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2. Update on new treatments for recurrent cervical cancer Ursula Matulonis, M.D. Associate Professor of Medicine, Harvard Medical School Director/Program Leader, Medical Gynecologic Oncology Dana-Farber Cancer Institute Boston MA Email: Umatulonis@partners.org

3. Agenda Discuss new treatments for recurrent cervical cancer: --available therapies --biologic agents and new therapies based on rationale signaling pathway aberrations

4. Cervical Cancer Cervical cancer is the second leading cause of cancer deaths among women worldwide. 275,000 women die from it annually. Only 10-20% of patients with recurrent or advanced disease survive 5 years, despite treatment. Urgent need to develop new therapies. Jemal A, et al., CA Cancer J Clin, 2011

5. Chemotherapy for recurrent cervical cancer Chemotherapy agents with activity in recurrent cervical cancer: platinum (carboplatin, cisplatin) 1,2 platinum doublets 3,4,5 Paclitaxel 6 Ifosfamide 7 Topotecan 8 Others: gemcitabine, VP-16, altretamine Equivalency of carboplatin and cisplatin 9,10 1 Bonomi et al, JCO 1985, 2 ASCO 2012 3 Long et al, JCO 2005,4 Moore et al, JCO 2004, 5 GOG 204, 6 McGuire et al, JCO 1996, 7 Sutton et al, Am J Obstet Gynecol 1993, 8 Muderspach, Gyn Onc 2001, 9 Kitagawa et al, ASCO 2012, 10 Moore et al, Gyn Onc 2007

6. Biologic agents tested in cervical cancer Anti-angiogenics Bevacizumab 1 Sunitinib 2 Pazopanib 3 EGFR inhibitors Cetuximab 4,5 --alone and in combination with cisplatin Gefitinib Erlotinib -- alone and in combination with cisplatin 6,7 PDGFR inhibitors Imatinib 8 Others celebrex 1 Monk et al, JCO 2009, 2 Mackay et al, Gyn Onc 2011 3 Monk et al, JCO 2010 4 Santin et al, Gyn Onc 2011 5 Farley et al, Gyn Onc 2011, 6 Schilder et al, Int J Gynecol Cancer 2009 7 Ferreira et al, ASCO 2008, 8 Candelaria et al, Int J of Gyn Cancer, 2009

7. Bevacizumab in recurrent cervical cancer Overall RR 11% and 6 month PFS rate of 24% Monk et al, JCO 2009

8. Pazopanib vs Lapatinib versus combination 230 pts with recurrent cervix cancer 1:1:1 1) pazopanib 800 mg PO daily 2) lapatinib 1500 mg PO daily 3) combination (pazopanib 400/lapatinib 1000 or pazopanib 800/lapatinib 1500); Combination arm eventually dropped Primary endpoint: PFS Monk et al, JCO 2010

9. Results: PFS 18.1(P) vs 17.1(L) weeks Monk B J, Pandite L N JCO 2011;29:4845-4845

10. Topotecan 0.75 mg/m2 IV days 1,2,3 and cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks x 6* Paclitaxel 135 mg/m2 IV over 24 hours and cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks x 6* Vinorelbine 30 mg/m2 IV days 1 and 8 cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks x 6 Gemcitabine 1000 mg/m2 IV, days 1 and 8 along with cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks x 6 GOG 204 JCO 2009 Eligibility: measurable disease GOG performance status 0-1 ANC ≥ 1500/mcl platelets ≥100,000/mcl serum creatinine <1.5 mg/dl no CNS disease no past or concomitant invasive cancer no prior chemotherapy (unless concurrent with radiation) Primary Stage IVB or recurrent/persistent carcinoma of the cervix N=513

11. GOG 204 GOG 204 conclusions: VC, GC, and TC are not superior to PC in terms of overall survival (OS). However, the trend in RR, PFS, and OS favors Paclitaxel/cisplatin Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.

12. GOG 240 Does addition of bevacizumab to chemotherapy improve efficacy and does a non-platinum doublet have efficacy in advanced cervical cancer? Eligibility: Primary Stage IVB or recurrent/persistent carcinoma of the cervix Measurable disease GOG performance status 0-1 GOG 240

13. Eligibility confirmed Paclitaxel + cisplatin Paclitaxel + cisplatin + bevacizumab Paclitaxel + topotecan Paclitaxel + topotecan + bevacizumab Primary Endpoints: Overall survival (OS) Frequency and severity of toxicity Secondary Endpoints: Progression-free survival (PFS) Tumor response Opened: 4/6/2009 accrual met 450 pts.

