Toxicity of Systemic Melanoma Therapies. Alex Guminski Melanoma Institute Australia Royal North Shore Hospital University of Sydney

Transcription

1 Toxicity of Systemic Melanoma Therapies Alex Guminski Melanoma Institute Australia Royal North Shore Hospital University of Sydney

2 Disclosures Advisory Board Novartis, BMS, Sanofi, Pfizer Travel support Astellas, BMS

3 Topics Targeted therapy Immunotherapy Spectrum and severity of potential toxicity Time course Management Special populations pre-existing autoimmune disease, elderly Clinical and research notables

4 Toxicity Grading Common Terminology Criteria for Adverse Events (CTCAE Ver 4.0) Grade 1 5 1,2 Mild 3,4 Moderate to Severe, require intervention and potentially hospitalisation 5 Death Grade 3 Lipase elevation vs Grade 3 colitis vs Grade 2 pruritis Is the toxicity manageable? Interrupt, continue ± dose reduce or have to stop treatment?

5 BRAF and MEK Inhibitors BRAF Inhibitors Common toxicities Agent specific Vemurafenib Dabrafenib Cobimetinib Mek Inhibitors Common Toxicities

6 BRIM2 & 3

7 Flaherty NEJM 2012 MEK162 Ascierto et al ASCO 2012 Toxicity Gr 1/2 (%) Nausea 23% 0% Gr 3/4 (%) Vomiting 20 0 Diarrhoea Rash 20 3 Acneiform Dermatitis 60 3 Elevated creatinine phosphokinase Oedema 33 3 Retinopathy events 18 0

8 Combined BRAF + MEK Inhibitors Flaherty et al NEJM 2012

9 Management Fever (Dab+Mek-I) Dose interruption and re-commence when settled Often limited to the first few months of treatment Low to moderate dose steroids e.g. prednisone up to 25mg/day Retinopathy (Mek-I) Eye review especially baseline, interrupt and can continue, CRVO stop permanently Cardiac (Mek-I) ECG ± Echo at baseline, attention to symptoms Hepatoxicity (Vem) Careful monitoring and prompt drug cessation Arthralgias (Vem) Paracetamol, NSAIDS, drug holiday Photosensitivity (Vem) Careful UV protection, including indoors General If need to reduce drug exposure full dose on fewer days or dose reduction

10 Immunotherapy toxicities Any body part or organ that can have the suffix itis added to it gives the spectrum of immunotherapy toxicity However some organs more commonly affected and distinct patterns seen for classes of agents Anti-CTLA4 (Ipilimumab) Rash, colitis, hepatitis, thyroiditis/hypothyroidism, hypophysitis Anti-PD1 (Pembrolizumab, Nivolumab) Rash, thyroiditis/hypothyroidism, pneumonitis, colitis, sinusitis

11 CTLA4 Inhibitor - Ipilimumab Hodi et al NEJM 2010

12 Eggermont et al NEJM 2016 (EORTC Adjuvant Study 10mg/kg)

13 Time to Onset and Resolution Weber JCO 2012

14 Checkmate 067 Larkin et al NEJM 2015

15 Time courses of toxicities Faster earlier onset with combined CTLA4+PD1 immunotherapy? PD1 antibody mediated Autoimmune thyroiditis accelerated course (hyper to hypo) compared with spontaneous autoimmune thyroiditis

16 Management of Immune Related Toxicity Algorithm driven Mild Supportive Care, dose interruption Moderate Oral steroids, dose delay Severe Intravenous steroids, long wean of oral steroids Very Severe/Steroid refractory Infliximab Mycophenolate Transplant immunosuppressives Anti-thymocyte globulin Plasmapharesis

17 Colitis Images courtesy of Dr Stephen Tattersall

18 Naidoo et al JCO Sep 2016

19 Hypophysitis Features Can develop late after ipilimumab treatment May be initially subtle associated with headache, nonspecific malaise, pre-syncope, collapse Can have abrupt onset Rarely reversible

20 Endocrinopathy Usually not reversible Multiple toxicities in same patient hypothyroid, hypoadrenal, hypogonad Replace and continue treatment Hypophysitis and adrenal insufficiency stress steroids Respiratory tract infections Fasting for scans Minor procedures

21 Rare but severe toxicities from anti-pd1 Pancreatitis/Diabetic Ketoacidosis leading to insulin requiring diabetes Severe musculoskeletal syndrome Demyelinating polyneuropathy, Autonomic neuropathy Managed with high dose steroids, plasmapheresis, mycophenolate

22 Toxicity in elderly Targeted Therapy Immunotherapy

23 Hauschild et al SMR 2015 Vemurafenib EAP Open Label Safety Study

24 Anti-PD1 immunotherapy No difference in toxicity for patients aged over 75 versus those under 75 (Rai et al ESMO 2016) Characteristic >75 yo (N = 38) 75 yo (N = 297) p-value Toxicity (irae) No 23 (60%) 193 (65%) Yes 15 (40%) 102 (35%) irae grade I / II 13 (86%) 86 (84%) III / IV 2 (14%) 16 (16%)

25 Immunotherapy and pre-existing autoimmune disease Johnson DB JAMA Oncol patients with metastatic melanoma, all with pre-existing significant auto-immune disease (inflammatory bowel disease, SLE, multiple sclerosis, rheumatoid arthritis) 13 on immune suppression All treated with ipilimumab, 8 had flare of pre-existing autoimmune disease managed with steroids 10 had grade 3-5 irae, one patient with psoriasis died from colitis after delayed presentation 15 patients no severe flare or irae, 20% response rate of melanoma Use of steroids CNS mets and ipi control in 1/21 if on dex and symptomatic vs 9/51 (not randomised, Margolin Lancet Oncol 2012) Low dose steroids do not appear to prevent responses with PD1

26 Notable Points Close monitoring and early intervention can prevent toxicities from becoming severe and allow patients to continue treatment Patient education and engagement critical Unlike chemotherapy, toxicities can arise long after treatment finished Combinations may give severe toxicity Vemurafenib + Ipilimumab - Severe liver toxicity Risk Benefit stratification Biomarkers for risk of toxicity Newer combinations with less toxicity