Next Generation Sequencing in Early-Phase Clinical Trials in Cancer Filip Janku

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1 11 th International Congress on Targeted Anticancer Therapies Paris March 4-6, 2013 Next Generation Sequencing in Early-Phase Clinical Trials in Cancer Filip Janku Investigational Cancer Therapeutics (Phase I Clinical Trials Program) MD Anderson Cancer Center Houston, TX

2 Disclosures Research Funding Novartis Roche Biocartis Transgenomic Trovagene

3 Drug hitting more common target always win the race in a randomized trial DRUG A DRUG B DRUG C NO RESPONSE RESPONSE DRUG D

4 The Inverted Pyramid of Biomarker-Driven Trials Garrido-Laguna et al. Nat Rev Clin Oncol 2011

5 Response rates in selected early-phase clinical trials with targeted therapies using molecular matching Drug Biomarker Disease Response rate Reference in % Imatinib BCR-ABL fusion CML 77* Druker et al., N Engl J Med 2001 Imatinib KIT mutation GIST 53 van Oosterom et al., Lancet 2001 Olaparib BRCA 1, BRCA 2 Diverse cancers 39 Fong et al., N Engl J Med 2009 mutations PLX4032 Vemurafenib BRAF Melanoma 77** Flaherty et al., N Engl J mutation Med 2010 GDC-0449 Vismodegib PTCH1 Basal cell 55 Von Hoff et al., N Engl J mutation cancer Med 2010 Crizotinib EML4-ALK NSCLC 57 Kwak et al., N Engl J PI3K/AKT/mTOR inhibitors*** fusion PIK3CA mutation Diverse cancers Med Janku et al. Mol Cancer Ther 2011 *Complete hematologic response. **BRAF-mutant melanoma patients treated in dose-escalation phase ***Therapies that included PI3K/AKT/mTOR inhibitors. Janku, Garrido-Laguna, Kurzrock. ASCO 2011 Educational Book

6 Early-Phase Clinical Trials: Paradigm Shift The Time is Now Dose-finding studies Proof-of-concept studies BENCH BEDSIDE

7 Targeting PI3K/AKT/mTOR The PI3K/AKT/mTOR axis is activated in many tumors. Activation is frequently mediated by PIK3CA mutations or loss of PTEN function. Preclinical studies suggested that increased PI3K/mTOR signaling may predict sensitivity to PI3K/mTOR inhibitors. 1,2,3 Simultaneous activation of the MAPK pathway (KRAS, NRAS, BRAF mutations) may mediate resistance. 1,2,3 1 Engelman J. Nat Med Ihle N. Cancer Res Di Nicolantonio F. J Clin Invest 2010 Janku et al. Nat Rev Clin Oncol 2010

8 Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors in early-phase trials Tested: 217 PIK3CA mutations: 25 PIK3CA mutations treated with PI3K/mTOR: 17 PR rate = 35% (6/17) Janku et al. Mol Cancer Ther 2011

9 Janku et al. Presented at 24th EORTC-NCI-AACR, November 2012 Patients with PIK3CA/PTEN aberrations treated with early-phase therapies targeting the PI3K/AKT/mTOR pathway PR rate: 17% (23/134, 95% CI ) SD > 6 months: 7% (9/134, 95% CI ) One patient who was never evaluated for response is not depicted No difference observed in PR/CR rate among PIK3CA vs. PTEN vs. both aberrations (p=0.83)

10 Patients with PIK3CA and/or PTEN aberrations have a higher PR/CR rate on PI3K/mTOR inhibitors than patients with wild-type/unknown PIK3CA/PTEN treated on the same protocols Patients treated on clinical trials with PI3K/AKT/mTOR inhibitors PIK3CA and/or PTEN aberration TREATED with PI3K/AKT/mTOR inhibitors Wild-type or unknown PIK3CA and/or PTEN TREATED with PI3K/AKT/mTOR inhibitors PIK3CA and/or PTEN aberration NOT TRATED with PI3K/AKT/mTOR inhibitors N PR/CR (%, 95% CI) P-value (17%; 95% CI ) (6%; 95% CI ) < * 3 (4%; 95% CI # * Of the 175 patients with PIK3CA and/or PTEN aberrations not treated with PI3K/AKT/mTOR inhibitors, 108 were not treated due to ineligibility or patient/doctor preference and 67 received other experimental therapies often because PIK3CA/PTEN mutation status was not available at the time of decision making. # Confirmed on multivariate analysis. Janku et al. Presented at 24th EORTC-NCI-AACR, November 2012

