Evolving Treatment Strategies in the Management of Metastatic Melanoma: Novel Therapies for Improved Patient Outcomes. Disclosures

Transcription

1 Evolving Treatment Strategies in the Management of Metastatic Melanoma: Novel Therapies for Improved Patient Outcomes Fall Managed Care Forum November 11, 2016 Matthew Taylor, M.D. Disclosures Consulting/Advisory board member Eisai Inc. Bristol Myers Squibb Blueprint Medicines Trillium Pharma 1

2 Objectives FDA approved systemic therapies for metastatic melanoma Patient candidacy for systemic therapy Anti PD1 inhibitor therapies NCCN treatment guidelines Patient participation in therapy decisions Background 2

3 FDA approved drugs for melanoma: A rapidly changing landscape Ipilimumab+Nivolumab Talimogene laherparepvec T Vec Cobimetinib Pembrolizumab, Nivolumab Dabrafenib, Trametinib Ipilimumab, Vemurafenib Dacarbazine High dose IL Patient Candidacy for systemic therapy Determination of unresectable disease Physician assessment of co morbid illness Overall health/performance status, organ dysfunction, autoimmune illness, organ transplant history, etc Transparent discussion regarding potential benefits and risks of therapy 3

4 High dose interleukin 2 (IL 2) FDA approved 1992 High dose IL-2: 270 patients evaluated on 8 trials. 17 (6%) with CR 26 (10%) with PR 2% died from treatment complications Atkins; J Clin Oncol 17: Immune Checkpoints 4

5 Anti CTLA 4: Ipilimumab (FDA approved 3/2011) Hodi, N Engl J Med 2010;363: Anti CTLA 4: Ipilimumab 9/ /2013 5

6 Anti CTLA 4: Ipilimumab: immune mediated toxicity Skin rash/itching Diarrhea/colitis Endocrinopathies Hypophysitis Adrenal insufficiency Hepatitis neuropathy Ipilimumab MOA: anti CTLA 4 (co inhibitory immune checkpoint) Overall response rate: 11 a 19 b % Median progression free survival: 2.9 b 4.4 c months 2 year overall survival: 25 d % Grade 3/4 adverse events: 24 c 56 b % a: Hodi, et al. NEJM 2010;363: b: Larkin, et al. NEJM 2015;373:23 34 c: Postow, et al. NEJM 2015;372: d: McDermott, et al. Ann Oncol 2013;00:1 5 6

7 Genetic alterations in melanoma Flaherty, et al. Nature Reviews Cancer BRAF inhibitor: Vemurafenib (FDA approval 8/2011) Overall response rate: 48% Overall response rate: 5% Chapman, N Engl J Med 2011;364:

8 BRAF inhibitor: Vemurafenib (FDA approval 8/2011) Chapman, N Engl J Med 2011;364: Side effects of BRAF/MEK inhibitors Management of side effects Skin rash Topical antibiotics/corticosteroids Fatigue Fevers NSAIDS/acetaminophen Diarrhea Antidiarrheal agents Arthralgia NSAIDS/acetaminophen Lower extremity edema Decreased left ventricular ejection fraction Central serous retinopathy **Dose reductions** 8

9 BRAF inhibitor: Vemurafenib BRAF + MEK inhibitors: Dabrafenib + Trametinib vs Vemurafenib Overall Response Rate Dabrafenib/Trametinib: 64% Vemurafenib: 51% Median PFS Dabrafenib/Trametinib: 11.4 months Vemurafenib: 7.3 months Robert, et al NEJM; 372:30-9 Combination FDA approved

10 Dabrafenib + Trametinib MOA: Dabrafenib (oral BRAF inhibitor) Trametinib (oral MEK inhibitor) Overall response rate: 64 a % Median progression free survival: 11.4 a months 2 year overall survival: 51 b % Grade 3/4 adverse events: 48 a % a: Robert, et al. NEJM 2015;372:30 39 b: Long, et al. JCO 2016;34:1 8 FDA approved in 2013 Vemurafenib + Cobimetinib MOA: Vemurafenib (oral BRAF inhibitor) Cobimetinib (oral MEK inhibitor) Overall response rate: 68 a % Median progression free survival: 10 a months 2 year overall survival: 48 b % Grade 3/4 adverse events: 62 a % a: Larkin, et al. NEJM 2014;371: b: Ascierto, et al. Lancet Oncol 2016;17: FDA approved in

