Implementing Precision Medicine in Oncology: The IMPACT Clinical Trials at MD Anderson Cancer Center

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1 Implementing Precision Medicine in Oncology: The IMPACT Clinical Trials at MD Anderson Cancer Center Apostolia M. Tsimberidou, MD, PhD Professor Department of Investigational Cancer Therapeutics

2 Disclosures Research Funding (my institution): Foundation Medicine, Immatics, Merck/EMD Serono, Boston Biomedical, Onyx, Bayer, OBI Pharmaceuticals, Karus, Tvardi, Parker Institute Advisory Board: Roche, Europe

3 Initiative for Molecular Profiling in Advanced Cancer Therapy (IMPACT) Hypothesis, 2007 Selection of therapy based on patients tumor molecular analysis will improve clinical outcomes compared to the standard approach Methods Patients who exhausted standard treatment options or had incurable rare cancers were referred to our Phase I program for treatment. CLIA-certified tumor molecular testing in consecutive patients referred for treatment. Genes analyzed: 1-50, depending on time of testing Trials available against various targets Treatment: matched targeted therapy, if available; if unavailable, non-matched. Retrospective analysis, exploratory. NCT

4 IMPACT: Results Molecular testing: N = 3,743 ( ) 1,307 (34.9%): 1 targetable molecular alteration 711 (54.4%): matched targeted therapy; 596 (45.6%) non-matched therapy. Median age: 57 yrs (range, 16-86); 39%, men. Median no. of prior therapies, 4 (range, 0-16); previously untreated = 2.8% Cancers: gastrointestinal, 24.2%; gynecological, 19.4%; breast, 13.5%; melanoma, 11.9%; lung, 8.7%. Response, evaluable Matched, Non-matched, N = 697 N= 571 Objective response, % P Stable disease 6 months, % Total, % <.001 ASCO 2018, Press Briefing Presentation AM Tsimberidou, MD, PhD

5 Progression-Free Survival, % Progression-Free Survival by Type of Therapy Matched: Total Event Median 95%CI Yes: No: P <.001 HR = Months ASCO 2018, Press Briefing Presentation AM Tsimberidou, MD, PhD

6 Overall Survival, % Overall Survival by Type of Therapy Matched: Total Died Median 95% CI Yes: No: P <.001 HR = Months ASCO 2018, Press Briefing Presentation AM Tsimberidou, MD, PhD

7 Multivariate Analysis, Overall Survival (N = 1,307) Risk Factor (vs. other) HR 95% CI P PAM pathway alterations Liver metastases <.001 LDH > ULN <.001 PS > <.001 Albumin < ULN <.001 PLT > ULN Age 60 yrs CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase; PAM, PI3K/Akt/mTOR, PLT, platelet count; PS, performance status; ULN, upper limit of normal ASCO 2018, Press Briefing Presentation AM Tsimberidou, MD, PhD

8 Overall Survival, % Prognostic Score. Overall Survival (N = 1,307) Score Total Died Median 95% CI P < Apostolia-Maria 48 60Tsimberidou, 72 MD, 84PhD Months ASCO 2018, Press Briefing Presentation AM Tsimberidou, MD, PhD

9 Multivariate Analysis, Overall Survival Therapy Added (N = 1,307) Risk Factor (vs. other) HR 95% CI P Non-Matched therapy <.001 PAM alterations <.001 Liver metastases <.001 LDH > ULN <.001 PS > <.001 Albumin < ULN PLT > ULN Age 60 yrs CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase; PAM, PI3K/Akt/mTOR; PLT, platelet count; PS, performance status; ULN, upper limit of normal ASCO 2018, Press Briefing Presentation AM Tsimberidou, MD, PhD

10 IMPACT 1: Conclusions Long-term overall survival was noted in the matched therapy group. The 3-yr overall survival rate was 15% in the matched group compared to 7% in the non-matched group. The 10-yr overall survival rate was 6% vs. 1%, respectively. Matched therapy was an independent factor predicting longer survival in multivariate analysis. PI3K/Akt/mTOR pathway abnormalities were associated with inferior outcomes compared to other alterations. We developed a prognostic score for overall survival including molecular pathway abnormalities. 1 0 ASCO 2018, Press Briefing Presentation AM Tsimberidou, MD, PhD

