Recent Advances in Melanoma Therapy Adil Daud MBBS HS Clinical - PDF document

Recent Advances in Melanoma Therapy Adil Daud MBBS HS Clinical Professor of Medicine, Co-Director, Melanoma Program, University of California, San Francisco Even after melanoma, some people keep on using tanning beds - latimes.com HOME PAGE TODAY'S PAPER VIDEO MOST POPULAR TIMES TOPICS Subscribe to Home Delivery daudai... Help Membership Services Jobs Cars Real Estate Subscribe Rentals Weekly Circulars Custom Publishing Place Ad Sign In or Sign Up Like 450k Search All NYTimes.com Research HEALTH WORLD U.S. N.Y. / REGION BUSINESS TECHNOLOGY SCIENCE HEALTH SPORTS OPINION ARTS STYLE TRAVEL JOBS REAL ESTATE AUTOS Search Health 3,000+ Topics Inside Health Research Fitness & Nutrition Money & Policy Views Health Guide LOCAL U.S. WORLD BUSINESS SPORTS ENTERTAINMENT HEALTH LIVING TRAVEL OPINION SHOP BOOSTER SHOTS SCIENCE NOW MEDICINE FITNESS & NUTRITION MENTAL HEALTH HEALTH REFORM TRENDING NOW TOBIAS SUMMERS DORNER SETTLEMENT BOSTON BOMBINGS HOWIE KENDRICK GWYNETH PALTROW Advertise on NYTimes.com TARGET CANCER After Long Fight, Drug Gives Sudden Reprieve Log in to see what your friends are sharing Log In With Facebook on nytimes.com. Privacy Policy | What’s This? Connect By AMY HARMON Published: February 22, 2010 What’s Popular Now Recommended on Facebook Like 450k For the melanoma patients who signed on to try a drug known as RECOMMEND France Approves Allan Arbus, PLX4032, the clinical trial was a last resort. Their bodies were Same-Sex ‘M*A*S*H’ Actor, Create an account or Log In to see TWITTER Sign Up Even after melanoma, some people keep on using what your friends recommend. riddled with tumors, leaving them almost certainly just months to Marriage Dies at 95 LINKEDIN live. tanning beds With 'Girl Code' and 'Guy Code,' MTV COMMENTS (91) deciphers a franchise 87 people recommend this. Melanoma drug joins ‘breakthrough’ club : Spoonful of Medicine Well But a few weeks after taking their E-MAIL Enlarge This Image Comments Email Share 448 Like 384 12 Smoking and the right to dumb choices first dose, nearly all of them began to PRINT 15 38 l d h recover. Consequences of the ‘Cinnamon Challenge’ nature.com REPRINTS Sitemap Log In Register April 22, 2013 advertisement SHARE Lee Reyes, 30, of Fresno, Calif., who Do We Have to Cool Down After Exercise? had begun using a feeding tube April 24, 2013, 12:01 AM because of a growth pressing against Ask Well: Double the Workout, Double the Benefits? his throat, bit into a cinnamon roll. Neemah A. Esmaeilpour for The New York April 23, 2013 Times ALWAYS WATCHING Randy Nothing, he told his mother, had ever tasted as good. The Lies We Tell in the Exam Room Williams drove from Jonesboro, Ark., April 22, 2013 to Houston for treatment. Even after tumors disappeared, he says of his Rita Quigley, who had been grateful just to find herself How Therapy Can Help in the Golden Years Go cancer, “I don’t think I’ll ever believe that it’s not coming back.” breathing each morning since learning she had the April 22, 2013 Advanced search virulent skin cancer, went shopping for new clothes with Target Cancer her daughters at a mall in Huntsville, Ala. Advertise on NYTimes.com A Dose of Hope Randy Williams, 46, who drove 600 miles from his home Second article in the series. in Jonesboro, Ark., to the M.D. Anderson Cancer Center Nature Medicine Blog Post Complete Series » in Houston to get the experimental drug, rolled out of Q & A with Amy Harmon Related Series: Forty Years' War bed. “Something’s working,” he thought, “because advertisement Enlarge This Image nothing’s hurting.” Previous post Current issue Despite their dangers, tanning salons continue to appeal to 1 out of 50 people diagnosed with melanoma, the most deadly form of skin cancer, according to new research. (Robert Gauthier / Los Angeles Times) THIS WEEK'S CIRCULARS Bioengineered kidney It was a sweet moment, in autumn 2008, for Dr. Keith April 2013, Volume 19 No 4 makes urine after Flaherty, the University of Pennsylvania oncologist leading Journal home the drug’s first clinical trial. A new kind of cancer therapy, About Your Do you use tanning beds? it was tailored to a particular genetic mutation that was Current issue NATURE MEDICINE | SPOONFUL OF MEDICINE take? driving the disease, and after six years of disappointments Subscribe Recommend to library Yes No Sarah Phipps for The New York Times his faith in the promise of such a “targeted” approach Home Depot USA Save Mart Melanoma drug joins ‘breakthrough’ FINGERS CROSSED Kerri Adams at EXPIRES TODAY JUST RELEASED finally seemed borne out. His collaborators at five other Health & Fitness Tools 1,014 votes home near Oklahoma City. After seeing an improvement from her major cancer centers, melanoma clinicians who had tested club BMI Calculator E-alert RSS Facebook Twitter treatment, she tried not to jinx it, What’s your score? » dozens of potential therapies for their patients with no declining to seek new information about the drug, the gene or the success, were equally elated. http://www.latimes.com/health/boostershots/la-heb-tanning-bed-sunscreen-melanoma-20130408,0,6698321.story [4/24/13 2:39:29 PM] 24 Apr 2013 | 15:00 EDT | Posted by Elie Dolgin | Category: Cancer, cancer. Policy nature.com blogs home Earlier this year, the US Food and Drug Administration (FDA) granted its http://www.nytimes.com/2010/02/23/health/research/23trial.html?pagewanted=all&_r=0 [4/24/13 2:58:23 PM] first ‘breakthrough therapy designations’ to a pair of cystic fibrosis drugs Featured posts (see Nat. Med. 19 , 116–117, 2013). But since then, it’s been all about the cancer agents. Stem cells/cloning , Video Bioengineered kidney makes urine after The New Jersey drug giant Merck announced this morning that its transplantation investigational cancer drug lambrolizumab (MK-3475) had received the add a comment breakthrough blessing in recognition of the dramatic clinical benefits AIDS observed in an open-label, phase 1 trial involving people with advanced New, intensive trials planned on heels of melanoma. The FDA’s new development path is specifically designed for Mississippi HIV ‘cure’ experimental agents that produce large and unprecedented treatment add a comment effects in early clinical trials. Neuroscience/mental health , Policy Q&A: How the Brain Activity Map came together— According to preliminary data presented at an international melanoma and what its proponents hope to achieve meeting last year, 43 of 85 patients with inoperable and metastatic add a comment melanoma who received lambrolizumab showed an objective anti-tumor response after 12 weeks, including eight who experienced a complete View more response. The average duration of response was 7.6 months, and most of the reported side events were minor, although seven people Popular in this blog experienced potentially dangerous immune-related complications. 1