11 Patients with PIK3CA/PTEN Aberrations Treated with PI3K/AKT/mTOR Inhibitors: Subgroup Analysis Patients N PR/CR (%) PIK3CA /PTEN aberrations treated with monotherapies 40 1 (2.5) P-value PIK3CA /PTEN aberrations treated with combinations 94 22( 23) 0.002* PIK3CA /PTEN aberrations and colorectal cancer 23 0 (0) PIK3CA /PTEN aberrations and other cancers (21) PIK3CA /PTEN aberrations without codon 12, 13 KRAS mutations PIK3CA /PTEN aberrations with codon 12, 13 KRAS mutations 26 1 (4) (22) PIK3CA mutation H1047R 20 7 (35) Other PIK3CA mutations 62 7 (11) * Confirmed on multivariate analysis Janku et al. Presented at 24th EORTC-NCI-AACR, November 2012

12 Change in tumor size, % Change in tumor size, % Molecular Matching in Early-Phase Trials Examples of Tested Aberrations: PIK3CA, PTEN, BRAF, RAS, EGFR, KIT, ALK, MET Matched therapy N=175 p<.0001 Therapy without matching N=116 CR/PR = 27% CR/PR = 5% CR: 4 (2%) PR: 43 (25%) SD>6m: 40 (23%) CR: 0 (0%) PR: 6 (5%) SD>6m: 12 (10%) Patients Patients Tsimberidou et al. Clin Cancer Res 2012

13 Molecular Selection Strategies in Phase I A. B. Rodon et al. Nat Rev Clin Oncol 2012

14 Whole Genome Sequencing in Metastatic Bladder Cancer Treated with Everolimus Iyer et al. Science 2012

15 MI-ONCOSEQ STUDY - Whole-genome sequencing of tumor and normal DNA - Transcriptome sequencing of tumor - Two xenografts and two patients tested - Time from biopsy to the Sequencing Tumor Board presentation: 24 days Roychowdhury, Sci Transl Med 2011

16 Cancer Molecular Profiling Initiatives Global WIN Consortium -> WINTHER Trial National French Initiative Cancer Research UK: Stratified Medicine Programme Institutional MD Anderson: Clearing House Mass General: SNaPshot Dana Farber: OncoMap Institut Gustave Roussy: MOSCATO Vall d Hebron: OncoCarta Princess Margaret Hospital For Profit Foundation Medicine Knight Diagnostics Baylor College of Medicine Cancer Genetics Laboratory

17 Colorectal Cancer: Time to Treatment Failure on Matched vs. Unmatched Therapy Dienstmann et al. Mol Cancer Ther 2012

18 Colorectal Cancer: Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors PR/CR rate: 0% SD > 6 months rate: 6% (1/17, 95% CI ) Janku et al. ASCO GI 2012

19 Tumor Microhetergoeneity Molecular profile can differ even within the single lesion Discrepancy between molecular profile of primary and metastic lesion (~20%). 1, 2 1 Dupont-Jensen, Clin Cancer Res Gonzales-Angulo, Mol Cancer Ther 2011

20 Gerlinger, N Engl J Med 2012

21 Post-Progression Biopsies and Secondary Resistance to EGFR TKIs Sequist et al. Sci Transl Med 2011;3:75ra26 21

22 Concept of liquid biopsy Schwarzenbach Nat Rev Cancer 2011

23 Acquired Resistance to EGFR Blockade in Colorectal Cancers Diaz et al. Nature 2012; Misale et al. Nature 2012; Vilar, Tabernero Nature 2012

24 Concordance Analysis Mutations in ctdna vs. tumor tissue (CLIA laboratory) Janku et al. Presented at 24th EORTC-NCI-AACR, November 2012

25 CONCLUSIONS Matching specific molecular aberrations with appropriately selected targeted therapies is crucial should we make headway in the personalized treatment of cancers Next generation sequencing and large scale genotyping is a step towards truly personalized cancer therapy; however, it brings up multiple challenges, which require multidisciplinary cooperation among clinicians, laboratory scientists and bioinformatics Implementing proof-of-concept studies into early-phase clinical trials can shorten drug development timelines Since most responders to appropriately selected targeted therapies ultimately develop progression, mechanisms underlying tumor resistance need to be studied

26 Acknowledgements MD Anderson ICT faculty Dr. Razelle Kurzrock Dr. David Hong Dr. Aung Naing Dr. Gerald Falchook Dr. Jennifer Wheler Dr. Apostolia Tsimberidou Dr. Stacy Moulder Dr. Siqing Fu Dr. Sarina Piha-Paul Dr. Vivek Subbiah Dr. Ralph Zinner Dr. Dan Karp ICT fellows, ICT research staff MD Anderson referring physicians ICT Lab Dr. Laura Angelo Dr. Helen Huang Division of Cancer Medicine Dr. Waun Ki Hong Dr. Robert Wolff Pathology Dr. Russell Broaddus Molecular Diagnostic Lab Dr. Raja Luthra Dr. Stan Hamilton Biostatistics J. Jack Lee OUR PATIENTS AND THEIR FAMILIES