Initial Results from an Open-label, Doseescalation Phase I Study of the Oral BRAF Inhibitor LGX818 in BRAF V600 mutant Advanced Melanoma Reinhard Dummer, 1 Caroline Robert, 2 Marta Nyakas, 3 Grant McArthur, 4 Ragini Kudchakar, 5 Carlos Gomez-Roca, 6 Ryan Sullivan, 7 Keith Flaherty, 7 Carla Murer, 1 Darrin Stuart 8, Daniela Michel 9, Zhongwen Tang 10, Laure Moutouh-de Parseval 9, Jean-Pierre Delord 6 1 University Hospital Zurich, Zurich, Switzerland; 2 Institut Gustave Roussy, Villejuif, France; 3 Oslo University Hospital, Oslo, Norway; 4 Peter MacCallum Cancer Centre, University of Melbourne, Victoria, Australia; 5 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 6 Institut Claudius Regaud, Toulouse, France; 7 Massachusetts General Hospital, Boston, MA, USA; 8 Novartis Institutes for Biomedical Research, Emeryville, CA, USA; 9 Novartis Pharma AG, Basel, Switzerland; 10 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
IC 50, M LGX818 Is a Potent Inhibitor of BRAF V600E With a Long Dissociation t 1/2 Increased cellular potency relative to vemurafenib and dabrafenib Antiproliferative Activity BRAF V600E/D/K Cells 4 1 Compound BRAF V600E IC 50, M Dissociation t 1/2, h LGX818 0.0004 > 30 Vemurafenib 0.0007 0.5 Dabrafenib 0.00007 2 0.4 0.1 0.04 0.01 0.004 t1/2: half-life.
Conditional Survival, % Tumor Volume, mm 3, mean SE Increased Durability of Response With Higher-Dose LGX818 2500 Maximum Efficacy at 5 mg/kg BID Vehicle 0 mg/kg 3000 2500 1 mg/kg LGX818 2000 1500 LGX 1 mg/kg BID LGX 5 mg/kg BID LGX 20 mg/kg BID 26 PO 26 PO 26 PO 2000 1500 1000 1000 500 100 80 60 40 0 20 25 30 35 40 45 50 Days Postimplant Dose-Dependent Increase in PFS 1 mg/kg BID 5 mg/kg BID 20 mg/kg BID Tumor Volume, mm 3 500 1000 800 600 400 200 1000 800 0 20 40 60 80 100 120 140 5 mg/kg LGX818 0 20 40 60 80 100 120 140 160 20 mg/kg LGX818 Resistant tumors 20 0 20 20 60 90 120 150 Days Postimplant Conditional survival determined at the time tumor regrows to initial volume BID: twice daily; PO: orally; PFS: progression-free survival. 600 400 200 0 20 40 60 80 100 120 140 160 Time, days
Phase I First-in-Human Study of LGX818 Single Agent: Study Design (NCT01436656) Dose escalation Dose expansion: BRAF V600 mutant tumors N 21 BRAF V600 mutant melanoma MTD and/or RP2D Group A: patients with melanoma (n 40) At least 15 pretreated with a selective BRAFi At least 15 patients naive to a selective BRAFi Group B: patients with mcrc (n 22) LGX818 was administered orally once (QD) or twice daily (BID) Primary endpoint: MTD/RP2D Secondary endpoints: pharmacokinetics, tumor response, and safety BRAFi: BRAF inhibitor; mcrc: metastatic colorectal cancer; MTD: maximum tolerated dose; RP2D: recommended phase 2 dose. ClinicalTrials.gov. A phase I study of oral LGX818 in adult patients with advanced or metastatic BRAF mutant melanoma. http://www.clinicaltrials.gov/ct2/show/nct01436656. Accessed May 23, 2013.
Patient Treatment and DLTs Dose Escalation Phase (as of March 1, 2013) 54 patients with BRAF V600 mutant melanoma were enrolled across dose levels 7 patients across the dose groups had DLTs (all grade 3) 450 mg QD was determined to be the MTD in the dose-escalation phase 100 mg QD ME n = 5 1 DLT: G3 hand-foot skin reaction 50 mg QD ME n = 4 a 100 mg QD CPS n = 5 1 DLT: G3 pain (soles of feet) 150 mg QD CPS n = 6 200 mg QD CPS n = 4 300 mg QD CPS n = 5 75 mg CPS BID n = 3 100 mg CPS BID n = 5 150 mg CPS BID n = 4 1 DLT: G3 facial paresis/confusion 1 DLT: G3 pain/ neuralgia MTD 450 mg QD CPS n = 6 1 DLT: G3 fatigue 2 DLTs: G3 insomnia/asthenia G3 diarrhea/rash/headache 550 mg QD CPS n = 5 700 mg QD CPS n = 2 CPS: capsule; G: grade; DLT: dose limiting toxicity; ME: microemulsion. a 1 patient was dosed with CPS instead of ME.
