Acute drug reactions associated with the novel targeted therapies used in treating skin cancer

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1 Acute drug reactions associated with the novel targeted therapies used in treating skin cancer Dr Rishika Sinha Consultant Dermatologist Chelsea & Westminster Hospital NHS Foundation Trust West Middlesex University Hospital

2 Aims Talk about common skin toxicities with newer targeted agents used to treat melanoma skin cancers: BRAF MEK Vemurafenib (Zelboraf) Dabrafenib (Tafinlar) Trametinib (Mekinist) Immunotherapies Ipilimumab (Yervoy) PD1 Pembroluzimab (Keytudra) Nivolumiab (Opdivo)

3 Targeted therapies Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumour growth and progression. In melanoma, certain genetic mutations promote the growth of the tumour: BRAF (50%), NRAS (20%) c-kit (2-5%) Davies et al. Nature. 2002;417:949-54

4 Other targeted therapies Aswell as Targeted therapies, Immunotherapy can be considered a form of targeted therapy specifically targeting the immune system IPILUMMUAB NIVOLUMAB

5 Targeted therapies in Melanoma BRAF inhibitors Vemurafenib licensed in February 2012 Dabrafenib MEK inhibitors Often in combination with BRAF inhibitors Ipilimumab Anti PD1 C Kit inhibitors

6 Why are skin toxicities relevant? Skin toxicities can cause significant discomfort and distress to the patient Considerable impact on overall QOL (anybody who has come across an eczema or psoriasis sufferer can tell you that first hand) Can lead to early cessation of anti-cancer treatment Unfamiliarity with skin toxicities may lead to physician doubt, therefore causing unnecessary interruptions (or at worst, cessation) in treatment

7 Manageable side effects Counselling Early recognition Management of skin side effects can lead to treatment success

8 BRAF inhibitors vemurafenib dabrafenib

9 NRAS BRAF Proto-oncogene Critical serine/threonine Activated by somatic mutation V600E RAF BRAF V600E MEK ERK Abnormal Cellular Cellular Proliferation

10 NRAS Vemurafenib Dabrafenib Potent BRAF inhibitor Oral therapy BRAF V600E MEK ERK Abnormal Normal cellular Cellular Proliferation

11 Vemurafenib

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13 Skin toxicities with Vemurafenib Our experience at the Marsden Studied 107 patients retrospectively Looked at common skin toxicities When they occurred Management

14 Adverse event Male : female ratio, n (%) Mean time to Rash 28 (54) : 24 (46) onset, days Adverse-event treatment and dose modifications applied Grade 1 21 (81) : 5 (19) 60 No additional treatment required or managed with emollients. None required systemic corticosteroids Grade 2 6 (30) : 14 (70) 12 Four patients required treatment interruption and restarted at 720 mg twice daily Grade 3 1 (20) : 4 (80) 11 All patients had treatment interruption and restarted at a lower dose. Three patients were treated with prednisolone mg Photosensitivity 19 (59) : 13 (41) 53 Grade 1 11(55) : 9 (45) 49 Grade 2 6 (67) : 3 (33) 48 Grade 3 1 (100) : Folliculitis 6 (100) : 0 83 Three patients required treatment with lymecycline Dry skin 11 (58) : 8 (42) 68 All patients were treated with emollients Keratoacanthoma or squamous-cell carcinoma Squamoproliferative growths 9 (56) : 7 (44) 97 Majority surgically excised; 1 patient received topical 5-fluorouracil 19 (54) : 16 (46) 79 ± 74 All patients were treated with cryotherapy Erythema nodosum 0 : 7 (100) 44 Two patients required systemic corticosteroids mg Hyperkeratosis 8 (47) : 9 (53) 76 ± 44 Treated with urea-containing emollient (Flexitol, LaCorium Health UK, Milton Keynes, UK); pedicure provided symptomatic relief Alopecia 13 (43) : 17 (57) 89 ± 41 No effective treatment available Milia 0 : 3 (100) 89 ± 68 No effective treatment available

15 Rash

16 Vemurafenib related toxicity: Management of Skin Toxicities Grade 1 Grade 2 Macular / Papular or Perifollicular Eruption No symptoms Macular / Papular or Perifollicular Eruption With symptoms (itching or soreness) <50% skin surface Observation, emollients Antihistamines, emollients If persistent refer to Dermatologist and consider topical steroids, Elocon or Betnovate ointment If intolerable consider dose reduction Emollients Shampoos soap substitutes/bath additives Dermal 500, Balneum plus water base Doublebase, Cetraben ointments Epaderm, 50:50 WSP:LP Dermax or Capasal twice weekly Antihistamines SEDATING : Hydroxyzine 25-50mg nocte (do not use if driving) NON SEDATING: Cetirizine 10-40mg od, Fexofenadine 180 mg od

