Timing of targeted therapy in patients with low volume mrcc. Eli Rosenbaum Davidoff Cancer Center Beilinson Hospital

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1 1 Timing of targeted therapy in patients with low volume mrcc Eli Rosenbaum Davidoff Cancer Center Beilinson Hospital

2 2 Wont be discussing: Symptomatic patients High volume disease Rapidly growing metastases Resectable metastases Immunotherapy Phase III data

3 Survival by MSKCC Risk Groups: IFN data (=no active therapy) MSKCC Criteria Risk Groups Favorable Intermediate Poor Median OS 29.6 mos 13.8 mos 4.9 mos A subset of pts with indolent disease and long term survival without any active therapy Motzer RJ, et al. J Clin Oncol. 2002; 20:

4 Survival (%) PERCY Quattro Trial in mrcc: Overall Survival MPA Median 14.9 months IFN Median 15.2 months IL-2 Median 15.3 months IFN+IL-2 Median 16.8 months Months from randomization Negrier S et al. Paper presented at: ASCO; May 13-17, 2005; Orlando, FL.

5 Sunitinib: daily oral administration (Schedule 4/2) 1:1 Randomization Planned N=690 Actual N=750 No Crossover IFN- : administered subcutaneously TIW Motzer et al, NEJM 2007;356:

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7 VOTRIENT: Phase III study (VEG105192) design Subjects with advanced RCC (n=435) Stratification ECOG performance status 0 versus 1 Prior nephrectomy Treatment-naïve (n=233) versus one cytokine failure (n=202) Randomisation 2:1 Placebo (n=145) VOTRIENT 800 mg qd (n=290) Option to receive VOTRIENT at progression via a roll over study 1. Sternberg CN et al. J Clin Oncol 2010; 28:

8 Subgroup Analysis of PFS Baseline Factor Hazard Ratio (95% CI) Primary analysis MSKCC risk: Favorable MSKCC risk: Intermediate Female Male Age < 65 yrs Age 65 yrs ECOG PS 0 ECOG PS P < by log-rank test for all. Favors pazopanib Favors placebo

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10 ASSURE Trial (E2805) Negative: Neither Sorafenib Nor Sunitinib Recommended as Adjuvant Therapy for RCC Median disease-free survival was 5 8 years for sunitinib (HR 1 02, p=0 8038), 6 1 years for sorafenib (HR 0 97, p=0 7184), and 6 6 years for placebo

11 ASSURE Trial (E2805) Negative: Neither Sorafenib Nor Sunitinib Recommended as Adjuvant Therapy for RCC All groups did better than predicted at the time of study design; median OS has not yet been reached in any group (5 year OS 78% sunitinib, 81% sorafenib, and 80% placebo) These results provide a strong rationale against the use of these drugs for high-risk non metastatic RCC in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis

12 Active surveillance for metastatic or recurrent RCC patients Median f/u 31 months Median TTP 12.4 months Median OS not reached Predictors of a shorter PFS: KPS<100%, liver metastases, diagnosis to AS<1y Park I et al. J Cancer Res Clin Oncol 8/2014

13 Prospective RCC Observation Study Clinically-evident metastatic RCC of any histologic subtype First documentation (radiographic or histologic) of metastatic RCC up to 12 months prior to registration on study No prior systemic therapy for RCC in the metastatic or neo/adjuvant setting. Prior XRT (including for CNS metastases) and prior nephrectomy/metastasectomy permitted but not required No disease-related symptoms Measurable / evaluable disease per RECIST v 1.0 CTs q 3 months year 1; q4m year 2, then q 6 months FKSI-DRS (QOL) and HADS (anxiety/depression) administered at baseline and every CT scan timepoint. Peripheral blood for immune cell quantification drawn at baseline and every CT scan timepoint. Initiation of systemic treatment per MD / pt discretion Rini et al. Lancet Oncology 2016

14 OS: 38.6 months Obs: 14.9 months PFS: 9.4 months

15 Median time on observation (from study registration to start of systemic therapy) was 14.1 months

16 Median time on observation (from study registration to start of systemic therapy) was 14.1 months Favourable group - patients with 0 or 1 IMDC risk factors and 2 organs involved with metastatic disease Unfavourable group -all other patients (i.e. more than 1 IMDC risk factor and/or more than two organ sites of metastases).