2018 Master Class for Oncologists New Therapeutic Approaches to Malignant Melanoma F. Stephen Hodi, M.D. Dana-Farber Cancer Institute, Boston, MA
Disclosure I have nothing to disclose. Off Label/Investigational Discussion In accordance with Annenberg Center policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.
Question #1 A 53 yo female with BRAF wild-type metastatic melanoma to the lungs, bone, and brain comes to see you for a consultation regarding treatment. A single lesion in the right parietal lobe was recently treated with stereotactic radiosurgery. What aspects of her care should be discussed with this patient?
Question #1 A. Radiation therapy has been shown to decrease T cell function, so should not be done prior to immune therapy B. Ipilimumab, pembrolizumab, and nivolumab have not been effective in patients with CNS metastases as the antibodies do not cross over into the CNS. CNS is a common site for progression with checkpoint blockade. C. Clinical responses to anti-pd1 are frequently delayed D. Pneumonitis inflammation of the lung is a potentially serious and fatal side effect to anti-pd-1 therapy and requires both radiographic and clinical close follow up. E. High grade diarrhea due to inflammatory colitis is common with anti-pd-1 and should be treated with oral steroids tapered over 1-2 weeks
Question #2 A 64 yo man with metastatic melanoma is being treated with dabrafenib (BRAFi) plus trametinib (MEKi). He reports high grade fevers to 104 o F. What treatment management should be considered?
Question #2 A. High grade fevers are a common intolerant adverse event, and progression frequently occurs do to this. Consider holding both drugs. Add short course of steroids as needed. B. Hold the trametinib as continued treatment with BRAFi (dabrafenib) is most important. Add short course of steroids as needed. C. Hold the dabrafenib as the addition of trametenib leads to fever. Add short course of steroids as needed. D. Fevers indicate an immune response from treatment. Consider adding immune checkpoint blockade. E. High fevers usually preclude a rash/skin toxicity. Examine the patient closely. Consider holding both drugs. Add short course of steroids as needed.
Melanoma The Problem Incidence in US rising faster than any other cancer Approximately 60,000 new cases in US; 8,000 deaths Incidence varies by region US: 15/100,000 New South Wales Australia: 1 in 20
Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) to Treat Melanoma T-cell activation T-cell inhibition T-cell potentiation T cell T cell T cell APC TCR MHC CD28 B7 CTLA4 APC TCR MHC CD28 B7 CTLA4 CD28 APC TCR MHC CD28 B7 X CTLA4 Antibody binds CTLA-4 Wolchok et al., Ann NY Acad Sci, 2013
MDX010-20: Melanoma Study Design Screening Induction > 1 Re-induction in eligible patients Previosly treated HLA-A*0201 positive Pre-treated CNS metastases allowed R A N D O M I Z E Ipilimumab (3 mg/m2 IV q3wks X 4 doses) + gp100 Ipilimumab (3 mg/m2 induction) + placebo gp100 + placebo R E I N D U C E Ipi + gp100 Ipi + placebo gp100 + placebo Follow-up Hodi et al. NEJM 2010
Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone 1-yr 44% 46% 25% 2-yr 22% 24% 14%
Potential Side Effects in Melanoma Patients Any Grade >Grade3 Dermatitis 40% 3% Diarrhea/Colitis 30% 8% Hypophysitis/Thyroiditis 6% 1% Hepatitis and Pancreatitis 9% 6% Other 6% 2% Nephritis Uveitis or Episcleritis Neuritis Overall 70% 20% IRAEs can be waxing and waning
Re-induction: Eligibility Criteria Signs of clinical benefit Patients with progression after: Stable disease of 6 months duration (from baseline) or Confirmed objective response (PR or CR) Acceptable safety No grade 3 iraes No grade 4 toxicity
Best Overall Response Rate at induction Ipi+gp100 Ipi gp100 PR SD PD SD PR Time to Re-induction and Follow-up PR SD Induction Re-induction: #1 #2 #3 * Ongoing x Dead x * * x * * * * * * x x * x x * x x * * x * * * x * * * * 1 2 3 4 5 YEARS * * * * * * * * *