11 Implementation of Precision Medicine Precision Medicine uses targeted therapy, immunotherapy, and other strategies to target specific biological abnormalities causing carcinogenesis in individual patients. Precision Medicine in cancer requires: 1. Complete understanding of tumor biology, including immune features, that drives carcinogenesis 2. Use of effective drugs and therapeutic strategies that inhibit carcinogenesis (rigorous definition) 3. Access to testing and effective drugs for all patients starting at diagnosis and during the course of their disease ASCO 2018, Press Briefing Presentation AM Tsimberidou, MD, PhD

12 Precision Medicine in a Patient with Salivary Cancer (BRAF V600E Mutation, Vemurafenib)

13 THE WALL STREET JOURNAL June 6, 2011 Major Shift in War on Cancer The MD Anderson program pooled 1,144 patients in a phase I study after profiling their tumors for mutations that might be targets of the tested drugs. Apostolia Tsimberidou, the researcher who led the study, reported that 40% had mutations in 10 molecular pathways that were targeted by the experimental compounds. Tumors in 27% of those given agents that targeted their mutations responded to treatment compared to 5% for those with unmatched therapies.

14 THE ECONOMIST June 9, 2011 Taking aim sooner If personalized medicine is to achieve its full potential, it should be used earlier on in clinical trials Many scientists believe that matching volunteers' genetic profiles to the drugs being tested will not only be better for the volunteers, but may also speed up the trials, and save millions of dollars in the process. One such is Apostolia-Maria Tsimberidou of the University of Texas's MD Anderson Cancer Center, in Houston. And her preliminary results, presented at a meeting of the American Society of Clinical Oncology in Chicago, suggest she is right.

15 Challenges: Current Barriers Actual Goal Biopsy for molecular profile Not standard Standard of care Tumor biology, markers Limited Complete Bioinformatics Limited Optimized Tumor heterogeneity Tumor/blood Validated cell-free DNA analysis Drug discovery Limited More and effective drugs Time to analysis days 1-3 days Clinical trial, drug available 5-30% of patients All patients Timing (course of disease) Advanced, metastatic Starting at diagnosis Targeted drug definition Imprecise Precise Selection of optimal therapy Subjective Evidence-based, tumor board, artificial intelligence Adaptive learning, N of 1 <10% 100%

16 Randomized Study Evaluating Molecular Profiling and Targeted Agents in Metastatic Cancer (IMPACT 2) Primary Objective To determine whether patients treated with a targeted therapy selected on the basis of mutational analysis of the tumor have longer progression-free survival from the time of randomization than those whose treatment is not selected based on alteration analysis PI: Tsimberidou, AM NCT Supported in part by a research grant from Foundation Medicine

17 IMPACT 2. Study Design (I) Metastatic disease Tumor biopsy for molecular profiling, 100% Targetable molecular aberrations ( 1 aberration) Yes, 50% No, 50% FDA-approved drugs within labeled indication Yes, 30% No, 70% Excluded; patient followed for progression but not randomized Is there a clinical trial or commercially available targeted therapy? Yes, 70% Randomize

18 IMPACT 2. Study Design (II) 1 1 Targeted therapy If: Progressive disease Toxicity Treatment not selected based on molecular analysis Crossover

19 Cumulative plot of patients enrolled in IMPACT2 450 PATIENTS ENROLLED IN IMPACT

20 Cumulative plot of patients randomized in IMPACT2 70 PATIENTS RANDOMIZED IN IMPACT

21 Head and Neck Squamous Cell Carcinoma with FGF Amplifications: CR to FGFR Inhibitor Genomic Alterations FGF19 amplification FGF4 amplification FGF23 amplification FGF3 amplification FGF6 amplification CCND1 amplification CCND2 amplification CDKN2A/B loss CHD2 D213N CREBBP R1392* EMSY amplification KDM5A amplification KRAS amplification MYC duplication exons 2-3 TP53 E204* Dumbrava I, Tsimberidou, AM, JCO Precision Oncology In Press

22 Head and Neck Squamous Cell Carcinoma with FGF Amplifications: CR to FGFR Inhibitor A C B D Dumbrava I, Tsimberidou, AM, JCO Precision Oncology In Press

