Abstract CT102: APACHE: An open label, randomized, phase II study of Durvalumab (Durva), alone or in combination with Tremelimumab (Treme), in patients (pts) with advanced germ cell tumors (GCT): Results at the end of first stage
Authors: Necchi Andrea , Mariani Luigi , Raggi Daniele , Giannatempo Patrizia , Colecchia Maurizio , Calareso Giuseppina , Salvioni Roberto , Ali Siraj M. , Chung Jon H. 
Published: August 2018

Abstract
Background:
The prognosis of chemorefractory GCT pts is dismal. PD-L1 is frequently expressed by immunohistochemistry (IHC) in GCT. Durva is an anti-PD-L1 monoclonal antibody (mAb). Treme is anti-CTLA4 mAb. We aimed to investigate the activity of Durva, alone or with Treme, in these pts.
Methods:
Apache (NCT03081923) is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 chemotherapy (CT) regimens (including HDCT) are randomized to receive Durva, 1.5 gr via IV infusion q4w, for up to a total of 12 months (13 doses/cycles, arm A) or Durva plus with Treme, 75 mg IV q4w, starting on week 0, for up to 4 months (4 doses/cycles) followed by Durva alone for up to a total of 12 months (arm B). Serum tumor markers (STM), computed tomography and FDG-PET scans are repeated q8 weeks. The primary endpoint is the modified objective response-rate (mORR=RECIST 1.1 complete or partial response [PR] or stable disease [SD]+STM reduction &gt;10%). H0: mORR rate ≤10%, H1: mORR ≥25%, type I and II error rates at 10%.
The total sample size of 120 pts is split into 3 stages: in stage 1, according to Gehan's rule, each arm is terminated whenever no response is observed. Biomarker analyses include: IHC PD-L1 expression on immune cells (Ventana SP142) and genomic sequencing with FoundationOne assay (Foundation Medicine Inc., Cambridge, MA, USA). Results of first stage are presented.
Results:
From 02/17-11/17, 18 pts were enrolled (17M, 1F), 9 per arm. 14 had gonadal and 4 extragonadal GCT, and 9 had received HDCT, 15 ≥3 prior CT regimens.
One pt (5.6%) had reversible G3 irAE (pneumonitis) in arm B. In arm A, 100% of pts had disease progression (PD), all with features of hyperprogression (hyper-PD): 4 had clinical PD and death before restaging, median increase in sum of tumor diameters (RECIST 1.1) was 146%, median increase in elevated STM was 462%. In arm B, 2 responses (22.2%, 1 RECIST-PR and 1 SD with STM reduction) were observed. PD features were similar to arm A. PD occurred in both arms regardless of PD-L1 expression and tumor mutational load. 2 hyper-PD pts had KRAS amplification (confirmed on liquid biopsy in one case).
Conclusion:
Single-agent durvalumab should not be pursued further in GCT; conversely, despite hyper-PD were also observed, combination immunotherapy showed promising activity and will be expanded to 2nd stage. Elucidating pt selection criteria and mechanisms of PD will be of paramount importance in GCT.
Citation Format: Andrea Necchi, Luigi Mariani, Daniele Raggi, Patrizia Giannatempo, Maurizio Colecchia, Giuseppina Calareso, Roberto Salvioni, Siraj M. Ali, Jon H. Chung. APACHE: An open label, randomized, phase II study of Durvalumab (Durva), alone or in combination with Tremelimumab (Treme), in patients (pts) with advanced germ cell tumors (GCT): Results at the end of first stage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT102.