Primary Analysis of Pooled OS Data: 1861 Patients 1.0 0.9 0.8 Median OS (95% CI): 11.4 (10.7 12.1) Proportion Alive 0.7 0.6 0.5 0.4 0.3 3-year OS Rate (95% CI): 22% (20 24%) 0.2 0.1 0.0 Ipilimumab CENSORED 0 12 24 36 48 60 72 84 96 108 120 Months Patients at Risk Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0 Schadendorf et al.jco 2015
Conclusions Ipilimumab is the first drug to demonstrate prolonged survival in a randomized trials in patients with metastatic melanoma Ipilimumab represents a new class of potent targeted T-cell stimulants Activity first/second line (following XRT, chemo, IL-2) and CNS disease Provides long-term survival benefit for a subset of patients
Role of PD-1 in Suppressing Antitumor Immunity Activation (cytokines, lysis, prolif., migration) APC T cell B7.1 CD28 MHC-Ag TCR Signal 1 PD-1 (-) (-) (-) Tumor PD-L1 Inhibition (anergy, exhaustion, death) Tumor Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Role of PD-1 in Suppressing Antitumor Immunity Activation (cytokines, lysis, prolif., migration) APC T cell B7.1 CD28 MHC-Ag Tumor TCR Signal 1 PD-1 PD-L1 Inhibition (anergy, exhaustion, death) (-) (-) Tumor (-) Anti- PD-1 Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Nivolumab: Changes in Target Lesions Over Time in Melanoma Patients 1 mg/kg Dose administered IV Q2wk
Drug-Related Adverse Event Nivolumab Adverse Events All Grades Grades 3-4 Tot Pop* MEL Tot Pop MEL No. (%) of Patients, All Doses Any adverse event 207 (70) 82 (79) 41 (14) 21 (20) Fatigue 72 (24) 30 (29) 5 (2) 2 (2) Rash 36 (12) 21 (20) Diarrhea 33 (11) 18 (17) 3 (1) 2 (2) Pruritus 28 (9) 15 (14) 1 (0.3) Nausea 24 (8) 9 (9) 1 (0.3) 1 (1) Appetite 24 (8) 7 (7) Hemoglobin 19 (6) 7 (7) 1 (0.3) 1 (1) Pyrexia 16 (5) 5 (5) *AEs occurring in 5% of the total population. Common grade 3-4 AEs also included lymphopenia (3 pts) and abdominal pain and lipase increased (2 each). An additional 27 grade 3-4-related AEs were observed and one or more occurred in a single patient. Topalian et al. NEJM 2012
Nivolumab Overall Survival at 5 Years of Follow-up 1.0 0.9 0.8 All Patients (events: 69/107), median and 95% CI: 17.3 (12.5 37.8) NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2 NR) Probability of Survival 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Months Number of Patients at Risk All Patients 107 86 64 51 49 43 41 36 29 17 15 12 3 1 0 NIVO 3 mg/kg 17 15 11 9 8 7 7 6 6 6 6 6 1 0 Hodi AACR 2016 20
Pembrolizumab (MK3475) is a Humanized IgG4, High-Affinity Anti-PD-1 Blocking Antibody Melanoma: Led to approval in ipilimumab refractory, prior BRAFi population: 173 patients 2 mg/kg Q 3 weeks 24% response rate Hamid O et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1305133
Rapid and Durable Changes in Target Lesions in Melanoma Change in target lesions from baseline (%) 1 mg/kg nivolumab + 3 mg/kg ipilimumab First occurrence of new lesion Weeks since treatment initiation A 52-year-old patient presented with extensive nodal and visceral disease Baseline LDH was elevated (2.3 x ULN); symptoms included nausea and vomiting Within 4 wk, LDH normalized and symptoms resolved At 12 wk, there was marked reduction in all areas of disease as shown Wolchok et al. NEJM 2013 Pretreatment 12 weeks At MTD 2 yr OS 88%
Nivolumab plus Ipilimumab Treatment-Related Select Adverse Events Occurring in 1 Patient Select Adverse Event Number of Patients (%) Concurrent Regimen All Cohorts (n=53) Sequenced Regimen All Cohorts (n=33) All Gr Gr 3-4 All Gr Gr 3-4 Pulmonary 3 (6) 1 (2) 1 (3 ) 0 Renal 3 (6) 3 (6) 0 0 Endocrinopathies 7 (13) 1 (2) 3 (9) 2 (6) Uveitis 3 (6) 2 (4) 0 0 Skin 37 (70) 2 (4) 8 (24) 0 Gastrointestinal 20 (38) 5 (9) 3 (9) 0 Hepatic 12 (23) 8 (15) 1 (3) 0 Infusion reaction 1 (2) 0 0 0 Lipase 10 (19) 7 (13) 4 (12) 2 (6) Amylase 8 (15) 3 (6) 1 (3) 1 (3) Presented by: Jedd D. Wolchok, MD, PhD