17 Vemurafenib related toxicity: Management of Skin Toxicities Grade 3 Macular / Papular Eruption or Perifollicular With symptoms (itching or soreness) + >50% skin surface Refer to Dermatologist Antihistamines, emollients, topical steroids; Elocon or Dermovate Consider oral steroids: Prednisolone 0.5mg/kg od x 5-7d (max of 60mg/day) Hold Vemurafenib until <grade 1 then restart at lower dose (720mg to 480mg bd) Grade 4 Stevens Johnson/Toxic epidermal necrolysis (widespread red skin with peeling or blister formation + mucosal involvement) Admission IV fluids and electrolytes Discontinue Vemurafenib Call Dermatologist for opinion, advise treatment and skin biopsy

18 Summary of Rash Mean time to onset 32 days into treatment Folliculocentric eruption typical ( goose bumps ) Distribution - Limbs and trunk Be aware of the rash that blisters. 1 case of TEN.

19 Photosensitivity

20 Photosensitivity Almost all of the patients initially enrolled to the BRIM 3 study developed photosensitive reactions to vemurafenib Within 15 minutes of exposure Chest, arms, face and feet within 1-2 weeks of starting the drug Patients reported-phototoxic symptoms indoors and driving Phototoxic risk remains throughout course of treatment

21 Management of phototoxicity Similar to sunburn Emollients Topical steroids Avoid and cover-up SPF and UVA rating 5* sun protection cream 1 patient required oral prednisolone, break of 17 days and dose reduction by 25%

22 Squamoproliferative lesions

23 Squamous papillomas, KA and SCC Proliferative growths on the skin KA and SCC classified as cancerous growths Skin type 1 2 Older patients Photo-damaged skin Mean time to onset 92 days Can be eruptive Once they have occurred effects are not repetitive

24 Management - Squamous papillomas, KA and SCC Refer to Dermatologist Small, irritating squamous papillomas Cryotherapy (liquid nitrogen) Keratoacanthoma / squamous cell carcinoma Excision/currettage suspected KA/SCC Efudix, Aldara Acitretin

25 Hyperkeratosis

26 Hyperkeratosis - feet Very problematic - painful Interferes with walking In one patient treatment break of one week necessary Hyperkeratosis may also be manifested as plantar verrucae

27 Management Analgesia Emulsiderm soaks Diprosalic salicylic acid with topical steroid Dermovate under occlusion Flexitol heel balm / urea containing emollients (calmurid, Eucerin)

28 Rare stuff

29 Radiation recall Acute inflammatory reaction confined to previously irradiated areas and triggered by the administration of precipitating systemic agents weeks to years after the radiation treatment Common agents: gemcitabine, docetaxol, etoposide, doxorubicin, vemurafenib

30 Management algorithm of BRAF-related skin side effects Sinha et al British Journal of Dermatology 2012, 167, p

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32 Dabrafenib Side effects similar to Vemurafenib Differences however include: Grover s disease (27%) No photosensitivity Pyrexia Anforth et al. Cutaneous manifestations of dabrafenib (GSK ): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. BrJ Dermatol

33 Grover s management No curative treatment Topical steroids eumovate, betnovate Moisturisers cetraben, diprobase Keep cool 2% menthol in aqueous cream Trial course of tetracyclines

34 Summary -BRAFi Skin side effects are common SE manageable and patients should remain on drug if possible Hypothesis - the adverse drug effects are primarily secondary to an upregulation of an alternative signalling pathway rather than a true hypersensitivity response. RASopathic - cutaneous side effects of BRAF inhibitors simulate some of the cutaneous findings seen in patients with germline RAS mutations e.g. cardiofaciocutaneous (CFC) syndrome

35 Summary -BRAFi Close collaboration with Dermatologists can prolong treatment course Advise regular skin checks Early recognition and prophylactic advice on photosensitivity essential Dabrafenib can be good alternative for patients intolerant of skin side effects of Vemurafenib

36 MEK inhibitors

37 Adverse events associated with TRAMETINIB therapy

38 Management of MEK inhibitor rashes At outset Topical emollients Sun screen Clindamycin topical solution 1% Consider lymecycline bd or doxycycline 100mg BD Grade 1 Add in topical steroids : Elocon or Betnovate ointment Grade 2 Continue systemic antibiotics Increase Topical steroids : Dermovate, Dermovate NN Stop topical antibiotic

