Andrew Poklepovic MD Massey Cancer Center Hematology, Oncology, and Palliative Care

1. Approaching Personalized Oncology as a Clinician and ResearcherWhere are we now, and how can we take it further? Andrew Poklepovic MD Massey Cancer Center Hematology, Oncology, and Palliative Care Associate Member Developmental Therapeutics Program

2. Personalized Cancer CareGoals and Definitions • Individualized care for each patient • Treatments prescribed based upon the unique nature ofthat person’s cancer • with the goal to maximize response, improve survival, and improve the ability to cure • Avoiding treatments that are likely to be ineffective • Adjusting doses of medications to accommodate each person’s own metabolism

3. The origins of personalized care • Breast Cancer • Estrogen Receptor (ER) /Progesterone Receptor (PR) • ~80% of breast cancers • Tamoxifen FDA approved in 1977 following studies showing benefits in advanced disease, but not until over a decade later did the idea that ER was associated with responsewasconfirmed. • Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin) Fulvestrant (Faslodex) • HER2 – Genetic amplification (more copies of the gene than there should be) in 15-20% of breast cancers. • Trastuzumab(Herceptin) – • Approved 1998 for stage IV breast cancer, the first antibody specifically targeting a cancer related protein • Approved in 2006 for adjuvant treatment of breast cancer with the intent for improving cure rates • Lapatinib (Tykerb) – 2007 stage IV breast cancer • Pertuzumab (Perjeta) 2012 stage IV breast cancer- seeking FDA approval 10-2013 for adjuvant • Trastuzumab-emtansine (Kadcyla) 2013 stage IV breast cancer • Triple Negative: ER, PR, and HER2 negative. • No targeted therapy identified to date.

4. Breast Cancer • Oncotype DX • Or…Do I need Chemo? • FDA approved genomic test for early stage ER+ breast cancer. • Additional studies to determine its role in lymph node positive (more advanced) disease

5. Taking it further than ER/PR/HER2 or Oncotype • Complete Gene Sequencing of 510 breast tumors – over 30,000 mutations found • 4 major sub-classes of breast cancer, with variability withineachsub-class.

6. Lung cancer • SCLC v. NSCLC • EGFR Mutation • EGFR aka HER1 – the first “kinase” discovered, 1978 • Its activated role in mutations was identified much later. • ALK/EML4 Fusion Mutation • First identified in 2007 in a single patient in Japan, now known to affect ~5% of all lung cancer patients (70,000 worldwide) • Others being identified

7. EGFR • Epidermal • Growth • Factor • Receptor • When mutated, sends a continuous signal into the cell. The cancer cell may be dependent on this broken signal for cell survival

8. Targeting the mutant EGFR with erlotinib • Erlotinib superior to chemotherapy in EGFR mutated lung cancer • Chemotherapy superior to erlotinib in EGFR non-mutated (wildtype) cancer. = chemotherapy = EGFR targeted therapy Garassino et al. Lancet 2013 Zhou et al. Lancet 2011

9. Open Access At: http://cancergrace.org/lung/2010/10/10/overview-of-molecular-markers-in-lung-cancer/

10. Targeted ALK therapy is better than chemotherapy Shaw et al. NEJM 2013

11. Lung Cancer Mutational Landscape

12. The KIT example • Kit is another protein that, when mutated, leads to uncontrolled cancer growth (similar concept to EGFR). • Kit mutated cancers are generally not responsive to chemotherapy. • Multiple newer “targeted therapies” can inhibit mutated Kit.

13. Kit mutations common in rare cancer Gastrointestinal Stromal Tumor (GIST) Imatinib is the standard of care for advanced, unresectable or metastatic GIST. It has improved median overall survival from 18 to 57 months, vastly changing the outlook for patients with this disease. Targeted therapy with a logical biologic target changed the course of this disease. Poklepovic et al, Gastrointenstinal stromal tumor: imatinib and beyond. InTech 2012 open access

14. Targeting KIT requires understanding what drug fits in the pocket to turn it off.

15. The KIT protein Imatinib

16. KIT in other cancers • GIST – 85-90% of a rare disease • Melanoma 5% • up to 35% of mucosal melanoma, a rare subtype of melanoma • Rare with unclear frequencies • Acute Myelogenous Leukemia • Clear cell sarcoma • Seminoma

17. Patient Example • Mucosal melanoma patient • Multiple sites of disease in the mouth and throat. • Surgically removed, but likely residual disease • KIT exon 11 mutation positive. • Same as dominant mutation in the GIST group.

18. KIT exon 11 mutated melanoma Clinical trial evidence of significant effect in a melanoma patient when targeting known KIT mutation with a drug with activity against that specific mutation. Unable to get insurance coverage for imatinib because drug was not FDA approved for melanoma. Despite peer to peer. Only option was a research trial, at least 5 states away. JCO 2011

19. Other cancers with similar problems • BRAF mutation = 40-50% melanoma • BRAF mutation – <1-3% of lung cancer • BRAF mutation – never previously reported in case of small cell neuroendocrine carcinoma of the intestine- an already exceedingly rare tumor. • BRAF mutation – present in GIST in very low frequencies of non KIT mutated cancer (1-2%)

20. How do you design the trial? • In unselected patients (not chosen based upon EGFR status), therapy against the EGFR was no better than a sugar pill. • This trial led the FDA to revoke approval for this agent in the US in 2005.

21. How do you design the trial? • Be wary of trying to hit a home run in a big ballpark. Low frequency events will be lost in the noise of the high frequency events. • Development of companion biomarkers or targets is easier in concept than in practice.

22. How are we trying to do this? • In Glioblastoma (GBM) a rare and deadly brain tumor, there are very few treatment options. • MCC 14816 looks at triple therapy in patients who have progressed on primary treatment. • In the lab, the presence of PDGFR was associated with the greatest tumor cell kill • Only 30% of GBM has the PDGFR • Our trial will test first in all GBM, if no positive result, shrink the ballpark and only include PDGFR+ GBM PDGFR + PDGFR -

23. Diagnostic tests may identify if a treatment is effective early on. • On MCC-13874, the preclinical science suggests that the combination of pemetrexed & sorafenib causes a new type of cancer cell death, toxic autophagy. • This trial is in the stages of becoming a collaborative effort with University of Virginia • We are using circulating tumor cell technology (capturing cancer cells from the blood of cancer patients with a regular blood draw) to test early on if the combination of drugs causes toxic autophagy. • This may help doctors one day know early on if the drugs they administer are working the way they should be, and can help tailor patient treatments

24. How do you help? • Support the funding for development of, and ultimately reimbursement of, genetic testing of patient tumors. • Supporting the tests that will find the targets the drugs can be used on, or developed for. • Build a repository of tumor information, to find the rare events that can generate new treatment ideas. • Also identify gene signatures in patients in which a treatment was remarkably successful, to generate new ideas.

25. How do you help? • Support the idea that there are scientific reasons for using drugs in personalized cancer care. Not every drug will work for everybody, and it may be that most drugs will work really well for only a few people in many cancers. • Insurance coverage should support logical use of known targeted drugs against the mutations they are active on, once at least some efficacy is shown. • The cost is generally not substantially different from an approved standard therapy. • FDA approval combining a mutation requirement (melanoma with BRAF mutation to get vemurafenib) but also histology (melanoma, not small cell cancer), can make it hard to get therapy for individual patients with rare diseases or low frequency mutations. • It can be traumatic for a patient to know that they have a rare disease, with a druggable target, but no ready access to the drug.

26. Thank YouPlease help to continue the fight, as you have been doing. It makes a difference, every day.