Patient Characteristics Dose Escalation BRAFi Naive Melanoma n = 26 BRAFi Pretreated Melanoma n = 28 Age, median (range), years 51 (33-70) 50 (22-78) Male/female, n 18/8 18/10 Baseline WHO PS, 0/1/2, n 20/5/1 15/12/1 Stage of melanoma at baseline, n III 1 0 IV 12 11 IV M1a/M1b/M1c 1/0/12 0/4/13 Type of BRAF V600 mutation, V600E/K/G, n 23/3/0 26/1/1 Number of prior antineoplastic therapies, 1 (0-3) 2 (1-5) median (range) 0 6 0 1 16 7 2 3 11 3 1 10 For BRAFi pretreated patients Days on prior BRAFi, median (range) NA 158 (34-706) Days since prior BRAFi discontinuation, median (range) PS: performance status; WHO: World Health Organization. NA 25 (12-319)
Median Concentration, ng/ml Clinical Pharmacokinetics 450 mg QD was defined as the MTD Median time to maximum concentration (T max ) was 2 hours Terminal half-life was about 3-4 hours Steady state was achieved in about 15 days Day 15 exposures were consistently lower (30%-60%) than those on day 1, probably due to induction of CYP enzymes 1E + 04 Mean Blood Concentration Over Time After LGX818 QD Treatment Day 1 Day 15 1E + 04 1000 1000 Efficacious concentration (in vivo preclinical models) 100 100 10 10 1 0 5 10 15 20 25 Time, hours 1 0 5 10 15 20 25 Time, hours 50 mg 100 mg 150 mg 200 mg 300 mg 450 mg 550 mg 700 mg
Efficacy: Response Rates Dose Escalation Best Overall Response, n (%) a Complete response (CR) Confirmed CR Partial response (PR) Confirmed PR BRAFi Naive Melanoma n = 26 0 0 17 (65) 15 (58) Response rate (PR + CR) 17 (65) Confirmed PR + CR 15 (58) BRAFi Pretreated Melanoma n = 28 1 (4) 1 (4) 2 (7) 2 (7) 3 (11) 3 (11) Stable disease (SD) 6 (23) 9 (32) Progressive disease (PD) 0 14 (50) Unknown b 5 (19) 2 (7) a All dose levels (50 to 700 mg) and dosing regimens (QD and BID) pooled; data cutoff March 1, 2013, including most recent data from June. b Reasons for unknown response for BRAFi-naive patients were PD too late (n = 1), SD too early (n = 2), and no valid postbaseline assessment (n = 2) and for BRAFi pretreated were SD too early (n = 1) and no valid postbaseline assessment (n = 1).
Maximum Tumor Reduction From Baseline Dose Escalation 100 80 60 40 20 BRAFi Naive Ongoing at data cutoff (March 1, 2013) n = 24 a Total daily dose 50 mg 100 mg 150 mg 200 mg 300 mg 450 mg 550 mg 0 20 K K b b 40 60 b b b b K 80 100 PR PR PR UNK UNK PR SD SD SD PR PR PR SD SD PR PR SD PR PR UKN PR PR PR PR Best response c K: BRAF V600K mutation; UNK: unknown. a Patients with missing best percent change from baseline are not included; b BID; c Best response is confirmed response.
Survival Probability Progression-Free Survival a Dose Escalation 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1: Naive 26 22 21 20 16 13 11 10 7 7 6 6 3 2 2 1 0 2: Pretreated 28 20 11 9 7 7 2 2 1 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 PFS, months 1: Naive 2: Pretreated Endpoint, months BRAFi Naive BRAFi Pretreated Median PFS 7.1 (95% CI, 4.4-> 11.1) 1.9 (95% CI, NA) Median DOR 10.4 (95% CI, 3.9-not reached) 3.7 (95% CI, 3.2-4.4) a Includes all dose levels (50 to 700 mg) and dosing regimens QD and BID pooled as of data cutoff, March 1, 2013. DOR: duration of response; NA: not available.