Cancer Mortality Rates by State Economic Area Melanoma, White Males, 1970-94 Devesa SS et al. Atlas of Cancer Mortality in the U.S., 1950 – 94 . Washington, DC: US Govt Print Off; 1999. A day at the beach, then and now 2

Skin Recurrence Wide Local Excision Sentinel Node Biopsy Image courtesy of Douglas Reintgen MD, Moffitt Cancer Center 3

GNAQ 32% Uveal G11 45 % NRAS 15 % Scalp/Face BRAF 28 % NRAS 18 % Trunk/Legs BRAF 57 % C-Kit 5 -10 % NRAS 25 % Acral BRAF 10% C-Kit 10%-20% NRAS 15 % Van Ramsdonk et al N Engl J Med 2010 Dec 2;363 Curtin et al J Clin Oncol 2006 Vol 24, No 26 Lee J H Br J Dermatol. 2011 Apr;164(4):776-84 Growth Factor RTK 15% NRAS GTP GSK 456 BKM 120 P E2F PI3Kinase 50% GDC-0941 C- RAF V600E RB 15-30% BRAF Vemurafenib Proliferation PTEN Daprafenib AKT CDK4/6 P p1 PDK 6 P Tremetinib MEK Cyclin D1 P GDC-0973 MK-2206 AKT P Temsirolimus p2 ERK 1 Everolimus MTORC-2 MTORC-1 P P 4E-BP1 p70S6K Protein Translation Growth/Survival 4

Flaherty et al, NEJM Bolag et al, Nature Chapman et al, NEJM Sossman et al, NEJM Response Rate = 81% Phase III BRIM3 Study design Vemurafenib Screening 960 mg po bid (N=337) BRAF V600E mutation Randomization Stage N=675 • ECOG PS (0 vs 1) Dacarbazine • LDH (↑ vs nl) • region 1000 mg/m 2 iv q3w (N=338) 5

Progression-free survival (February 01, 2012 cut- off) censored at crossover 100 Progression-free survival (%) 90 80 Vemurafenib (n=337) Hazard ratio 0.38 70 (95% CI: 0.32 – 0.46) 60 Log-rank p<0.001 (post-hoc) Dacarbazine 50 (n=338) 40 30 20 10 1.6 6.9 0 0 6 12 18 24 Time (months) No. at risk Dacarbazine 338 100 63 37 22 14 3 0 0 Vemurafenib 337 269 186 113 77 49 16 3 0 Overall survival (February 01, 2012 cut-off) censored at crossover 100 Vemurafenib (n=337) 90 Median f/u 12.5 months Overall survival (%) 80 Hazard ratio 0.70 (95% CI: 0.57 – 0.87) 70 60 p<0.001 (post-hoc) 50 Dacarbazine (n=338) 40 Median f/u 9.5 months 30 20 10 9.7 13.6 0 0 6 12 18 24 Time (months) No. at risk Dacarbazine 338 244 173 111 79 50 24 4 0 Vemurafenib 337 326 280 231 178 109 44 7 1 6

Growth Factor CELL MEMBRANE RTK 15% NRAS GTP GSK 456 BKM 120 P E2F PI3Kinase 50% GDC-0941 C- RAF RB V600E 15-30% BRAF Vemurafenib Proliferation AK PTEN Daprafenib T CDK4/6 P p1 PDK 6 P Tremetinib MEK Cyclin D1 P GDC-0973 AK MK-2206 T P Temsirolimus p2 ERK Everolimus 1 MTORC-2 MTORC-1 NUCLEUS CYTOPLASM P P 4E-BP1 p70S6K Protein Translation Growth/Survival 7