The Met Pathway as a Target in RCC

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1 The Met Pathway as a Target in RCC Harriet Kluger, M.D. Associate Professor Yale Cancer Center Disclosures pertinent to this presentation - none

2 c-met Pathway (Biocarta)

3 Rationale for c-met targeting in ccrcc Resistance to VEGF-R inhibitors and/or mtor inhibitors develops with time, and additional targets and/or co-targets are needed Addition of mtor inhibitors to VEGF/VEGFR inhibitors has proven to be toxic c-met is rarely mutated in >400 clear cell RCCs sequenced by TCGA, yet it might be activated by other mechanisms Loss of VHL results in increases in c-met expression and normal kidney secretes HGF Some renal tumors have gain of chromosome 7 or c-met gene amplification in the absence of a mutation

4 Is c-met over-expressed and active in RCC? Gibney et al, Annals of Oncology 2013 Expression measured by quantitative immunofluorescence in 330 nephrectomy cases 300 cases had matched normal kidney tumor Clinical and pathological data (age, gender, size, grade, histologic subtype, survival) available

5 Characteristic Median Patient Age Number (N=317 total) 64 years (range years) Male Gender 197 (62%) RCC Tumor Subtype Clear Cell 222 (70.0%) Papillary 45 (14.2%) Oncocytoma 20 (6.3%) Mixed Histology 12 (3.8%) Sarcomatoid 11 (3.5%) Chromophobe 7 (2.2%) Nuclear Grade I II III IV Stage I II III IV 41 (12.9%) 161 (50.8%) 84 (26.5%) 31 (9.5%) 179 (56.5%) 26 (8.2%) 9 (27.8%) 24 (7.6%)

6 Quantitative Immunofluorescence method developed by David Rimm and Robert Camp, adapted for renal cell carcinoma

7 166-1 P/M Technical reproducibility and intra-tumor homogeneity using matched cores Bivariate Fit of P/M By P/M Linear Fit Linear Fit P/M R=0.92, MET4 antibody from George Vande Woude

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9 Association between c-met levels and RCC specific survival c-met scores divided into quartiles for purposes of depiction

10 Multivariable survival analysis (continuous scores) All cases Variable Risk Ratio 95% CI P value c-met AQUA score Fuhrman grade III/IV vs. I/II Stage III/IV vs. I/II c-met AQUA score Fuhrman grade III/IV vs. I/II Stage III/IV vs. I/II < < Clear cell cases only < 0.001

11 Is c-met expression comparable in primary and metastatic specimens? AQUA Score from Primary Indications for systemic therapy in RCC include both neoadjuvant for nephron sparing prior to nephrectomy and therapy for metastatic disease c-met pathway might not be equally up-regulated in primary and metastatic sites Oneway Analysis of Mean Scores By Status Mean Scores P=0.1 Metastatic Status Primary Bivariate Fit of Mean Scores P By Mean Scores M Mean Scores P R= AQUA Mean Score Scores from M Metastasis

12 Is c-met active in RCC cells in culture, and can it be inhibited pharmacologically? Cell Line SU11274 (μm) ARQ 197 (μm) 769P A O ACHN Caki

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14 Examples of other studies supporting c- Bommi-Reddy A, Almeciga I, Sawyer J et al, PNAS 2008: screened 100 shrna vectors against 88 kinases, for ability to inhibit viability of RCC cells with VHL loss compared with isogenic cells with restored VHL function. Hits were CDK6, MET, and MEK1 Peruzzi B, Athauda G, Bottaro DP., PNAS 2006 showed that VHL loss results in increased beta-catenin signaling in RCC, partially mediated by c-met Met targeting in RCC

15 Clinical grade c-met inhibitors in RCC Chouerri et al, ASCO 2012, XL-184 (cabozantinib) given to 25 patients with ccrcc, 88% had prior VEGFRis and 60% prior mtoris, 52% had both. Median PFS months, ORR - 28% Foretinib (XL-880) active in papillary RCC, other met inhibitors, such as INC280, being studied ARQ-197 (tivantinib) alone or with sunitinib in advanced RCC (accrual complete)

16 Rationale behind co-targeting VEGF-R2 and c-met in RCC Resistance to VEGF-R2-targeted therapies may arise from up-regulation of alternative proangiogenic and pro-invasive signaling pathways, including the MET pathway (Sennino and McDonald, Nat Rev, 2012). Combined VEGFR and MET inhibition is more effective than either pathway alone in a prostate and pancreatic carcinoma tumor model (Aftab et al, Clin Trans Onc, 2011, Sennino et al, Cancer Discovery, 2012).

17 XL study A Phase 3, Randomized, Controlled Study of Cabozantinib (XL184) vs Everolimus in Subjects with Metastatic Renal Cell RCC that has Progressed after Prior VEGFR Inhibitor 375 patients, accrual almost complete Primary endpoint is PFS

18 Conclusions c-met is rarely mutated in clear cell RCC, but is often over-expressed High c-met expression is associated with advanced stage and decreased survival in clear cell RCC c-met inhibition in RCC cells, particularly with VHL silencing, inhibits cell proliferation and decreases pakt and ps6 co-inhibition of c-met and VEGFR2 might be more effective than either one alone; the current randomized trial is not designed to prove this Activity of the dual c-met/vegfr2 inhibitor, XL-184 is being studied in an ongoing phase III trial The role of drugs such as XL-184 in future treatment paradigms, including PD-1/PD-L1 inhibitors will need to be examined

19 Acknowledgements Kluger Lab Members Geoffrey Gibney Lucia Jilaveanu Patricia Conrad Saadia Aziz Collaborators Brian Shuch Adebowale Adeniran Brian Schwartz Chang-Rung Chen Robert Camp Funding sources: NCI, ACS