BRAF inhibitors Anti-angiogenic therapy Other molecular targets Discussion

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1 If you experience any technical difficulties call or Slides will advance automatically. You can also advance/ review the presentation using the control buttons at the top left of your screen Print slides by clicking on print slides in the box to your left Full references can be accessed by clicking print references Michael B. Atkins, MD Deputy Chief, Division of Hematology/Oncology Beth Israel Deaconess Medical Center Professor of Medicine Harvard Medical School Boston, Massachusetts At the conclusion of the program, click once on CME Credit to complete the program and receive up to 1. AMA PRA Category 1 Credit. BRAF inhibitors Anti-angiogenic therapy Other molecular targets Discussion Keith T. Flaherty, MD Medical Oncology Massachusetts General Hospital Cancer Center Lecturer Harvard Medical School Boston, Massachusetts Michael B. Atkins, MD Deputy Chief, Division of Hematology/Oncology Beth Israel Deaconess Medical Center Professor of Medicine Harvard Medical School Boston, Massachusetts Michael A Davies, MD, PhD Assistant Professor, Melanoma Medical Oncology, Systems Biology Kleberg Center for Molecular Markers University of Texas MD Anderson Cancer Center Houston, Texas Keith T. Flaherty, MD Medical Oncology Massachusetts General Hospital Cancer Center Lecturer Harvard Medical School Boston, Massachusetts Year Target Prevalence Drug % 22 BRAF 5% Sorafenib, PD32591, AZD6244, RAF-265, XL281, vemurafenib, GSK c-kit 1% imatinib, dasatinib, nilotinib 28 GNAQ/ 1% * GNA11 *(8-9% of uveal)

2 BRAF MEK CRAF ERK 5% of all melanomas -more likely in cutaneous, but also present in acral and mucosal Curtin J et al. JCO 26; 24: 434 Davies et al. Nature 22 BRAF mutation location (by amino acid position and substitution) % of all BRAF mutations V6E 97.3% V6K 1.% K61E*.4% G469A*.4% D594G*.3% V6R.3% L597V*.2% *Indicates most common amino substitution, but % represents all amino acid changes reported at that position Long G et al. ASCO 21 Assay IC 5 nm B-RAF-V6E 31 C-RAF 48 B-RAF 1 SRMS 18 ACK1 19 MAP4K5 (KHS1) 51 FGR 63 LCK 183 BRK 213 NEK BLK 547 LYNB 599 YES1 64 WNK3 877 MNK FRK (PTK5) 1884 CSK 2339 SRC 2389 Bollag et al. Nature 21 RED = TUNEL Tsai et al. PNAS 28 Bollaget al. Nature 21

3 #69 #63 %Change From Baseline (Sum of Lesion Size) Threshold for RECIST response Stage IV subclass: M1a M1b M1c #56 #59 Flaherty et al. NEJM 21 RECIST 3% Decrease Percent change from baseline in sum of tumor diameters Vemurafenib Ribas et al. ASCO 211 Chapman et al. NEJM 211 Duration of therapy with vemurafenib Probability of progression-free survival (%) No. at risk Median PFS 6.7 months (95% CI: 5.5, 7.8 months) PFS at 6 months 54% (95% CI: 45, 63%) Time (months) Months Flaherty et al. NEJM 21 Ribas et al. ASCO 211

4 Screening BRAF V6E mutation Stratification Stage ECOG PS ( vs 1) LDH level ( vs nl) Geographic region Randomization N=675 Vemurafenib 96 mg po bid (N=337) Dacarbazine 1 mg/m 2 iv q3w (N=338) Overall survival (%) Hazard ratio.37 (95% CI; ) Log-rank P< Months No. of patients in follow up Dacarbazine Vemurafenib Dacarbazine (N=336) Est 6 mo survival 64% Vemurafenib (N=336) Est 6 mo survival 84% Chapman et al. NEJM 211 Chapman et al. NEJM 211 Isolated kinase IC5 (nm): B-RAF V6E.6 2 C-RAF WT B-RAF WT Maximum % Reduction from Baseline Complete response Partial response Stable disease Progressive disease Maximum % Change from Baseline *V6K Patients * Kefford et al. SMR 21 Long. ESMO 21 Vemurafenib Adverse Event % of patients with toxicity Rash 68 % Arthralgia 48 % Photosensitivity 42 % Fatigue 32 % Cutaneous squamous cell carcinoma (keratoacanthoma) 23 % / 7 % GSK Adverse Event % of patients with toxicity Pyrexia 43 % Rash 3 % Headache 26 % Flaherty et al. NEJM 21; Kefford et al. SMR 21 Lacouture et al. ASCO 21

