Evidence-guided tumor profiling to individualize therapy decisions

How Genomics Accelerates Personalized Medicine EGFR mutants ALK ROS1 HER2 B-raf K-ras PERSONALIZED MEDICINE

Caris Life Sciences American bioscience company focused on developing and delivering innovative molecular diagnostic, prognostic and theranostic services to the treatment of cancer Leading company with with over tumors profiled since 2008 Partner in Romania: Farmaceutica Remedia Distribution & Logistics SRL

Caris Molecular Intelligence (CMI) Molecular profiling service Uses a multitechnology approach to investigate patient’s tumor: IHC, FISH/CISH, NGS, PCR, Sanger sequencing, Pyrosequencing, Fragment analysis Correlates biomarker targets to therapeutic agents, based on an extensive clinical literature assessment Reports agents associated with potential benefit and lack of benefit in an actionable report Identifies relevant clinical trials based on the biomarker unique profile

CMI helps in patients with therapeutic ambiguities Patients with uncommon or aggressive tumours, for whom there is no standard of care Patients in whom standard of care options have failed Patients who are fit, willing and needing further therapy 5 Patient with basal cell carcinoma Profiling found Hedgehog mutation Treatment with Hedgehog inhibitor led to CR Courtesy: Daniel Von Hoff, NEJM, 2009

Key Challenge 6 Typical Case 18 IHCs 3-6 CISH/FIS H 46+ gene NGS Need to optimize/prioritize tissue availability to most informative testing and maximize DNA yield

What Are My Options?? 7 How do I treat a patient with breast cancer where standard treatment options have failed? In fact, the treatment decision will already be individualised and based on local practice guidelines, physician experience, clinical judgement, patient physical condition and medical history Try A Different Cytotoxic Agent Rechallenge with a Prior Treatment Consider a Clinical Trial ?? Anthracyclines or Antimetabolites Hormone Therapy Off-label treatment ?? Taxanes or Abraxane Trastuzumab ?? Which One? cMET inhibitors, BRAF or MEK inhibitors PIK3Ca, mTOR, MEK, angiogenesis or IGF pathway inhibitors ??

Many Biomarkers are Linked with Therapeutic Options 8 How do I treat a patient with breast cancer where standard treatment options have failed? TOPO1 (IHC) TS (IHC) RRM1 (IHC) BRAF (NGS) MGMT (IHC) ER (IHC), HER2 (IHC), HER2 (CISH), PIK3CA (NGS) SPARC (IHC), TLE3 (IHC), Pgp (IHC) ER (IHC) or PR (IHC) HER2 (IHC), HER2 (CISH), PTEN (IHC), PIK3CA (NGS) cKIT (NGS), PDGFRa (NGS) TOPO2A (FISH) and HER2 (CISH) HER2 (IHC) or HER2 (CISH) RET (NGS) irinotecan fluorouracil, capecitabine, pemetrexed gemcitabine vemurafenib temozolomide, dacarbazine everolimus, temsirolimus paclitaxel, docetaxel, nab-paclitaxel hormone therapy trastuzumab imatinib doxorubicin, liposomal-doxorubicin, epirubicin lapatinib, pertuzumab, TDM-1 vandetanib

Each Biomarker Result May Help You Select Therapies How do I treat a patient with breast cancer where standard treatment options have failed? TOPO1 (IHC) TS (IHC) RRM1 (IHC) BRAF (NGS) MGMT (IHC) ER (IHC), HER2 (IHC), HER2 (CISH), PIK3CA (NGS) SPARC (IHC), TLE3 (IHC), Pgp (IHC) ER (IHC) or PR (IHC) HER2 (IHC), HER2 (CISH), PTEN (IHC), PIK3CA (NGS) cKIT (NGS), PDGFRa (NGS) TOPO2A (FISH) and HER2 (CISH) HER2 (IHC) or HER2 (CISH) RET (NGS) CONSIDER irinotecan AVOID fluorouracil, capecitabine, pemetrexed CONSIDER gemcitabine AVOID vemurafenib CONSIDER temozolomide, dacarbazine AVOID everolimus, temsirolimus AVOID paclitaxel, docetaxel, nab-paclitaxel AVOID hormone therapy CONSIDER trastuzumab CONSIDER imatinib CONSIDER doxorubicin, liposomal-doxorubicin, epirubicin CONSIDER lapatinib, pertuzumab, TDM-1 AVOID vandetanib Biomarker associated with potential benefit Biomarker associated with potential lack of benefit

Biomarker Results Are Actionable 10 How do I treat a patient with breast cancer where standard treatment options have failed? irinotecan fluorouracil, capecitabine, pemetrexed gemcitabine vemurafenib temozolomide, dacarbazine everolimus, temsirolimus paclitaxel, docetaxel, nab-paclitaxel hormone therapy trastuzumab imatinib doxorubicin, liposomal-doxorubicin, epirubicin lapatinib, pertuzumab, TDM-1 vandetanib SELECT AGENTS FROM AVOID AGENTS FROM Based on Biomarker Results Associated with Potential BENEFIT Based on Biomarker Results Associated with Potential BENEFIT Based on Biomarker Results Associated with Potential LACK OF BENEFIT Based on Biomarker Results Associated with Potential LACK OF BENEFIT In fact, the treatment decision will still be individualised and based on local practice guidelines, physician experience, clinical judgement, patient physical condition and medical history BUT PUT INTO THE CONTEXT AND UNDERSTANDING OF COMPREHENSIVE & PREDICTIVE BIOMARKER TESTING

