Overall Survival and Progressionfree Survival Hayashi et al

Overall Survival and Progression-free Survival Hayashi et al. , J Clin Oncol 2019

Forest Plot for Hazard Ratios of Site-specific Treatment versus Paclitaxel/Carboplatin Hayashi et al. , J Clin Oncol 2019

Overall Survival and Progression-free Survival Hayashi et al. , J Clin Oncol 2019

Overall Survival and Progression-free Survival Hayashi et al. , J Clin Oncol 2019

Clinical Trials Ø Clinical Trials CUPISCO To compare the efficacy and safety of molecularly-guided therapy versus standard platinum-containing chemotherapy in patients with newly diagnosed unfavorable cancer of unknown primary site Che. CUP To evaluate the efficacy and safety of nivolumab plus ipilimumab in patients with cancer of unknown primary site who are relapsed after or refractory to platinum-based chemotherapy

Panel Sequencing of CUP Cases • About 30% of CUP samples contain potentially druggable genetic alterations at evidence levels 2/3 • 14% of CUP samples show high tumor mutational burden levels (TMB ≥ 16 Mut/Mb) (n=150) Ross, J. S. , et al. (2015) JAMA Oncol 1: 40 -9; Löffler, et al. (2016) Oncotarget; Varghese et al. , (2017) Ann Oncol; Gay et al. , (2017) ASCO

CUPISCO - Study Design International phase II, randomized, active-controlled, multicenter study comparing efficacy and safety of targeted or immunotherapy guided by genomic profiling versus platinum-based chemotherapy in patients with newly diagnosed poor-risk CUP

CUPISCO - Timelines

CUPISCO – Participating Countries

CUPISCO – Recruitment Status and News Entrectinib added for NTRK and ROS 1 fusions

Che. CUP - Single Arm, Multicenter, Phase II Trial in Platinum-refractory CUP-Syndrome Nivolumab + Ipilimumab in platinum-refractory carcinoma of unknown primary Ø Immune checkpoint inhibitor treatment with nivolumab + ipilimumab prolongs survival in patients with platinum-resistant CUP syndrome Ø Tumor mutational burden predicts response to nivolumab + ipilimumab in patients with platinum-resistant CUP syndrome 6 Centers in Germany 194 Patients with platinum-refractory CUP Study starts in Q 2 / 2019

Tumor Mutational Load Predicts Survival After Immunotherapy Across Multiple Cancer Types 1662 advanced cancer patiens treated with immune checkpoint inhibitors Tumor mutational burden in CUP (n=6116) Samstein et al. , Nat Genet 2019 Gay et al. , ASCO 2017

Summary Ø Whether primary identification by gene expression profiling and tissue-oforigin specific treatment improves survival remains unclear Ø Some caveats limit the interpretation of the Japanese GEP study (lymphomas, GEP assay, hard-to-treat cancers) Ø Results of GEFCAPI 04 are awaited in 2019 Ø CUPISCO: A large, international, randomized trial analyzing the impact of targeted treatments and immunotherapy in first-line unfavorable CUP has started in 2018 Ø Che. CUP: A national trial on the TMB-based impact of nivolumab + ipilimumab in second-line, platinum-refractory CUP will start in June 2019