24 CA209-067: Study Design CA209-067: Study Design Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone* Stratify by: N=314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 BRAF mutation status AJCC M stage Tumor PD-L1 expression <5% vs 5%* N=316 NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression or unacceptable toxicity Co- Primary endpoints: PFS and OS vs IPI Secondary endpoints: ORR, NIVO vs NIVO+IPI (OS and PFS)*, Safety N=315 *The study was not powered for a comparison between NIVO and NIVO+IPI IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo Database lock: Sept 13, 2016 (median follow-up ~30 months in both NIVO-containing arms)
25 Melanoma Overall Survival Overall Percentage Survival of PFS (%) 100 90 80 70 60 50 40 30 20 10 0 NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) Median OS, months (95% CI) NR NR (29.1 NR) 20.0 (17.1 24.6) HR (98% CI) vs. IPI 0.55 (0.42 0.72)* 0.63 (0.48 0.81) -- 73% HR (95% CI) vs. NIVO 0.88 (0.69 1.12) -- -- *P<0.0001 74% 67% 64% 59% 45% NIVO+IPI NIVO IPI 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Number of patients at risk: NIVO+IPI 314 292 265 247 226 221 209 200 198 192 170 49 7 NIVO 316 292 265 244 230 213 201 191 181 175 157 55 3 IPI 315 285 254 228 205 182 164 149 136 129 104 34 4 0 0 0 Wolchok JD et al. NEJM 2017
26 Melanoma OS by Tumor PD-L1 Expression, 5% Cutoff Tumor PD-L1 Expression Level <5% Tumor PD-L1 Expression Level 5% NIVO+IPI NIVO IPI NIVO+IPI NIVO IPI 100 90 Median OS, mo (95% CI) HR (95% CI) vs NIVO NR (31.8 NR) 0.84 (0.63 1.12) NR (23.1 NR) 18.5 (13.7 22.5) 100 90 Median OS, mo (95% CI) HR (95% CI) vs NIVO NR 1.05 (0.61 1.83) NR 28.9 (18.1 NR) 80 80 70 70 72% OS (%) 60 50 40 63% 55% OS (%) 60 50 40 68% 54% 30 41% 30 20 10 20 10 NIVO+IPI NIVO IPI 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Number of patients at risk: NIVO+IPI 210 194 178 163 146 144 139 131 130 127 116 34 7 0 NIVO 208 189 169 151 144 133 123 118 112 110 99 34 2 0 IPI 202 179 158 140 125 108 100 90 81 78 63 18 2 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Number of patients at risk: NIVO+IPI 68 63 56 55 52 50 45 45 45 44 35 11 0 0 NIVO 80 79 75 73 68 63 61 58 57 54 49 18 1 0 IPI 75 72 67 65 61 55 46 43 40 39 33 13 1 0 Wolchok JD et al. NEJM 2017
Management of Inflammatory Adverse Events Algorithms Diarrhea/Colitis High grade/prolonged low grade Rule out other causes/endoscopy, IV steroids, slow taper (e.g. 1 month), infliximab for refractory cases Hepatitis: Follow LFTs, pancreatic enzymes High grade: steroids, mycophenylate Pneumonitis Asymptomatic infiltrate vs. symptom (cough, SOB) Rule out other causes (e.g. flu); hold drug vs. steroids, infliximab resistant cases Endocrinopathies clinical suspicion, pituitary and thyroid
Conclusions Blockade of the PD-1 pathway represents a new immune therapy for patients with melanoma Preliminary data correlating PD-L1 expression in pretreatment tumor biopsies with clinical outcomes Pembrolizumab and Nivolumab are approved Nivolumab+ Ipilimumab approval PD-1 based treatment considered front-line therapy Algorithms for management of inflammatory adverse events Further combinations under development
Downstream signaling events: The MAPK pathway R R Plasma membrane K K Ras Raf MEK RAS mutations: 15% cancers, 90% pancreat (farnesyl transferase inhibitors) BRAF mutations: 66% malignant melanomas (Davies and Futreal, Nature 2002) Erk Proliferation
Selective BRAFi Vemurafenib PET and CT Responses Flaherty et al. NEJM 2010
Phase III BRIM3 Study design Screening BRAF V600E mutation Vemurafenib 960 mg po bid (N=337) Stratification Stage ECOG PS (0 vs 1) LDH level ( vs nl) Geographic region No active CNS disease Randomization N=675 Dacarbazine 1000 mg/m 2 iv q3w (N=338) Chapman NEJM 2011
Melanoma Progression-Free Survival and Overall Survival Chapman PB et al. N Engl J Med 2011;364:2507-2516.
Conclusions Selective BRAF inhibitors are a breakthrough for melanoma Benefit seen in all subgroups and baseline characteristics Despite a 50-80% response rate, vast majority of patients recur and develop resistance
BRAFi Mechanisms of Resistance Luke and Hodi, The Oncologist
BRAFi + MEKi: Melanoma Overall Survival Improved Dabrafenib (BFAFi) + Trametinib (MEKi) Overall Survival Increased incidence of pyrexia Decreased incidence of skin manifestations of BRAFi Robert C et al. N Engl J Med 2015;372:30-39.