Evidence Can Support Off-Label Treatment Options 11 How do I treat a patient with breast cancer where standard treatment options have failed? irinotecan fluorouracil, capecitabine, pemetrexed gemcitabine vemurafenib temozolomide, dacarbazine everolimus, temsirolimus paclitaxel, docetaxel, nab-paclitaxel hormone therapy trastuzumab imatinib doxorubicin, liposomal-doxorubicin, epirubicin lapatinib, pertuzumab, TDM-1 vandetanib SELECT AGENTS FROM AVOID AGENTS FROM Based on Biomarker Results Associated with Potential BENEFIT Based on Biomarker Results Associated with Potential BENEFIT Based on Biomarker Results Associated with Potential LACK OF BENEFIT Based on Biomarker Results Associated with Potential LACK OF BENEFIT 13 of 25 patients experienced clinical benefit A Pilot Study Utilizing Molecular Profiling to find Potential Targets and Select Individualized Treatments for Patients with Metastatic Breast Cancer Jameson et al., ASCO 2013 A Pilot Study Utilizing Molecular Profiling to find Potential Targets and Select Individualized Treatments for Patients with Metastatic Breast Cancer Jameson et al., ASCO patients with heavily pretreated (4-12 prior lines) metastatic breast cancer received MP-guided treatments 9 of those 13 patients received an irinotecan-containing regimen (PFS 86 – 892+ days) 9 of those 13 patients received an irinotecan-containing regimen (PFS 86 – 892+ days)

Report available on paper and online 12 Provide a rationale for your next treatment To Determine What Not to Use Identify therapies which may not have been considered

Overall clinical benefit in 27% - 60% of patients 13 v v v v v

Independent & Supportive Clinical Evidence for Caris Molecular Intelligence Is Accumulating Globally 14 Von Hoff DD et al. [2010] J Clin Oncol Nov 20; 28(33): Popovtzer A. et al. [2012] Presented at 8 th AHNS International Conference on Head and Neck Cancer (Abstract Number S172) Epelbaum R. et al. [2013] J Clin Oncol; 30 suppl 34; abstr 195 Jameson G. et al. [2013] J Clin Oncol (suppl; abstr TPS11123) Dean A. et al. [2013] Abstract presented at 2013 ECCO meeting

Clinical Experience with CMI Dan von Hoff, 2010: Pilot study on refractory cancers Gayle Jameson, 2014: Breast Cancer Study Ramesh Ramanathan, 2012: Pancreatic Cancer Study Andrew Dean, 2013: Rare and refractory solid tumors Aaron Popovtzer, 2012: Head &Neck Cancer Ron Epelbaum, 2013: Pancreatic Cancer Kate Oliver, 2013:Ovarian Cancer Registry In 134 patients the treatment decision prior to CMI, actual treatments, and outcomes were registered

16 G. Jameson et al.: CMI for metastatic breast cancer Gayle Jameson et al., ASCO 2013

Breast cancer study details patients with prior regimens 5 patients changed receptor status Treatment decision revised in all patients 13/25 (52%) had clinical benefit 9/13 had an Irinotecan containing regimen Molecular Profiling guided treatments: 19 chemotherapy 6 hormone 6 TKI 3 monoclonal antibody Gayle Jameson et al., Breast Cancer Res Treat 2014

18 ©2013 Caris Life Sciences and affiliates. Andrew Dean et al.; ECCO patients with rare cancer, 28 heavily pretreated patients 60% clinical benefit in patients with rare cancer 54% clinical benefit in heavily pretreated patients Overall: 26/29 chemotherapy 3/29 TKI

Adenoid cystic carcinoma of the salivary gland: Uncommon tumor with no established standard of care 11 patients diagnosed in 2011/12, 6 received CMI guided therapy Hormone therapy 2 Monochemotherapy2 Combination chemotherapy2 Very encouraging clinical results: 4/6 at least partial remission of >6 months one complete remission >15 months Source: Bio-marker driven tailored treatment for metastatic adenoid cystic carcinoma; Popovtzer A; 8 th international conference on head and neck cancer, Toronto July 2012, S172. Aaron Popovtzer et al., 2012

CMI guided therapy for advanced pancreatic cancer 20 Ron Epelbaum et al., ASCO GI 2013: 29 Molecular Profiling guided treatments: 13 combination chemotherapy 8 chemotherapy alone 6 chemotherapy with TKI 2 TKI alone Clinical benefit rate: 37.5%

CMI guided therapy for advanced pancreatic cancer 21 Ramesh Ramanathan et al., AACR 2012: 36 Molecular Profiling guided treatments: 22 combination chemotherapy 12 monochemotherapy 2 chemotherapy with TKI Median survival: 5 months

Drug selection for CMI-guided therapies 134 patients evaluated – Conventional chemotherapy11284% – Tyrosine kinase inhibitors 2116% – Hormone therapy 8 6% – Monoclonal antibodies 3 2% Treatment decision was revised in almost all patients Actionable biomarker results in over 95% of patients 22

Caris Molecular Intelligence can help to 23 Evidence-based rationale for your next treatment decision SELECT Determine what not to use AVOID Identify therapies which may not have been considered EXPAND

Personalized Medicine at your fingertips Comprehensive & Predictive Biomarker Testing Key Supportive Literature An Actionable Report for Your Patient