Safety Summary Dose Escalation The most common toxicities suspected to be related to treatment with LGX818 were cutaneous events There was a low incidence of adverse events (AEs) of special interest Squamous cell carcinoma (n = 2 [3.7%]; 1 BRAFi naive and 1 pretreated patient) Keratoacanthoma (n = 2 [3.7%]; 1 BRAFi naive and 1 pretreated patient) Pyrexia (n = 3 [5.6%]) Photosensitivity (n = 5 [9%]) 14 patients (25.9%) had a dose reduction, 19 patients (35.2%) had 1 dose interruption, and 4 patients discontinued treatment for AE (PPES, pain in extremities, hyperkeratosis, and headache) PPES: palmar-plantar erythrodysaesthesia syndrome.
AEs Suspected to Be Treatment Related ( 20% of Patients) a Dose Escalation All Melanoma Patients N = 54 All Grade, n (%) Total 48 (88.9) Cutaneous Palmar-plantar erythrodysaesthesia syndrome 26 (48.1) Hyperkeratosis 25 (46.3) Keratosis pilaris 20 (37.0) Pruritus 20 (37.0) Alopecia 17 (31.5) Dry skin 17 (31.5) Melanocytic nevus 12 (22.2) Xerosis 12 (22.2) Erythema 11 (20.4) Gastrointestinal Nausea 13 (24.1) Decreased appetite 12 (22.2) Musculoskeletal disorders/pain Arthralgia 17 (31.5) Pain in extremity 15 (27.8) Myalgia 12 (22.2) Other disorders Fatigue 16 (29.6) Asthenia 12 (22.2) a Data cutoff March 1, 2013; only AEs occurring during treatment or within 30 days of the last study medication are reported.
Grade 3 a Toxicities Dose Escalation 18 patients (33.3%) across doses had grade 3 AEs suspected to be treatment related (all reversible, occurring mainly during the first 14 days of treatment) The most common grade 3 AEs were fatigue (n = 5; 9.3%) and palmar-plantar erythrodysaesthesia syndrome (n = 3; 5.6%) Additional grade 3 AEs were 2 patients each with increased gamma-gt, confusional state, and neuralgia 1 patient each with acneiform dermatitis, increased ALT, arthralgia, asthenia, diarrhea, facial paresis, headache, hyperkeratosis, hyponatremia, ichthyosis, insomnia, malignant melanoma, b musculoskeletal pain, neck pain, neutropenia, pain in extremity, and rash a There was only 1 grade 4 AE reported (increased gamma-gt [deemed not clinically significant] in a patient who received LGX818 700 mg QD). b Occurred at day 15 in a patient previously treated with a selective BRAFi. ALT: alanine aminotransferase.
Current Study Status Dose Expansion The dose-expansion phase is ongoing with 38 patients with BRAF-mutant melanoma or mcrc enrolled at 2 doses as of June 26, 2013 450 mg QD (the MTD) 22 patients with BRAF V600 mutant melanoma (6 BRAFi naive and 16 BRAFi pretreated) 12 patients with mcrc 300 mg QD 3 patients with BRAF V600 mutant melanoma (2 BRAFi naive and 1 BRAFi pretreated) 1 patient with mcrc
Phase III LGX818 Study: COLUMBUS a Patients with newly diagnosed, BRAFi-naive, BRAF V600E or V600K mutant, advanced, unresectable or metastatic melanoma (N = 900) RANDOMIZATION 1:1:1 Stratification by stage (IIIB + IIIC + IVM1a + IVM1b vs. IVM1c), ECOG performance status (0 vs 1), and BRAF mutation status (V600E vs V600K) LGX818 + MEK162 n = 300 LGX818 n = 300 Vemurafenib n = 300 Preliminary results from a phase Ib/II, study of LGX818 + MEK162 will be presented in the poster session (#320) a COLUMBUS, Combination of LGX818 used with MEK162 in BRAF mutant unresectable skin cancer. ECOG: Eastern Cooperative Oncology Group.
Conclusions Results from the dose-escalation of this phase I study identified the MTD of LGX818 single agent as 450 mg QD LGX818 had a manageable and reversible toxicity profile, with cutaneous AEs being the most commonly reported AEs LGX818 showed early signs of promising activity, with a response rate of 65% (58% confirmed PR) in patients with advanced BRAF V600 mutant melanoma who were BRAFi naive Overall, LGX818 has demonstrated a promising efficacy and safety profile in BRAF V600 mutant melanoma A phase III study of LGX818 ± MEK162 vs vemurafenib (COLUMBUS) is due to start accrual by the end of this year
Acknowledgments The authors thank the patients and their families and each site participating in the phase I study presented CLGX818X2101. We also thank additional Novartis colleagues (Penny Zhu, Samia Kabi, Susan Nicholas, Regine Hansen, and Sandrine Moreau) for providing support for this presentation.