Precision Medicine Lessons from meta-analyses of 70,253 patients Razelle Kurzrock, MD

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1 Precision Medicine Lessons from meta-analyses of 70,253 patients Razelle Kurzrock, MD Senior Deputy Director, Clinical Science Director, Center for Personalized Cancer Therapy and Clinical Trials Office Chief, Division of Hematology/Oncology UCSD Moores Cancer Center

2 Meta-Analyses Conducted 1) Trials leading to FDA approval from trastuzumab (1998) until June ,104 patients; 112 trials 2) Phase II studies published between 2010 through ,149 patients; 570 trials Maria Schwaederle, PharmD

3 Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-analysis of Clinical Trials Leading to FDA Approval Denis L. Fontes Jardim, MD 1,2, Maria Schwaederle, PharmD 3, Caimiao Wei, PhD 4, J. Jack Lee, PhD 4, David S. Hong, MD 5, Alexander M. Eggermont, PhD 6,7, Richard L. Schilsky, MD, FACP 7,8, John Mendelsohn, MD 7,9, Vladimir Lazar, PhD 6,7, Razelle Kurzrock, MD 3,7 1 Department of Clinical Medicine, Hemocentro da Unicamp, University of Campinas, Sao Paulo, Brazil 2 Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo, Brazil 3 Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA, USA 4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Department of Functional Genomics, Institut Gustave Roussy, University Paris-Sud, Villejuif, France 7 Worldwide Innovative Network For Personalized Cancer Therapy 8 American Society of Clinical Oncology, Alexandria, VA, USA 9 The University of Texas MD Anderson Cancer Center, Houston, USA.

4 Trials leading to FDA approval Search: Newly approved agents from September 1998 (trastuzumab) until June 2013 PubMed or ASCO meetings abstracts. Excluded: Pediatric cancer, supportive care, loco-regional treatment, hormonal therapies, vaccines Endpoints: Response rate (RR), progression-free survival (PFS), overall survival (OS), and toxicity-related deaths.

5 Benefit of personalized therapy in random ized registration trials (RR, PFS, and OS) Statistical analysis: meta-analysis of relative response rate ratio (RRR) and hazards ratios (HRs) for PFS and OS for personalized trials versus not (random effect model) RRR: higher likelihood of response with a personalized compared to non-personalized strategy (RRR=3.82 [95%CI: ] vs [95%CI: ], (P=0.03 in meta-regression). HR for PFS: 0.41 (95%CI: ) for personalized compared to 0.59 (95%CI: ) for non-personalized studies, (P<.001 in meta-regression). HR for OS: 0.71 (95%CI: ) for personalized compared to 0.81 (95%CI: ) for non-personalized studies (P=0.07 in meta-regression)

6 Benefits of personalized therapy in a l trials (N =112) (RR, PFS, and OS) Stat analysis: random effect meta-analysis for RR; pooled analysis for PFS, and OS for personalized trials versus not (weighted multiple linear regression models) RR: 48% for personalized strategy [95%CI 42-55%] vs. 23% [95%CI 20-27%], P<.001 (also P<.001 after adjustement). PFS: 8.3 months for personalized strategy vs. 5.5 months, P<.001 (P=0.002 after adjustement). OS: 19.3 months for personalized strategy compared to 13.5 months, P=0.01 (P=0.04 after adjustement). Treatment-related mortality was 1.58 percent for personalized versus 1.44 percent for non-personalized trials, which was not statistically different (P=0.74).

7 Im pact of Precision Medicine in Diverse Cancers: a M eta-analysis of 32,149 Patients in Phase II Clinical Trials Journal of Clinical Oncology Maria Schwaederle, PharmD 1, Melissa Zhao, BS 1, J. Jack Lee, PhD 2, Alexander M. Eggermont, MD, PhD 3,4, Richard L. Schilsky, MD 4,5, John Mendelsohn, MD 4,6, Vladimir Lazar, MD, PhD 3,4, Razelle Kurzrock, MD 1,4 1 Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, La Jolla, U.S. 2 Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3 Department of Functional Genomics, Institut Gustave Roussy, University Paris-Sud, Villejuif, France. 4 Worldwide Innovative Network for Personalized Cancer Therapy. 5 American Society of Clinical Oncology, Alexandria, VA, USA. 6 The University of Texas MD Anderson Cancer Center, Houston, USA.

