Mutations and Targets Targeted Therapies in Melanoma ckit NRAS <5% (mucosal, acral) 2% ( age) ckit Kit inhibitors: imatinib, nilotinib Paul Lorigan Senior Lecturer in Medical Oncology University of Manchester The Christie Manchester UK 5% ( age) NRAS inhibitors: vemurafenib, dabrafenib inhibitors: trametinib, TAK733 Cancer cell proliferation and survival Targeted anti- therapy mutation by age 4-6% of melanomas RAS V6E Cellular Proliferation RTK VEMURAFENIB Age No. mutant V6E V6K 2-3 14 86% 83% % 31-4 3 8% 92% 8% 41-5 42 5% 76% 14% 51-6 58 41% 67% 29% 61-7 13 48% 71% 24% >7 65 22% 5% 21% Menzies ASCO 211 Screening V6E mutation Stratification Stage ECOG PS ( vs 1) LDH elevated vs normal Geographic region Phase 3 BRIM3 trial: study design Randomisation N=675 96mg po BID (n=337) DTIC 1mg/m 2 iv Q3W (n=338) Chapman PB, et al. N Engl J Med. 211;364:257 2516 PFS (%) 1 9 8 7 6 5 4 (N=275) (N=274) HR.26 (95% CI;.2 -.33) Log-rank P<.1 3 2 1 Median 1.6 mos Median 5.3 mos 1 2 3 4 5 6 7 8 9 1 11 12 No. of patients in follow up Progression-free survival (3/12/21 cutoff) 274 275 213 268 85 211 48 122 28 15 16 5 Months 1 35 6 16 3 4 3 1
Maximal tumour shrinkage by individual patient BRIM 2 Study Patient # 67 Percent change from baseline in sum of tumor diameters >1 5-5 -1 >1 5-5 -1 Baseline Day 15 OS (%) Number at risk Overall Survival (Feb cut-off) censored at crossover 1 9 (n=337) Median FU 12.5 months 8 HR.7 7 (95% CI:.57.87) 6 p<.1 (post-hoc) 5 4 (n=338) Median FU 9.5 months 3 2 1 9.7 13.6 6 12 18 24 Time (months) 338 337 244 326 173 28 111 231 79 178 5 19 24 44 4 7 1 : selected AEs (%) All Grades Adverse events n=336 DTIC n=282 Arthralgia 56 4 Rash 41 2 Fatigue 46 35 Photosensitivity 41 5 LFTs 26 6 cuscc (cutaneous squamous cell carcinoma) 19 <1 Chapman ASCO Overall Survival by baseline characteristic (February cut-off) censored at crossover Toxicity in older patients Number Factor of patients All patients 675 Age: <65 years 65 years 514 161 Sex: Female Male ECOG status: 1 Disease stage: IIIc M1a M1b M1c LDH: Normal Elevated 294 381 459 216 33 74 127 441 391 284 Favours vemurafenib Favours dacarbazine CYP1A2 inhibited (increased exposure) Amitriptyline Naproxen Ondansetron Verapamil warfarin CYP 2C9 inhibited (increased exposure) ACE II inhibitors Losartan Irbesartan Sulfonylureas Glicazide Fluoxatine warfarin CYP3A4 increased (reduced exposure) Macrolides antibiotics Antihistamines Immunemodulators Benzodiazepinrs Calcium channel blockers Atorvatatsin Lorvastatin Simvastatin Progesterone Testosterone Hydrocortisone Fentanyl Docetaxel Tamoxifen.2.4.6 1. 2 4 6 1 2 HR and 95% CI 2
Dabrafenib in Metastatic Malignant Melanoma BREAK-3: study design Primary endpoint: Investigator-assessed PFS > 95% power to detect HR of.33 Screened N=733 Enrolled n=25 Dabrafenib 15 mg twice daily n=187 3:1 randomization Stratification factors: unresectable stage III, stage IV; M1a+M1b vs M1c DTIC 1 mg/m2 IV every 3 weeks n=63 Cross-over allowed at radiologic PD Dabrafenib 15 mg twice daily n=28 (68% of PD patients) Secondary objectives: OS, ORR in both groups and after cross-over, PFS2 (after cross-over), duration of response, safety/tolerability and mutation assay validation Proportion Alive Without Progression 1..9.8.7.6.5.4.3.2.1 PFS: Independent reviewer-assessed (cut-off: 19/12/211) HR.35 (95% CI.2,.61) DTIC: median PFS 2.9 mths. 1 2 3 4 5 6 7 8 9 Time from Randomization (Months) Number at risk 187 182 167 112 98 39 28 7 4 63 53 32 16 12 5 4 2 Dabrafenib: median PFS 6.7 mths Skin GI Hematologic Other Treatment-related AEs: 5% of patients Dabrafenib, n (%) DTIC, n (%) AE All Grade 3 Grade 4 All Grade 3 Grade 4 Hyperkeratosis 95 (51) 1 (<1) 1 (<1) Palmar-plantar hyperkeratosis 39 (21) 4 (2) 1 (2) SCC/KA 13 (7) 9 (5) Nausea 18 (1) 21 (36) Vomiting 8 (4) 12 (2) Neutropenia 2 (1) 1 (<1) 9 (15) 3 (5) 4 (7) Thrombocytopenia 1 (<1) 1 (<1) 5 (8) 1 (2) 2 (3) Leukopenia 1 (<1) 3 (5) 1 (2) Arthralgia 3 (16) 1 (<1) Fatigue 32 (17) 2 (1) 13 (22) Headache 32 (17) 2 (3) Pyrexia 28 (15) 5 (3) Asthenia 26 (14) 7 (12) Photosensitivity: dabrafenib (3%), DTIC (5%) New primary melanoma: dabrafenib (2%) Dabrafenib brain metastases: No prior brain treatment: Maximum percent change from baseline intracranial measurement 1 8 6 4 2-2 -4-6 OIRR: 39% ORR: 38% Intracranial disease control rate: 81% Overall disease control rate: 8% Trametinib in malignant melanoma METRIC Study -8-1 3
