT increased (%) 3 (21.4) 3 (16.7) 2 (12.5) 0 (0.0) Anemia (%) 3 (21.4) 5 (27.8) 2 (12.5) 0 (0.0) AST increased (%) 3 (21.4) 3 (16.7) 4 (25.0) 0 (0.0) Constipation (%) 3 (21.4) 3 (16.7) 8 (50.0) 2 (15.4) Decreased appetite (%) 2 (14.3) 5 (27.8) 1 (6.3) 2 (15.4) Dehydration (%) 3 (21.4) 0 (0.0) 0 (0.0) 0 (0.0) Diarrhea (%) 7 (50.0) 10 (55.6) 9 (56.3) 2 (15.4) Dry eye (%) 3 (21.4) 1 (5.6) 1 (6.3) 1 (7.7) Fatigue (%) 5 (35.7) 7 (38.9) 7 (43.8) 4 (30.8) Headache (%) 3 (21.4) 4 (22.2) 4 (25.0) 1 (7.7) Hypertension (%) 3 (21.4) 1 (5.6) 0 (0.0) 1 (7.7) Hypokalemia (%) 1 (7.1) 7 (38.9) 2 (12.5) 0 (0.0) Hypomagnesemia (%) 3 (21.4) 5 (27.8) 0 (0.0) 0 (0.0) Keratopathy* (%) 3 (21.4) 2 (11.1) 1 (6.3) 0 (0.0) Myalgia (%) 3 (21.4) 3 (16.7) 1 (6.3) 0 (0.0) Nausea (%) 6 (42.9) 9 (50.0) 7 (43.8) 3 (23.1) Neutropenia (%) 2 (14.3) 8 (44.4) 4 (25.0) 0 (0.0) Peripheral neuropathy** (%) 4 (28.6) 6 (33.3) 5 (31.3) 4 (30.8) Proteinuria (%) 5 (35.7) 0 (0.0) 0 (0.0) 0 (0.0) Small intestinal obstruction (%) 3 (21.4) 0 (0.0) 1 (6.3) 1 (7.7) Stomatitis (%) 3 (21.4) 0 (0.0) 2 (12.5) 0 (0.0) Thrombocytopenia (%) 4 (28.6) 10 (55.6) 2 (12.5) 0 (0.0) Urinary tract infection (%) 3 (21.4) 1 (5.6) 5 (31.3) 0 (0.0) Vision blurred (%) 6 (42.9) 10 (55.6) 4 (25.0) 2 (15.4) Vomiting (%) 4 (28.6) 5 (27.8) 5 (31.3) 1 (7.7) Shaded cells indicate incidence >40% The safety profiles for these combinations were manageable and as expected based on known profiles of each agent BEV: gr3 hypertension and small-bowel obstruction occurred in 3 and 2 patients, respectively Carbo: gr3 neutropenia, anemia, thrombocytopenia and hypokalemia occurred in 3, 2, 2, and 2 pts, respectively PLD: gr 3 anemia and vomiting occurred in 2 patients each *Includes corneal cyst, corneal disorder, corneal deposits, corneal epithelial microcysts, keratitis, keratopathy, limbal stem cell deficiency, and punctate keratitis **Includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paraesthesia, and hypoesthesia

7 ORR and PFS Across Escalation Dose Levels Endpoint Mirvetuxumab + Bevacizumab n = 14 Mirvetuximab + Carboplatin n = 17 Mirvetuximab + PLD n = 16 ORR (confirmed) 95% CI 29% (8, 58) 65% (38, 86) 13% (2, 38) mpfs (months) 95% CI 9.5 (3.5, 15.2) 12.1 (9.0, 15.0) 7.0 (1.7, -)

8 Efficacy Comparison of Carboplatin/Mirvetuximab Combo OCEANS 1 GOG213 2 FORWARD II Regimen Carbo/Gem Carbo/Tax Carbo/Mirv Median age Patient population plat sensitive, 1 prior plat sensitive, 1 prior median 3 priors Prior bevacizumab 0 10% 28% ORR 57% 56% 65% mpfs 8.4 (95% 8.3, 9.7) 10.4 (95% ) 12.1 (95% 9.0, 15.0) Encouraging clinical benefit in patients with platinum-sensitive disease who had received multiple prior lines of therapies 1. Aghajanian C, et al. J Clin Oncol. 2012;30(17): Coleman RL, et al. Lancet Oncol. April 21, 2017 [Epub ahead of print].

9 Percent Changes in Tumor Target Lesions Mirvetuximab +Carboplatin Note: Data are presented from 15/17 evaluable patients as measurements were not available for 2 individuals Combination with carboplatin demonstrates consistent depth and duration of response associated with FRα expression Combination with carboplatin active in low expressors Data cutoff 28 APR 2017

10 Efficacy Comparison of Mirvetuximab/Bev Combo AURELIA 1 FORWARD II Regimen Chemo/Bev Mirv/Bev Median age Patient population Platinum resist 1-2 priors 60% - 1 prior 40% - 2 prior Median of 6 priors 7% 1-2 priors Prior bevacizumab 7% 64% ORR 27% 28% mpfs 6.7 (95% 5.7, 7.9) 9.5 (95% 3.5, 15.2) Encouraging clinical benefit in heavily pretreated patients with platinumresistant disease 1. Pujade-Lauraine E, et al. J Clin Oncol. 2014;32(13): Data cutoff 28 APR 2017

11 Percent Changes in Tumor Target Lesions Mirvetuximab + Bevacizumab Note: Data are presented from 12/14 evaluable patients as measurements were not available for 2 individuals Combination with bevacizumab demonstrates the depth and duration of response associated with FRα expression Data cutoff 28 APR 2017

12 Percent Tumor Changes in Target Lesions Mirvetuximab + PLD Note: Data is presented from 13/16 evaluable patients as measurements were not available for 3 individuals

13 Conclusions The recommended phase II dose of mirvetuximab soravtansine was readily combined with the highest doses (per protocol) of bevacizumab, carboplatin, PLD, and pembrolizumab The adverse event profiles for all combinations were mainly low grade, manageable, and as expected based on the known profiles of each agent The encouraging signs of activity observed in a heavily pretreated subset of patients treated with mirvetuximab soravtansine plus bevacizumab supports the planned expansion cohorts evaluating this combination Clinical benefit was also observed with the carboplatin combination in patients with platinum-sensitive disease, who had also received multiple prior lines of therapy Potential avenue for future exploration in the platinum-sensitive setting