5 Melanoma Normal or RAS mutant cell CRAF BRAF BRAFi BRAF CRAF 2 CR and 1 PR ~ 9% M1c; 48% history of brain metastases No prior treatment with a BRAF inhibitor MEK ERK MEK ERK Maximum % Reduction from Baseline Preliminary RR is 41% (95% CI, 23-61%) Complete response Partial response Subjects Stable disease Progressive disease Heidorn et al. Cell 21; Poulikakos et al. Nature 21; Hatzivassiliou et al. Nature 21 Scans unavailable for 2 patients with clinical PD and 1 WD Fecher et al. ESMO 21 Median PFS 7.4 months [95% CI ( months)] 11 patients are ongoing at time of data cutoff Progression Free Survival Time (Days) Subjects at Risk Fecher et al. ESMO 21 Events 2 mg QD (%) G1-2 G3 G4 Rash 74 4 Diarrhea 53 1 Fatigue 39 4 Nausea 37 Peripheral Edema 32 Vomiting 25 1 Decreased Appetite 21 3 Fecher et al. ESMO 21 Melanoma Normal or RAS mutant cell CRAF BRAF MEKi BRAF CRAF GSK GSK Squamous cell carcinoma < 1% vs. 7-15% Decreased skin toxicity MEK MEK BRAFi refractory patients ERK ERK BRAFi naïve patients Gilmartin et al. CCR 211 Infante et al. ASCO 211

6 CTLA-4 blockade IL-2 VEGF inhibition BRAF PI3K/Akt Epigenetic CDK4 MITF/ apoptosis MDM2 C-kit mutations present in 1% of mucosal and acral melanomas c-kit inhibitors active in a subset BRAF inhibitors associated with high response rate & symptom improvement Duration of response highly variable MEK inhibition is active in BRAF mutant melanoma Combination of BRAF & MEK inhibitors may improve toxicity & efficacy

7 Overall response rate (%) 3 F 1 ECOG PS M1a/ M1c M1b Stage 1 >1 Yes No # prior therapies Normal x >1.5x ULN ULN LDH at enrollment VEGF IHC (brown) Pigmented Nevus Malignant Melanoma Tu, et al. Clin Exp Derm 26 Ugurel, S. et al. J Clin Oncol 21

8 x x x Progression on non-targets Fruehauf et al. ASCO 28 Algazi et al, UCSF, ASCO 211 * Confirmed after 6 weeks, independently reviewed Dummer et al, ASCO 21

9 2:1 Stratification: Performance Status: vs. 1 Stage: M1a/M1b vs. M1c (visceral involvement or abnormal LDH) Key Statistical Assumptions: PFS HR:.67 (improvement from 4 to 6 months) O Day, Kim et al, ECCO 29 O Day ECCO 29 n n HR Proportion surviving CPP (n=52) CPB (n=14) Proportion surviving CPP (n=31) CPB (n=53) NE = not estimable Overall ORR of 53% (IRC) RR (size proportional to the number of patients in the subgroup) 95% Confidence intervals All <65 65 F M 1 M1a/ M1c 1 >1 Yes No Normal x >1.5x treated M1b ULN ULN Age Sex ECOG PS # prior Previous IL-2 patients Stage therapies LDH at enrollment Baseline characteristics Ribas et al ASCO 211

10 Michael A Davies, MD, PhD Assistant Professor, Melanoma Medical Oncology, Systems Biology Kleberg Center for Molecular Markers University of Texas MD Anderson Cancer Center Houston, Texas Patients with Wild-Type BRAF Cutaneous: ~55% Mucosal: > 9% Uveal: 1% High prevalence of BRAF mutations in nevi Possible role in De Novo and Acquired Resistance PI3K-AKT Pathway C-KIT G-Protein Coupled Receptors (GPCRs) Courtney, J Clin Oncol 21

