Oncology Highlights from ASCO 2009 Melanoma August 1, 2009 Santa Monica, CA Jeffrey Weber M.D. Ph.D. Moffitt Cancer Center Tampa, FL
COI Disclaimers • Honoraria from Novartis, Roche, Medarex and BMS, all less than $10,000 dollars in any year • I was named on a patent relating to ipilimumab that was assigned to the Univ of Southern California and later was abandoned by the filer
ASCO 2009 Theme: Melanoma enters the era of personalized, targeted therapy
Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer: abstract #9000 K. Flaherty, 1 I. Puzanov 2 , J. Sosman 2 , K. Kim 3 , A. Ribas 4 , G. McArthur 5 , R. Lee 6 , J. Grippo 6 , K. Nolop 7 , P. Chapman 8 1 University of Pennsylvania 5 Peter MacCallum Cancer Centre 2 Vanderbilt University 6 Hoffmann-La Roche Inc 3 MD Anderson Cancer Center 7 Plexxikon Inc 4 University of Califorinia, Los Angeles 8 Memorial Sloan-Kettering Cancer Center
PLX4032: novel, small molecule inhibitor Selectivity for BRAF V600E in vitro and in vivo Selective for BRAF V600E kinase Selective in cellular assays among 70 kinases screened BRAF Phospho-ERK IC 50 (nM) IC 50 (nM) A375 20 V600E COLO829 10 – 100 10 COLO205 30 100 – 1000 SW620 1000 – 10000 >40,000 SKMEL2 WT 14,000 Selective regression of V600E tumors Kinase domain binding 1205Lu C8161 V600E WT Tumor Size 100 mm 3 + PLX4032 + PLX4032 PLX4720 co-structure with kinase domain of 2006 EORTC-NCI-AACR Molecular Targets & Cancer Therapeutics BRAFV600E (Tsai J et al. 2008 PNAS)
PLX4032: phase I study Design: Open-label, sequential dose escalation study Intra-patient dose escalation permitted Primary objectives: • Evaluate safety and PK of PLX4032 in patients with solid tumors • Measure activity, including response and symptom improvement Secondary objectives: • Measure PD activity of PLX4032 via inhibition of biomarkers - pMEK, pERK & Ki67 in paired tumor biopsy samples 18 FDG uptake - Eligibility standard for phase I trials; no requirement for BRAF V600E
PLX4032 optimized formulation achieves preclinical target exposure for tumor regression Initial Formulation Optimized Formulation 1120 BID 3000 3000 3000 3000 2900 2900 4 pts 2800 2800 2700 2700 2600 2600 2500 2500 AUC 0-24 hr (uM*hr) AUC 0-24 hr (uM*hr) 2400 2400 2300 2300 2200 2200 2100 2100 2000 2000 1900 1900 2000 960 BID 2000 2800 1800 1800 4 pts 2600 1700 1700 AUC ( μ M*hr) 1600 2400 AUC ( μ M*hr) 1600 720 BID 2200 1500 1500 7 pts 2000 1400 1400 1800 1300 1300 1200 1600 1200 1400 1100 1100 1000 1200 1000 1000 900 900 800 900 800 1000 700 700 1000 700 5 pts 600 600 600 500 500 500 4 pts shrinkage 400 400 300 300 Target for regression All Comers PK Bridging n = 18 4 pts 4 pts 200 Max Dose: 1600 (Bid) Study 200 4 pts 4 pts 400 400 100 100 stasis 3 pts 3 patients 100 200 400 800 1600 160 240 360 720 1120 960 Daily Dose (mg) Daily Dose (mg) BID BID Target for stasis 100 100 100 200 400 800 1600 160 240 360 720 1120 960 Daily BID dose (mg) Daily BID dose (mg)
BRAF V600E melanoma patients treated with PLX4032 > 240 mg BID % change from baseline (sum of lesion size) M1a/M1b patients 100 M1c patients 75 50 25 0 -25 (RECIST cutoff for PR, 30%) -50 -75 -100 * Patients (n=15)* * One M1c patient had 55% reduction in target lesions, but PD in non-target lesions; died before end C2 (not included above)
Conclusions PLX4032 Phase I dose escalation study • Twice daily administration tolerable up to 720 mg • 960 mg BID dose under evaluation as MTD • Pharmacokinetics show limited variability and exposure adequate to inhibit target in animal models • Responses observed in V600E+ melanoma patients > 240 mg BID: • 9 PRs (7 confirmed 49% - 100%, 2 unconfirmed 31% - 62%) • Regression of liver, lung and bone lesions • Symptom improvement in many patients • Interim PFS ~ 6 months, with many patients still on therapy • In 3 V600E+ thyroid patients, 1 confirmed PR and 2 SD
A Phase II Study of Imatinib Mesylate (IM) for Patients with Advanced Melanoma Harboring Somatic Alterations of KIT (Abst ID: 9001) R. D. Carvajal, P. B. Chapman, J. D. Wolchok, L. Cane, J. B. Teitcher, J. Lutzky, A. C. Pavlick, B. C. Bastian, C. R. Antonescu, G. K. Schwartz
