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The Royal MarsdenOverview– Melanoma key facts– Case presentation– Molecular classification of melanoma– Selection of patients for therapy– c-KIT: Proof-of-concept– BRAF: Breakthrough– The Future

The Royal MarsdenMelanoma Key Facts (1)– Over 10,000 cases in 2006 in UK– 2nd commonest cancer age 15-34– 6th most common cancer overall (~3%)– Incidence rising faster in UK than any othercancer– Melanoma arises mainly in the skin– Main risk factor = UV light– Rare forms though e.g. ocular, mucosal

The Royal MarsdenMelanoma Key Facts (2)– Treatment = surgery (~80% 5 yr survival)– Melanoma is notoriously resistant to radiotherapyand cytotoxic chemotherapy– ‘Standard’ palliative chemotherapy (DTIC) has notchanged since 1970s and no trial vs best supportivecare– BUT molecular classification heralds a newapproach to treatment

The Royal MarsdenCase Presentation: 33 yo male– Pilot, married, no children– Change in mole in suprasternal notch– Lesion excised = 0.9mm melanoma– Seen in clinic: mass in right SCF– FNA = melanoma– CT thorax, abdomen and pelvis clear– Right neck dissection 1/25 lymph nodes involved withmelanoma

The Royal MarsdenCase Presentation: 33 yo male– Link with Clinical Nurse Specialist– Stage III disease: fitness to fly?– Stage III disease: role of adjuvant therapy?– Further CT scan (AVAST-M work up) ?haemangioma in liver– US of liver: probably benign– Randomised to observation– Further CT scan 3 months later

The Royal MarsdenCase Presentation: 33 yo male– Widespread metastatic disease– LDH twice upper limit of normal so ineligible for aclinical trial– Sperm banking done– Treated with 3 cycles of dacarbazine– Two hospital admissions for symptom control– Palliative care links set up– Further CT scan

The Royal MarsdenCase Presentation: 33 yo male– Despite enormous advances in molecular biology inthe last 10 years, so far this has not translated intoimproved outcomes for patients with advancedmelanoma– There is a lot of work to do to try to change this– There are some early signs that progress may bebeing made

The Royal MarsdenRTK e.g. c-KITNRASRAFBRAF V600EMEKERKAbnormal Cellular CellularProliferationc-KIT ~ 2%BRAF ~ 50%NRAS ~ 25%GNAQ ~ 2%

The Royal MarsdenMolecular classification of melanoma– Melanomas can be classified according mutuallyexclusive BRAF, NRAS and c-KIT mutations– Mucosal and acral melanomas have c-KIT mutations– c-KIT mutated in majority of GISTs– Prolonged survival with imatinib in GISTCurtin et al. N Engl J Med. 2005;353(20):2135-47.Curtin et al. J Clin Oncol. 2006;24(26):4340-6.

The Royal Marsdenc-KIT: Proof-of-concept– Initial case reports in 2008 of efficacy of c-KITtherapy in acral/mucosal melanoma– Imatinib in 3 cases / sorafenib in 1 case– All 4 patients had c-KIT alterations– This was proof-of-concept for targeted therapy inmelanomaHodi et al. J Clin Oncol. 2008 Apr 20;26(12):2046-51Lutzky et al. Pigment Cell Melanoma Res. 2008 Aug;21(4):4Kim et al. Br J Cancer. 2008 Sep 2;99(5):734-40Quintás-Cardama et al. Nat Clin Pract Oncol. 2008 Oct 21

The Royal MarsdenNICAM: A Phase II Trial of Nilotinib in c-KIT MutantAcral and Mucosal Melanoma– 9 centres around UK led from RMH/ICR– Subjects screened for c-KIT mutations (~120 over 2years)– Primary endpoint = PFS at 6 months (n=24 subjectswith mutations)– An important goal is to investigate biology (SamraTurajlic, Richard Marais ICR)

The Royal MarsdenRTK e.g. c-KITNRASRAFBRAF V600EMEKERKAbnormal Cellular CellularProliferationc-KIT ~ 2%BRAF ~ 50%NRAS ~ 25%GNAQ ~ 2%

The Royal MarsdenBRAF: Breakthrough– Activating mutations of non-receptor TK BRAF in~50% of cutaneous melanomas– The (weak) BRAF inhibitor sorafenib is not active inthis setting– PLX4032 is a potent BRAF inhibitor– Data from the PLX4032 Phase I study and anextension cohort presented in 2009Flaherty et al. ASCO 2009 Abstract 9000Chapman et al. ECCO/ESMO 2009

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The Royal MarsdenWhat about other drugs?– Ipi: increased overall survival 2 nd line– NOT ‘targeted’ cf anti-BRAF/c-KIT drugs– ASCO 2010: GSK BRAF and MEK inhibitors areactive in BRAF mutant melanoma

The Royal MarsdenWhat about GNAQ and NRAS?– ~25% of patients with cutaneous melanoma haveNRAS mutations– ~80% of ocular melanomas have mutually exclusivemutations in GNAQ or GNA11– We do not know how to target these groupstherapeutically– Further work is neededVan Raamsdonk NEJM 2010

The Royal MarsdenConclusions (1)– Some melanomas are dependent on signallingthrough certain pathways (cf. c-KIT in GIST andEGFR in NSCLC)– Molecular classification of melanoma is clinicallyrelevant– Further trials are needed to define safety, efficacy,biology and resistance– Tissue collection for genotyping and for research iscritical

The Royal MarsdenConclusions (2)– Biopsy of progressing metastatic lesions to definemechanism of resistance may form part of futureclinical practice– The NICAM trial for c-KIT mutant melanoma is open– GSK MEKi trial and wider access to RG7204 /PLX4032 are imminent– If licensed, access to these drugs on the NHS may notbe guaranteed