39 Management of MEK inhibitor rashes If rash progresses to Grade 3 Interrupt treatment Continue same topical treatment and systemic antibiotic (lymecycline or doxycycline) Consider short term oral steroid (0.5 to 1 mg/kg for 7 days) if very severe rash OR, if extensive infection, change oral antibiotics; consider IV s 1.If grade 1 or 2 rash is considered tolerable by the patient, treatment can be continued at the same dosing with supportive treatment (level 1 topical steroids and antibiotics) 2. If grade 1 or 2 rash is considered not tolerable by the patient despite maximal supportive treatment, treatment can be transitory interrupted (management as in grade 3)

40 Summary MEK inhibitors The clinical spectrum of cutaneous lesions observed resembles the known cutaneous toxicities that occur with EGFR inhibitors. Inhibition of the MAPK signaling pathway in keratinocytes appears to result in similar side effects either by blockade of the EGF receptor or the MEK kinase.

41 Summary MEK inhibitors Additionally depigmentation of scalp hair occurs as has already been observed in therapy with c-kit inhibitors. Oedema is a significant problem (seen with other TKI s) Management of skin toxicities very similar to EGFRI s

42 Immunotherapy ipilimumab nivolumab

43 Ipilumumab Ipilimumab is a fully human monoclonal antibody (IgG1) that blocks CTLA-4 to promote antitumor immunity Recently used to treat patients with un-resectable metastatic melanoma Associated with significant side effects

44 Most frequent immune-related adverse events with Ipilumumab Ipilumumab 3mg/kg* Dermatological 43.5% 1-2% grade 3 Gastrointestinal 29% Colitis 7.6% (5.3% grade 3) Endocrine 7.6% Hepatic 3.8% 29% Ipilumumab 10mg/kg (plus Dacarbazine)# 49% 3.2% grade % Colitis 4.5% (1.6% grade 3) *Hodi FS, O'Day SJ, McDermott DF, et al. N Engl J Med Aug 19;363(8): Improved survival with ipilimumab in patients with metastatic melanoma. #Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med Jun 30;364(26):

45 Ipilimumab-related toxicity: Management of Skin Toxicities Grade 1 Grade 2 Grade 3 Grade 4 Macular / Papular Eruption No symptoms Symptoms (Pruritus) <50% skin surface Symptoms + >50% skin surface Generalised, exfoliative, ulcerative, bullous dermatitis Observation If persistent consider antihistamines (see box below) Antihistamines If persistent consider steroids; either topical if localised rash (Dermovate cream bd) systemic for more extensive rash (Prednisolone 1mg/kg od x 3d, maximum of 60mg/day) Antihistamines Oral steroids: Prednisolone 1mg/kg od x 5-7d (max of 60mg/day) Hold ipilimumab until <grade 2 Admission IV fluids and electrolytes Hydrocortisone IV 100mg QDS once rash controlled taper over > 1 month Permanent discontinuation of ipilimumab Refer to Dermatologist may need skin biopsy and advise treatment Antihistamines Clorphenamine maleate (Piriton ) 4mg every 6-8 hours. Duration: Causes drowsiness do not use if driving Until all skin lesions Cetirizine 10mg od have disappeared Loratadine 10mg od The Royal Marsden Hospital Sept 2010

46 Ipilimumab Vemurafenib Sensitivity Skin Reaction after Ipilimumab N Engl J Med 2012; 366: March 1, patients treated within 4 weeks of stopping Ipilimumab 4 (31%) developed grade 3 reaction within 6 to 8 days Grade 3 rash was reported in only 7 to 8% of patients treated in phase 2 and phase 3 trials Not responsive to glucocorticoids All responded to a treatment break and re-started at a lower dose

47 Nivolumab Pembrolizumab Not as many skin side effects observed Vitiligo in KEYNOTE-001 study

48 c-kit inhibitors c KIT (CD117) a tyrosine kinase receptor Mutated in up to 10% of acral and mucosal melanomas (5% of all melanomas caucasians, 70% in Asian population) and those melanomas arising in chronically sun damaged skin Nilotinib (NICAM study at the Marsden) 20% developed skin rash

49 Summary Cutaneous toxicities associated with the newer targeted anticancer agents Rapidly advancing field Significant cutaneous toxicities Develop good management algorithms Side effects are generally tolerable Combination therapies will be standard of care

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