14. Identification of molecular alterations in subtypes Epidemiological shift in cervical cancer: squamous cell cancers (SCC) decreasing and adenocarcinomas (AC) rising from 5%  24%. AC worse prognosis: 10-20% lower 5-year OS, and higher rates of local and distant spread. Currently SCC and AC are treated similarly. Wang SS, et al., Cancer, 2004; Gien LT, et al., Gynecol Oncol, 2010.

15. A Paradigm Shift: The Genomic View of Cancer Slide courtesy of Levi Garraway

16. Reported Alterations in Cervical Cancer 1 Arias-Pulido H, Int J Gynecol Cancer, 2008; 2 Iida K, Br J Cancer, 2011; 3 Janku F, PLoS One, 2011, 4 Bertelsen BI, Int J Cancer, 2006; 5 Pappa KI, Gynecol Oncol, 2006; 6 Kang S, Gynecol Oncol, 2007; 7 Mammas IN, Gynecol Oncol, 2004; 8 Wingo SN, PLoS One, 2009. 1

17. Genomic analysis reveals PI3K pathway mutations in cervical cancer Key components of the PI3kinase pathway: Receptor tyrosine kinase PI3kinase PTEN AKT, mTORC1 and 2 PI3K mTORC1 mTORC2 AKT Many other targets that regulate: Growth, energy utilization and cell survival Many other targets that regulate: Growth, energy utilization and cell survival RTK PTEN

18. Study Aims 1) Describe the most common oncogenic mutations in cervical cancer. 2) Compare the type and frequency of somatic mutations present in cervical AC versus SCC. 3) Identify novel therapeutic targets. Wright, ASCO 2012

19. “OncoMap” Strategy for Profiling Known Genomic Mutations Archival tumor samples examined by a gynecologic oncology pathologist. Areas >80% tumor cored and DNA extracted. Tumor-derived DNA was subjected to whole genome amplification, and multiplexed PCR was performed to amplify regions harboring loci of interest. Primer extension products were spotted onto a specially designed chip and analyzed by MALDI-TOF mass spectrometry to determine the mutation status. Results were validated by hME with unamplified tumor DNA. Examined 1284 mutations in 172 genes. Also examined PTEN loss by immunohistochemistry. Thomas et al., Nature Genetics, 2007; MacConaill et al., PLoS One, 2009; and Dias-Santagata et al., EMBO Mol Med, 2010.

20. Patient Characteristics (n=78) Wright, ASCO 2012

21. Results 43/78 (55.1%) of cervical cancer specimens harbored candidate mutations. 6/78 (7.7%) had ≥2 co-mutations. 5/6 of these had co-mutations in exon 9 of PIK3CA; only 1 sample had coexisting PIK3CA and KRAS mutations. 3/48 (4.9%) had evidence of PTEN loss on immunohistochemistry (both AC and SCC). Wright, ASCO 2012

22. High Rates of PIK3CA Mutations in Both AC and SCC Overall n=78 P=0.47 Wright, ASCO 2012

23. KRAS Mutations Detected in AC Only Overall n=78 P=0.004 Wright, ASCO 2012

24. Clinical Correlations We did not observe any associations between validated mutations and patient characteristics: – Stage, grade, tumor size – Lymph node involvement – Disease free survival – Overall survival Limited by small sample size, low frequency of events, and short follow-up time (median 27 months). Wright, ASCO 2012

25. Conclusions of mutational data First report of a high throughput mutational analysis of cervical cancer. Data revealed distinct genomic alterations in SCC and AC; KRAS mutations found in AC and PIK3CA mutations found in SCC. This data supports the importance of further studies to better understand these mutations and exploit them for clinical use. Wright, ASCO 2012

26. Conclusions: Overall Cervical cancer is the 2 nd leading cause of cancer death in the world. Existing treatment for recurrent cancer has little effectiveness Newer therapies are needed Aberrant signaling pathways Immunologic therapies