11 Anti programmed death receptor 1 treatment with pembrolizumab in ipilimumab refractory advanced melanoma: a randomized dose comparison cohort of a phase 1 trial Overall Response Rate: 26% Robert et al, Published online July 15, (14) FDA approved in 2014 Side effects of PD1 inhibitors Rash/itching Diarrhea/colitis Endocrinopathies (hyophysitis, thyroiditis, adrenal insufficiency, diabetes, etc) Pneumonitis Hepatitis uveitis Nephritis Neuropathies (myasthenia like syndromes) 11

12 Management of immune mediated side effects Mild: Topical corticosteroids (skin rash, uveitis) Moderate: Treatment interruption (*no dose reductions) Oral systemic corticosteroids (0.5 1 mg/kg/day, slow taper) Severe: Permanent discontinuation of causal agent IV systemic corticosteroids (1 2 mg/kg/day, slow taper with oral steroids) Anti TNFα (infliximab) *Note: endocrinopathies infrequently resolve best managed with hormone replacement therapy (levothyroxine, hydrocortisone, etc) Pembrolizumab MOA: anti PD1 (co inhibitory immune checkpoint) Overall response rate: 26 a 33 b % Median progression free survival: b months 2 year overall survival: 50 c % Grade 3/4 adverse events: 13 b % a: Robert, et al. Lancet Oncol 2014;384: b: Robert, et al. NEJM 2015;372: c: Robert, et al. ASCO Annual meeting 2016; abstract 9503 FDA approved in

13 Nivolumab MOA: anti PD1 (co inhibitory immune checkpoint) Overall response rate: 38 a 44 b % Median progression free survival: 4.7 a 6.9 b months 2 year overall survival: 48 c % Grade 3/4 adverse events: 9 a 44 b % a: Weber, et al. Lancet Oncol 2015;16: b: Larkin, et al. NEJM 2015;373:23 34 c: Hodi, et al. ASCO annual meeting 2014; abstract 9002 Combinations of immune checkpoint inhibitors Nivolumab + Ipilimumab Postow MA et al. N Engl J Med DOI: /NEJMoa

14 Combinations of immune checkpoint inhibitors Nivolumab + Ipilimumab Postow MA et al. N Engl J Med DOI: /NEJMoa Combinations of immune checkpoint inhibitors Nivolumab + Ipilimumab Postow MA et al. N Engl J Med DOI: /NEJMoa

15 Nivolumab + Ipilimumab Overall response rate: 58 a 61 b % Median progression free survival: 11.5 a months 2 year overall survival: 64 c % Grade 3/4 adverse events: 54 b 69 a % a: Larkin, et al. NEJM 2015;373:23 34 b: Postow, et al. NEJM 2015;372: c: Hodi, et al. Lancet Oncol 2016 Combination FDA approved in 2015 Talimogene Laherparepvec (Tvec) Oncolytic virus HSV type 1 virus: replication competent, virulence genes deleted, hgm CSF expression cassette added. Trial included patients with unresectable/metastatic melanoma Randomized: Intra tumor injection of Tvec vs sub cutaneous GM CSF 436 patients enrolled Overall response rate: Tvec: 26.4% GM CSF: 5.7% Andtbacka, et al. JCO

16 2 Year Overall Survival 2 year OS (%) *Avril MF, JCO 2004 **Atkins MB, JCO 1999 Predictive biomarkers for patient selection for PD1 inhibitors PD L1 tumor expression Evidence of clinical benefit in both PD L1+ and PD L1 tumors (metastatic melanoma) FDA approved companion diagnostic PD L1 testing (not required for melanoma patients) NCCN regarding PD L1 testing:...in current form they are not sufficiently reproducible, widely available, nor discriminative for screening patients with melanoma (NCCN version ) 16

17 National Comprehensive Cancer Network (NCCN) guidelines Treatment selection in patients with BRAF mutant metastatic melanoma Disease burden & pace of progression Symptomatic disease Co morbidities Patientcomfort with potential risks of therapy 17

18 Summary Advances in melanoma tumor biology have led to several novel melanoma therapies New targeted and immunotherapies have unique toxicities that require careful management Novel melanoma therapies are demonstrating unprecedented efficacy resulting in improved survival outcomes 18