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

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

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

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

5. Clinical Trials 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
CheCUP
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

6. 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

7. in patients with newly diagnosed poor-risk CUP
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

8. CUPISCO - Timelines

9. CUPISCO – Participating Countries

10. CUPISCO – Recruitment Status and News
Entrectinib added for NTRK and ROS1 fusions

11. CheCUP - Single Arm, Multicenter, Phase II Trial
in Platinum-refractory CUP-Syndrome
Nivolumab + Ipilimumab in platinum-refractory carcinoma of unknown primary
Immune checkpoint inhibitor treatment with
nivolumab + ipilimumab prolongs survival
in patients with platinum-resistant CUP syndrome
Tumor mutational burden predicts response
to nivolumab + ipilimumab in patients with
platinum-resistant CUP syndrome
Centers in Germany
194 Patients with
platinum-refractory CUP
Study starts in Q2 / 2019

12. 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

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