8 M eta-a n alysis of 32,149 Patients in h P ase I I l C inical r T ials A PubMed search was conducted ( ). Only single agent s arms were included in the analysis. Exclusion criteria: pediatric cancers, supportive care, loco-regional treatments, hormonal therapies, and cellular or vaccine therapy. 570 Phase II studies were included, comprising 32,149 patients (641 single-agent arms). Maria Schwaederle, PharmD

9 Response rate (%) Response Rate (%, CI 95%) Personalized Not personalized Months Median PFS (Months, CI 95%) Personalized Not personalized Months Median OS (Months, CI 95%) Personalized Not personalized Pooled analysis Meta-analysis

10 CONCLUSIONS Non-personalized targeted arms led to poorer outcomes than cytotoxics arms (All P<0.0001, except P=0.048 for OS meta-analysis). Worst outcome Best outcome ARMS type Non-personalized targeted RR (%) POOLED Analysis PFS (Mos) OS (Mos) RR (%) Meta-analysis PFS (Mos) OS (Mos) Cytotoxic Personalized targeted

11 PRECISION ONCOLOGY Wheler JJ, Parker BA, Lee JJ, Atkins JT, Janku F, Tsimberidou AM, Zinner R, Subbiah V, Fu S, Schwab R, Moulder S, Valero V, Schwaederle M, Yelensky R, Miller VA, Stephens MP, Meric-Bernstam F, Kurzrock R. Unique molecular signatures as a hallmark of patients with metastatic breast cancer: Implications for current treatment paradigms. Oncotarget. 5(9): , Wheler JJ, Lee JJ, Kurzrock R. Unique Molecular Landscapes in Cancer: Implications for Individualized, Curated Drug Combinations. Cancer Research. 74(24):7181-4, Tsimberidou AM, Iskander NG, Hong DS, Wheler JJ, Falchook GS, Fu S, Piha-Paul SA, Naing A, Janku F, Luthra R, Ye Y, Wen S, Berry DA, Kurzrock R. Personalized medicine in a Phase I clinical trials program: The MD Anderson Cancer Center initiative. Clinical Cancer Research. 18(22): , Kurzrock R, Giles FJ. Precision Oncology for Patients with Advanced Cancer: The Challenges of Malignant Snowflakes. Cell Cyle. 14(14): ,

12 A 38-year-old man with BRAF-mutant melanoma and miliary, subcutaneous metastatic deposits, treated with PLX4032 (Vemurafenib). Baseline 23 weeks 15 weeks Wagle N et al. JCO 2011;29:

13 NEW TRIAL DESIGNS?? Equipoise abandoned? Randomization and clinical trials. Kurzrock R 1, Stewart DJ. Ann Oncol Oct;24(10): doi: /annonc/mdt358. Fool's gold, lost treasures, and the randomized clinical trial. Stewart DJ 1, Kurzrock R. BMC Cancer Apr 16;13:193. doi: /

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15 Frequency (%) of Mutations In Common Cancers Tumor Type Braf Kras EGFR PIK3CA NRAS ckit GNA1 1 GNAQ /GNAS Lung & Bronchus Colon Pancreatic Melanoma & GE/Gastric Kidney 2* 1* 0 4* Leukemia & Lymphoma 1* 3* 4* 0 6* Prostate * 2* 2* 0 0 Breast Ovarian Mutations determined by Cobas, Sanger, and /or Illumina NGS *n 100 & Ascierbo et al Lancet, 14:249-56, 2013 Cancer Progress by Defined Health New York, NY March 17-18, 2015 Gatalica et al. ASCO 2013

16 FORWARD GENOMIC ONCOLOGY Tumor Biopsy >60% tumor Sequencing Tumor Board Informed Consent & Genetic Counselor Sequencing & Analysis 1) Actionable 2) Incidental Buccal swab or Blood (germline) Cancer Progress by Defined Health New York, NY March 17-18, 2015 Genetic Counselor Disclosure of Results

17 FoundationOne Report Patient and ordering physician information Summary of results and genomic alterations identified Targeted therapies and clinical trials that may be relevant based on genomic alterations identified Cancer Progress by Defined Health New York, NY March 17-18, 2015