Study Design Phase II, open-label, multicenter, 2-stage study of imatinib in molecularly selected patients based on the presence of a mutation (exons 9, 11, 13, 17, 18) or amplification of KIT (FISH) Screening Phase Treatment Phase • KIT sequencing (Bastian)and • Eligible pts receive imatinib FISH performed (Antonescu) 400 BID in 6-week cycles • Tumor MUST have either a • Restaging imaging studies mutation or amplification to performed after each cycle proceed to treatment phase Patients with a response or SD continue daily treatment until disease progression or unacceptable toxicity
Key Eligibility Criteria • Inoperable melanoma arising from acral, mucosal, or chronically sun-damaged sites • Tumor must harbor KIT amplification by FISH or a detectable mutation in KIT by sequencing • No prior therapy with other KIT tyrosine kinase inhibitors • Other standard eligibility criteria apply
Response Data (n = 12) n % Complete Response 2 17% Partial Response 2 17% Stable Disease 6 50% Progression 2 17% Overall RECIST RR 4/12 33% (Updated 5/12/09)
KIT Alteration and Response # Melanoma KIT Mutation KIT Amp Best Cycles Wks Subtype Response 1 Mucosal Exon 11 L576P Yes CR 7 37+ 2 Acral Exon 11 L576P Yes CR 4 18+ 3 Mucosal Exon 11 L576P No PR 7 40+ 4 Acral Exon 13 K642E No PR 3 13+ 5 Mucosal No SD 3 18 Exon 13 K642E 6 Mucosal No SD 2 12 Exon 11 L576P 7 Mucosal None Yes SD 2 11 8 Mucosal None Yes SD 2 11 9 Acral Exon 13 K642E No SD 2 8+ 10 Acral Exon 13 K643X Yes SD 2 6+ 11 Mucosal No POD 1 6 Exon 13 V654A 12 Mucosal No POD 1 4 Exon 9 N463S Exon13 N655S Red – on study; Blue – off study (Updated 5/18/09)
Conclusions • There is 21% prevalence of a KIT mutation and/or amplification in this selected cohort. • We have observed 4 responses in 12 evaluable patients thus far, allowing expansion to the second stage of the study (ongoing). • The 2 CRs were in tumors with both an exon 11 L576P mutation and amplification of KIT. • It is feasible to identify appropriate patients prospectively for treatment with imatinib. • Only molecularly appropriate patients with melanoma should be treated with imatinib.
Clinical relevance of miRNA expression in metastatic melanoma Abstract #9006 Eva Hernando, Ph.D. Interdisciplinary Melanoma Program
microRNAs: small, non-coding RNAs with a critical role in cancer • miRNA genes are frequently located at fragile sites and chromosomal regions frequently altered in human cancer (e.g. amplifications, deletions, translocations) • miRNA patterns are able to sub-classify tumor types (Calin and Croce,2006) • miRNAs can act as tumor suppressors (e.g. let-7) or oncogenes (e.g. miR-17- 92) • Some miRNAs are known to contribute to metastasis (e.g. miR-10b, miR- 335). ADVANTAGES TO THEIR ANALYSIS Tissue/cell-type specificity Stable in formalin-fixed paraffin-embedded tissues. Can be tested by standardized methods (qRT-PCR) Represent closely the functional level of the gene.
The 18 miRNA signature clusters melanoma patients based on post-recurrence survival
A 6-miRNA subset separates melanoma patients based on post-recurrence survival 1.0 miRNA predictor: p= 0.001 miR-150 miR-455-3p miR-145 0.8 miR-497 miR-155 miR-342-3p Survival Probability 0.6 n=29 0.4 n=30 0.2 Low Risk High Risk 0.0 0 500 1000 1500 2000 Survival (days)
The 6 miRNA signature retains its predictive value in an optimized multivariate model
Conclusions A miRNA signature associates with post-recurrence survival of a cohort of 61 melanoma patients miRNAs add to the power of clinicopathological parameters (Stage, site of metastasis) in predicting post- recurrence survival. miRNA profiles discriminate between Stages IIIB and IIIC. A model that integrates a miRNA predictor and Stage accurately predicts post-recurrence survival. Certain miRNAs might hold prognostic information at the time of diagnosis.
A Phase III Multi-institutional Randomized Study of Immunization with gp100:209-217(210M) Peptide Followed by High Dose IL-2 vs High Dose IL-2 Alone in Patients With Metastatic Melanoma CRA #9011 Doug Schwartzentruber, MD, FACS Medical Director, Goshen Center for Cancer Care Clinical Associate Professor of Surgery Indiana University Authors: D. Schwartzentruber, D. Lawson, J. Richards, R. Conry, D. Miller, J. Treisman, F. Gailani, L. Riley, D. Vena, P. Hwu Support: NCI, Chiron, Novartis, Goshen Health System, Goshen Hospital and Health Care Foundation, Luke Brennen Research Fund
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