11 Affected by Activating Genetic Events More Than Any Other Pathway in Cancer RAS Family PI3K AKT Growth Factor Receptors (EGFR, HER2, KIT) PTEN Prevalence: 1-3% Pattern Mutually exclusive with mutations Generally with BRAF mutations Mechanism of Loss Genetic Epigenetic Retained Reduced Tumor Tumor Tumor Survival Angiogenesis Proliferation Invasion Courtney, J Clin Oncol 21 Functional Data BRAF V6E Mice: melanocyte hyperplasia BRAF V6E + PTEN -/- : invasive melanomas (1%) Dankort, Nature Genetics, 29 Absent E.C. E.C. = Endothelial Cells [(+) Control] IGF1 PI3K P11α ~2% AKT ~1-2% All with BRAF mutation AKT1 E17K Also reported in other cancers AKT3 E17K Only melanoma 15-2% pcdna3 HA-AKT3 HA-AKT3-E17K GF Receptors PTEN HA PI3K AKT mtor P-AKT S473 P-AKT T38 AKT3 BRAFi MEKi *RAS *RAF P MEK P MAPK IGF1-R TORC1/2i PI3Ki AKTi TORC2 Pl3K PDK1 P AKT/PKB Survival Combinatorial Approaches De Novo & Secondary Resistance PTEN Loss, RTK Overexpression PTEN Davies, Br J Ca 29 Proliferation Gopal, Cancer Res, 21; Paraiso, Cancer Res, 211; Villanueva, Cancer Cell, 21 mtor Forms 2 complexes mtorc1: activates protein translation, inhibits PI3K mtorc2: phosphorylates AKT Ser473 (activating) mtorc1 inhibitors Rapamycin, RAD-1, Temsirolimus Inhibit protein translation BUT activate PI3K/AKT mtorc1i mtorc1 PI3K AKT mtor P7S6K mtorc2 FOXO BAD GSK3 TSC2 BEZ235 GT226 SF1126 XL-265 GSK AKT Inhibitors MK226 Perifosine TSC1 AKT ps473 Pre-Tx RAD1 1 mg QD Temsirolimus Phase II N=33, 1 PR (2 mos) Margolin, Cancer, 25 PI3K/mTOR Inhibitors mtorc2 mtorc1 TOR Catalytic Domain Inhibitors P7S6K AZD855 OSI27 S6 mtorc1 Inhibitors Tabernero and Baselga JCO 28

12 Bastian, NEJM, 25 CGH: Different regions of DNA copy number gain and loss in acral/mucosal melanomas C-Kit 4q12 Selectively amplified in acral/mucosal Candidate genes -> identification of focal amplifications and point mutations in c-kit JAK RAS PI3K C-KIT C-KIT Receptor protein tyrosine kinase STATs RAF AKT Capable of activating multiple pathways Mutated in ~8% GISTs Imatinib = KITi, standard of care for GIST Phase II Studies (3) N=62, 1 PR Unselected pts Ugurel, 25; Wyman, 26; Kim, 28 Pre-Tx + Imatinib Associated with resistance to imatinib KIT-Mutant Melanoma Case Reports Hodi, J Clin Oncol 28 Point mutations versus deletions/insertions Exon 13 & 17 mutations Amplified wild-type c-kit Lack of 2ndary mutations Phase II Imatinib in KIT-Mutant/Amplified 28 treated, 25 evaluable 2 CR, 2 confirmed PR ORR 16% Carvajal, JAMA 211 Recurrent Sensitive Mutations (K642E, L576P) 4% vs % Mutation + Amplified 36% vs 14%, p=.35 Mut: WT Ratio > 1, 71% vs 6%, p=.1 G-Protein Coupled Receptors (GPCRs) Carvajal, R. D. et al. JAMA 211

13 Treatment 1 Treatment 2 Treatment 3 Treatment 4 Treatment 5 PI3K-AKT Activated Multiple Ways Multiple Inhibitors Pharmacodynamics Which target/inhibitor /combination for which patient? P11βi for PTEN (-)? AKT3 inhibition c-kit Predictive Markers Resistance Mechanisms De novo resistance Secondary resistance Amplified Wild-Type GNαQ/GNα11 Pathways Primary versus Metastasis Inhibitors To receive up to 1. AMA PRA Category 1 Credit Click on CME Credit You will be directed to the FreeCMEsite to complete the CME post test & evaluation, and can receive credit immediately online If any problems connecting to the test or receiving credit call or webcaster@freecme.com See all 4 webcasts in this program Thank you for participating InforMEDical Communications, Inc. info@informedicalcme.com