18 Cancer Progress by Defined Health New York, NY March 17-18, 2015

19 TheraLink Results on Initial Biopsy Cancer Progress by Defined Health New York, NY March 17-18, 2015

20 Blue: Downregulated & CNV: Loss Red: Upregulated & CNV: Gain Cancer Progress by Defined Health New York, NY March 17-18, 2015

21 Recommended Treatment SEQUENCING PROGRESS NOTE History of present illness: Wanda is a 71 y/o with history of stage IIIC ovarian cancer. Treatment Recommendations: AKT2 amplication- no approved therapies. Clinical trials of Akt inhibitors for various tumor types. mtor inhibitors everolimus and temsirolimus are FDA approved for other indications. PIK3CA mtor inhibitors everolimus and temsirolimus are FDA approved for other tumor types. Associated with resistance to Egfr-targeted therapies. CCNE1 amplification primary resistance to platinum-based treatment in patients with ovarian carcinoma. MYC amplification Preclinical evidence suggests may be more sensitive to 5- fluorouracil (5fu) and paclitaxel. Our treatment recommendation for this patient would be Taxol +/- 5Fu with Everolimus. We thank you again for the referral and working with us. Sincerely, Dr. Brian Leyland-Jones and team Avera Cancer Medical Progress Group by Defined Genomic Health Medicine New York, NY March 17-18, 2015

22 Darwin and cancer branched evolution Cancer Progress by Defined Health New York, NY March 17-18, 2015

23 mtor active in all primary regions except R4 and metastases On Off Cancer Progress by Defined Health New York, NY March 17-18, 2015

24 As of Sep, 2015,More than 200 patients with breast or gynecology cancer were referred to our MEM group A committed result was suggested by the clinical outcome of the patients on MEM suggested drugs We have clinical outcome from patients on MEM therapy for up to 24 months Clinical outcome were collected on 74 patients Cancer Progress by Defined Health New York, NY March 17-18, 2015

25 Almost 60% of patients on MEM therapy have responded positively (Complete response or partial response) More than 80% of the patients got their disease under control Best Clinical Outcome Count Complete Response 19 Partial Response 27 Stable 17 Progressed 11 TOTAL Cancer Progress by Defined 74 Health New York, NY March 17-18, 2015 Disease only progressed in 19% of the patients

26 Likelihood of Response by Extent of Prior Treatment* Probability of Response By Line of Therapy 70% 60% 50% 40% 30% 20% 10% 0% Number of Prior Regimens Probability of Response patients who benefit from chemotherapy (in the metastatic setting) may be treated successfully with other regimens at the time of progression. However, the chance of response decreases by about half with each subsequent treatment. DeVita VT. Cancer Prin & Prac of Oncol, 5th Edition, pp Cancer Progress by Defined Health New York, NY March 17-18, 2015 *Graph was NOT taken from DeVita but is provided to illustrate the effects of the quote above and assumes an initial response of 60%.

27 Cancer Progress by Defined Health New York, NY March 17-18, 2015

28 Neoadjuvant B ios pecimens Collection Neoadjuvant Treatment SCREENING : Baseline 3 weeks 9 weeks Surgery TIMELINE Eg, CT/PET MUGA/ECHO + Start Treatment CONSENT Tumour Biopsy Cores: 1-2 FFPE+ 5 FROZEN Tumour Biopsy Cores: 1-2 FFPE+ 5 FROZEN Other Cycles Evaluation (at Clinician s discretion) Tumour Biopsy Cores: 1-2 FFPE+ 5 FROZEN Serum,Plasma Serum,Plasma Whole blood MRI MRI Ki67 Ki67 Cancer Progress by Defined Health New York, NY March 17-18, 2015 Serum,Plasma MRI

29 THE CHALLENGES. 1. MULTIPLATFORM* 2. COMBINATIONS OF THERAPIES (SOME OF WHICH HAVE NEVER BEEN COMBINED BEFORE): N OF ONE* 3. SHIFT TO EARLY TREATMENT 4. THE NEXT GENERATION OF CUTTING EDGE THERAPIES ARE ALL IN CLINICAL TRIALS: BUILDING THE DRUG UMBRELLA* 5. REGULATORY AUTHORITIES* 6. RE-EDUCATION..NCCN GUIDELINES 7. INSURANCE COVERAGE: TESTING/ DRUGS Patients that live longer cost more