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1 99m Tc-etarfolatide (EC20) SPECT imaging for the identification of ovarian and non-small cell lung cancer patients who are most likely to benefit from folate-receptor targeted agent vintafolide (EC145) Phillip Kuo, MD, PhD Section Chief of Nuclear Medicine Associate Professor of Medical Imaging, Medicine and Biomedical Engineering University of Arizona

2 Disclosure Information AACR-SNMMI Joint Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy Phillip Kuo, MD, PhD I have the following financial relationships to disclose: Consultant for Endocyte Consultant for Merck I will discuss the following investigational use in my presentation: 99m Tc-etarfolatide and Vintafolide

3 The Folate Receptor in Cancer Many advanced, difficult-to-treat cancers overexpress the FR In some tumor types, such as ovarian cancer, FR expression correlates with poor prognosis The FR may be an effective target for several tumor types

4 99m Tc-etarfolatide and Vintafolide Vintafolide Targeting Ligand (Folate) Spacer Linker System Drug (Vinca alkaloid) 99m Tc-etarfolatide Covalent Bond Imaging Agent Targeting Ligand (Folate) 99m Tc

5 Vintafolide Mechanism of Action Folate conjugate binds the folate receptor The folate conjugate is internalized via endocytosis The drug is cleaved inside endosome Drug escapes endosome and exerts activity on cell FR recycles back to the surface

6 99m Tc-etarfolatide as a Companion Diagnostic Agent for Vintafolide therapy Two single-arm phase II studies were conducted in heavily pre-treated patients with ovarian cancer (OC) and non-small cell lung cancer (NSCLC) EC-FV-02: Phase 2 single-agent vintafolide in patients with platinum resistant or refractory ovarian cancer EC-FV-03 Phase 2 single-agent vintafolide in advanced NSCLC patients who have had more than 2 prior chemotherapy regimens The objective of this analysis was to determine if identifying FR positivity with etarfolatide can identify patients that will respond to vintafolide treatment

7 EC-FV-02: Phase II Study of Advanced Ovarian Cancer with Vintafolide and Etarfolatide Patient eligibility 99m Tc-etarfolatide assessment Vintafolide treatment N = 45 Age 18 years ECOG status 2 Platinum-resistant or -refractory ovarian cancer Intravenous injection 0.5 mg folic acid, followed by 0.1 mg etarfolatide Planar and SPECT imaging Tumor lesions classified as positive (mild/marked) or negative (no uptake) Patients classified as FR (100%), FR (10% to 90%), FR (0%) Induction phase: IV bolus 1.0 mg daily x 5 wks 1,2,3 q 4 wks for 2 cycles Maintenance phase: IV bolus 2.5 mg TIW wks 1,3 q 4 wks Primary outcome: Correlation of 99m Tc-etarfolatide uptake with response to vintafolide therapy Secondary outcome: ORR, DCR, OS and safety (Morris, et al. MS in preparation)

8 EC-FV03: Phase II Vintafolide Activity in FR-Positive Chemorefractory Lung Adenocarcinoma Patient eligibility 99m Tc-etarfolatide assessment Vintafolide treatment N = 43 Age 18 years Advanced lung adenocarcinoma >2 prior cytotoxiccontaining chemotherapeutic regimens ECOG PS 2 Intravenous injection 0.5 mg folic acid, followed by 0.1 mg etarfolatide Planar and SPECT imaging Etarfolatide uptake classified as no uptake, mild, and marked Induction phase: IV bolus 1.0 mg daily x 5 wks 1,2,3 q 4 wks for 2 cycles Maintenance phase: IV bolus 2.5 mg TIW wks 1,3 q 4 wks Primary outcome: Clinical benefit response (CBR) ( 4 cycles of therapy) Secondary outcome: ORR, DCR, PFS, OS, Safety Correlation of CBR to intensity or uniformity of FR expression on etarfolatide scans (Edelman, et al. 2012)

9 Folate Receptor-Positive Legions Whole Body Scan FR(100%) All target lesions positive ~40% of pts are FR(100%) FR(10-90%) Some target lesions positive ~40% of pts are FR(10-90%) FR(0%) No positive target lesions ~20% of pts are FR(0%)

10 99m Tc-etarfolatide Imaging of Lung Cancer: FR(+) lesion Standard CT CT with windowing SPECT

11 99m Tc-etarfolatide Imaging of Ovarian Cancer: FR(+) lesion Target lesion FR+

12 99m Tc-etarfolatide Imaging of Ovarian Cancer: FR(-) lesion Target lesion FR-

13 High inter- and intra-reader agreements on 99m Tc-etarfolatide scans Inter-Reader Agreement Intra-Reader Agreement 1 Intra-Reader Agreement 2 FR(10-90%) 1 positive lesion 87% 90% 95% FR(100%) all lesions positive 85% 100% 95% Independent reader study validates 99m Tc-etarfolatide to select FR positive cancer patients for treatment with vintafolide

14 Lesion Response in Ovarian Cancer and NSCLC EC-FV02 Ovarian EC-FV03 Lung FR positive lesions FR negative lesions

15 FR(100%) Patients Received Greatest Benefit from Vintafolide EC-FV-02 Results EC-FV-03 Results FR(100%) (n=14) FR(10 90%) (n=23) FR(100%) (n=14) FR(10 90%) (n=14) DCR % (n) 57% (8) 36.4% (8) 57.1% (8) 14.3 % (2) PFS 15.2 weeks 7.4 weeks 31.1weeks 7.3 weeks HR (CI) (0.362, 1.756) (0.115, 0.919) OS 63.6 weeks 41.7 weeks 47.2 weeks 14.9 weeks HR (CI) (0.213, 1.542) (0.209, 1.395) CI = confidence interval, DCR=CR+PR+SD, Disease control rate; FR, folate receptor; HR = hazard ratio, OS = overall survival, PFS = progression-free survival.

16 Safety evaluation in EC-FV-02 and EC-FV-03 99m Tc-etarfolatide was well tolerated 1 patient had grade 3 nausea/vomiting (1.6%) in the EC-FV-02 trial In the EC-FV-03 trial, of the 60 patients evaluated, 1 patient had anemia (grade 1) and 1 had constipation (grade 2) Vintafolide was also well tolerated The most common drug-related vintafolide toxicities (all grades) for both studies were constipation (OC 47%, NSCLC 33%) fatigue (OC 37%, NSCLC 37%) The most common grade 3 vintafolide drug-related toxicities were constipation and fatigue in both trials and peripheral neuropathy in NSCLC patients There were no grade 4 vintafolide drug-related toxicities in either study

17 Conclusions Imaging with 99m Tc-etarfolatide represents a non-invasive, real-time approach to identifying patients with FR-positive lesions 99m Tc-etarfolatide has the potential to select patients for vintafolide therapy without the need for a biopsy Additional advantages of evaluation with 99m Tc-etarfolatide include the identification and assessment of all lesions, not just those selected for biopsy Data from these studies support a combined approach to personalized therapy in heavily pre-treated OC and NSCLC patients Using 99m Tc-etarfolatide as a companion agent to identify patients most likely to benefit from FR-targeted treatment with vintafolide is a promising approach to personalized and predictive medicine