Vemurafenib (BRAFi) + Cobimetinib (MEKi) Improves Melanoma Survival Larkin J et al. N Engl J Med 2014;371:1867-1876.
BRAF Targeted Therapy Side effects: rash, arthritis, diarrhea, squamous cell skin cancer, keratoacanthoma, photosensitivity, LFTs, prolonged QTc FDA approved for unresectable or stage IV melanoma with BRAF V600E (Dabrafenib + Trametinib, Vemurafenib + Cobimetinib) Not indicated for wild type BRAF Secondary skin cancers: paradoxical activation of MAPK in HRAS mutated keratinocytes Pyrexia and less skin toxicity with BRAFi + MEKi combination
What to do for a patient with BRAF mutated melanoma? Immune Therapy vs. Targeted Therapy PD-1 based therapy front-line regardless of BRAF status Immune combo vs. PD-1 alone Efficacy weighed with potential side effects Biomarker: PD-L1 expression? After PD-1 based therapy Targeted therapy vs Ipilimumab alone (if not get previously) Clinical trials/further data maturation to guide
Does the benefit of immune and targeted therapies in the metastatic setting offer benefit for adjuvant patients?
EORTC 18071/CA184-029: Study Design High-risk, stage III, completely resected melanoma N=951 N=475 R N=476 INDUCTION Ipilimumab 10 mg/kg Q3W X4 INDUCTION Placebo Q3W X4 MAINTENANCE Ipilimumab 10 mg/kg Q12W up to 3 years MAINTENANCE Placebo Q12W up to 3 years Week 1 Week 12 Week 24 Stratification factors: Treatment up to a maximum 3 years, or until disease progression, intolerable toxicity, or withdrawal Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC 4 positive lymph nodes) Regions (North America, European countries and Australia) Eggermont et al. Lancet Oncology 2015
Overall Survival 4 Eggermont et al NEJM 2016
CA209-238: CA209-067: Study Design Study Design Patients with high-risk, completely resected stage IIIB/IIIC or stage IV melanoma Stratified by: 1:1 n = 453 n = 453 1)Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c 2)PD-L1 status at a 5% cutoff in tumor cells NIVO 3 mg/kg IV Q2W and IPI placebo IV Q3W for 4 doses then Q12W from week 24 IPI 10 mg/kg IV Q3W for 4 doses then Q12W from week 24 and NIVO placebo IV Q2W Follow-up Maximum treatment duration of 1 year Enrollment period: March 30, 2015 to November 30, 2015 42
Recurrence-free Survival, According to Disease Stage. Weber J et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1709030
Recurrence-free Survival in the Intention-to-Treat Population and According to Tumor PD-L1 Expression. Weber J et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1709030
45 Combi-AD: Study design Key eligibility criteria Completely resected, high-risk stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma BRAF V600E/K mutation Surgically free of disease 12 weeks before randomization ECOG performance status 0 or 1 No prior radiotherapy or systemic therapy Stratification BRAF mutation status (V600E, V600K) Disease stage (IIIA, IIIB, IIIC) R A N D O M I Z A T I O N N = 870 1:1 Treatment: 12 months a Dabrafenib 150 mg BID + trametinib 2 mg QD (n = 438) 2 matched placebos (n = 432) Followup b until end of study c Primary endpoint: RFS d Secondary endpoints: OS, DMFS, FFR, safety Long GV et al. NEJM 2017
Relapse-free Survival and Overall Survival. Long GV et al. NEJM 2017
Treatment options for patients with Stage III melanoma Observation IFN Participation in a clinical trial Ipiluminab (antictla4) clinical trials EORTC Ipilimumab vs. observation ECOG study Ipilimumab vs. high dose IFN Nivolumab (short follow-up) Dabrafenib plus Trametinib
Melanoma Treatment Advances Future is Fast Paced Immune modulation CTLA-4 Blockade PD-1 Blockade CTLA-4 + PD-1 Blockades PD-1 based therapy front-line Ipilimumab considered following PD-1 Improved genetic understanding BRAFi + MEKi Sequencing: Immune Therapy vs. Targeted Therapy Adjuvant Therapies: Immune therapy attractive Interferon vs Ipilimumab; Nivolumab; Dabrafenib/Trametinib Longer follow up
Disclosures and Questions Advisor Novartis, Merck Non-paid Advisor and/or Research Support Bristol-Myers Squibb, Genentech Questions: stephen_hodi@dfci.harvard.edu