Targeted anti- therapy METRIC: Phase III Melanoma Study 4-6% of melanomas RAS V6E Cellular Proliferation RTK TRAMETINIB Trametinib 2mg QD (n=214) FSFV: Dec 21 LSFV: July 211 Screened (N=159) V6E/K mutation (n=322) PFS Chemotherapy * (n=18) Stratification factors LDH (> ULN vs. < ULN) Prior chemotherapy (Yes vs. No) Primary endpoint Progression-Free Survival (PFS) in V6E positive melanoma Cross-over** Trametinib 2mg QD *Chemotherapy = DTIC or paclitaxel **Allowed after independent confirmation of progression METRIC Adverse Events (>15% of patients) Preferred Term (>15% of subjects) Trametinib n=211 i known events with Trametinib: Decreased Ejection Fraction / Ventricular dysfunction = 14 (7%) Chorioretinopathy = 1 (<1%) No reported case of cutaneous SCC or hyperproliferative skin lesions Chemotherapy n=99 Rash 121 (57%) 1 (1%) Diarrhoea 91 (43%) 16 (16%) Oedema peripheral 54 (26%) 3 (3%) Fatigue 54 (26%) 27 (27%) Dermatitis acneiform 4 (19%) 1 (1%) Nausea 38 (18%) 37 (37%) Alopecia 36 (17%) 19 (19%) Hypertension 32 (15%) 7 (7%) Constipation 3 (14%) 23 (23%) Vomiting 27 (13%) 19 (19%) 21 Proportion Alive and Progression-Free 1..9.8.7.6.5.4.3.2.1 METRIC Investigator-Assessed PFS ITT Events n (%) Median (months) HR (95% CI) P-value Response Rate Trametinib 118 (55) 4.8.45 (.33,.63) 22% Chemotherapy 77 (71) 1.5 <.1 8%. 1 2 3 4 5 6 7 8 9 Time From Randomization (Months) Number at risk Trametinib 214 25 163 1 88 28 22 5 Chemotherapy 18 87 43 24 21 1 6 1 1..9.8 METRIC Overall Survival ITT RAS i Dabrafenib + Trametinib combination rationale Proportion Alive.7.6.5.4.3 i (dabrafenib) RR 59% Key toxicity: Hyperkeratosis i (trametinib) RR 22% Key toxicity: rash Goals of combination 1. Synergy in combination 2. Prevent/overcome potential monotherapy resistance.2.1. Events, Median HR (95% CI) 6 Month OS n (%) (months) P-value (95% CI) Trametinib 35 (16) --.54 (.32,.92) 81 (73, 86) Chemotherapy 29 (27) --.136 67 (55, 77) p 1 2 3 4 5 6 7 8 9 1 Time From Randomization (Months) Number at risk Trametinib 214 28 23 192 17 15 53 24 5 Chemotherapy 18 96 94 9 72 47 28 15 4 1 47% of the patients in the chemotherapy arm crossed over to trametinib Proliferation Survival Invasion Metastasis 4
Phase II combination study Progression Free Survival Efficacy End Points in Part C (Intention-to-treat Population) HRs and P values are for comparison between each combination-therapy group and the monotherapy group End point Dabrafenib Monotherapy (N=54) Combination 15/1 (N=54) Combination 15/2 (N=54) PFS (mths) Median (95% CI) 5.8 (4.6-7.4) 9.2 (6.4-11) 9.4 (8.6-16.7) HR for death or progression (95% CI) Reference.56 (.37 -.87).39 (.25 -.62) P value Reference.6 <.1 PFS at 12mths (95% CI) - % 9 (3-2) 26 (15-39) 41 (27-54) Best response no. (%) Complete response 2 (4) 3 (6) 5 (9) Partial response 27 (5) 24 (44) 36 (67) Stable disease 22 (41) 24 (44) 13 (24) Progressive disease 3 (6) 2 (4) Could not be evaluated 1 (2) Complete/ partial response % Patients (95% CI) 54 (4-67) 5 (36-64) 76 (62-86) P value Reference.77.3 Duration of response (mths) Median 5.6 9.5 1.5 95% CI 4.5-7.4 7.4 - NA NHS Foundation 7.4-14.9 Trust Phase II combination study Subgroup Analyses Toxicity dabrafenib + trametinib Adverse Events Reported in Part C Mechanisms of Resistance to Inhibitors Conclusions Nazarian et al. Nature 21 Johannessen et al. Nature 21 NRAS Q61 COT -dependent progression CRAF inh V6E Wagle et al. JCO 211 P P Poulikakos et al. Nature 211 Shi et al. Nature PDGFRb or IGF1R PI3K AKT -independent progression Nazarian et al. Nature 21 Villanueva et al. Cancer Cell 21 Targeted therapy a major advance in metastatic disease Improvements in PFS & OS Dramatic improvement in QOL & function Mutation status changes with age No clear age related toxicity but concomitant meds may impact on this Combination therapy deliverable at full dose with reduced toxicity Survival 5
Strategic Direction New combinations and sequences to overcome resistance Thank you Combination of inhibitors and immunotherapy to try to maximise benefits of both High response rate Long term survival Adjuvant therapy 6