23 Enrollment on Genotype-Matched Trials Underwent Genomic Testing N = 2000 Mutation in Potentially Actionable Gene Yes (789) No (1211) Genotype-matched trial after genomic testing? 11% of pts with mutations in actionable genes went on genotype-matched trials Yes (83) No (706) Genotype-Selected Trial N = 54 Genotype-Relevant Trial N = 29 Meric-Bernstam et al, JCO, 2015

24 Workflow: Development of Personalized Cancer Therapy Gene Data Kurnit et al. Cancer Res 2017

25 Clinical Practice: Phase I Program, MD Anderson 1. Molecular profile is ordered as: Standard of care or For clinical trials: i.e. IMPACT2, NCI-MATCH, MPACT Interpretation of molecular profile: Precision Oncology Decision Support team Expert oncologists in precision medicine Selection and treatment on clinical trials is based on: Recommendation of tumor molecular board Clinical trial availability Patient preference and eligibility Study sponsor and insurance approval 2. Stringent regulatory CRC/IRB/DSMB review and trial prioritization

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27 ASCO s Targeted Agent and Profiling Utilization Registry (TAPUR) To describe the anti-tumor activity and toxicity of commercially available, targeted therapy of patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target. To learn from the real world practice of prescribing targeted therapies and to educate oncologists about implementation of precision medicine in clinical practice Richard Schilsky, CMO and VP ASCO

28 Intra-tumor Heterogeneity: How to Resolve it? Circulating free tumor DNA

29 Targeted Therapy and Immunotherapy

30 Pembrolizumab: FDA Approval Based on Tumor Markers Unresectable/metastatic, MSI-H or mismatch repair deficient (dmmr) solid tumors that have progressed following prior treatment or with MSI-H or dmmr colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. PD-L1 positive recurrent or advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma with 2 lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy: KEYNOTE-059 study: 143 of 259 patients had PD L1-positive tumors (combined positive score 1), non-msi high; ORR: 13.3% (CR 1.4%; PR 11.9%); Duration of response: 2.8+ to months

31 Nivolumab in Mismatch-Repair Deficient Non- Colorectal Cancers: NCI-MATCH Trial: N= 34: PR, 24%; SD 2 months, 32% Depth of response

32 Mutational Burden and ORR to PD1/PDL1 Inhibitors in Selected Tumor Types

33 Study of Immuno-Markers That Predict Response to Immunotherapy Slide 4 Presented By Lisa Butterfield at 2016 ASCO Annual Meeting

34 Hot and Cold Tumors Presented By Mary Disis at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

35 ACTolog: Endogenous CD8+ T cells in Advanced Cancer HLA phenotype HLA-A*02:01 Screening Production phase Treatment/Observation Follow-up NCT , Immatics PI, AM Tsimberidou; Co-PI, Borje Andersson

36 Precision Medicine 2018 Multiple alterations, complex molecular networks, immune mechanisms, transcriptomic, proteomic and epigenetic changes can be identified in individual patients These markers should be integrated into clinical practice to select optimal therapy Complexity of biomarkers is increasing Development of infrastructure is needed to use artificial intelligence to integrate all available patient data to perform algorithm analysis in decision making for optimal drug selection, for More Effective Drugs, For More Patients, Faster.

37 Acknowledgements Patients and Families MD Anderson or WIN Leadership Pathology Dr. John Mendelsohn Dr. Stanley Hamilton Dr. Razelle Kurzrock Dr. Russell Broaddus Dr. Richard Schilsky Biostatistics Dr. Patrick Hwu Dr. Donald Berry (IMPACT 2) Investigational Cancer Therapeutics Dr. Jack Lee (IMPACT 1) Dr. Funda Meric, Chair Graciela Nogueras (IMPACT 1) Dr. David Hong Institute for Personalized Cancer Therapy Dr. Filip Janku Dr. Aung Naing Dr. Siqing Fu Dr. Sarina Piha-Paul Dr. Vivek Subbiah Dr. Jordi Rodon Dr. Timothy Yap Dr. Jennifer Wheler (former faculty) Funding Donors: Alberto Barretto Alberto Barretto, Jamie Hope, and Mr. and Mrs. Zane W. Arrott (IMPACT 1) Foundation Medicine (IMPACT 2) Multiple pharmaceutical Companies (individual clinical trials) Dr. Gerald Falchook (former faculty)

38 Department of Investigational Cancer Therapeutics

39 Thank you!