1866 - Ipilimumab or FOLFOX in combination with Nivolumab and Trastuzumab in previously untreated HER2 positive locally advanced or metastastic EsophagoGastric Adenocarcinoma (EGA) - the randomized phase 2 INTEGA trial (AIO STO 0217)

Background

Inhibition of PD-1 has demonstrated improved survival as single agent in refractory EGA compared to placebo. In 1^st line HER2 negative EGA combination regimens of PD-1 inhibitors (i) with chemotherapy or CTLA4i are currently investigated. Since a survival benefit could not be shown for the addition of pertuzumab, the TOGA regimen with platinum, fluoropyrimidine and trastuzumab remains the standard of care in 1^st line HER2+ EGA. Combination regimens with PD-1i +/- CTLA4i have not yet been evaluated in HER2+ EGA. Thus, the INTEGA trial will evaluate two trastuzumab and PD-1i based combinations to determine the best regimen to challenge the TOGA regimen in a phase 3 trial.

Trial design

INTEGA is a randomized exploratory phase II investigator initiated trial by the AIO esophagogastric working group with two experimental arms. Patients (pts) with previously untreated (for metastatic disease) HER2 + (IHC3+ or 2+/ISH+) EGA will be randomized to receive trastuzumab and nivolumab in combination with either mFOLFOX6 or ipilimumab (3mg/kg every 3 weeks). Treatment with nivolumab is limited to a maximum of 12 months, ipilimumab to 4 applications. Primary endpoint is 12month overall survival rate, which should be increased from 55% (TOGA regimen) to 70% in each arm. Based on a type I error of 5% and 80% power 41 pts per arm are required and with a 15% drop out rate overall 97 pts will be randomized. An early stopping rule will be applied in case of an increase in toxicity after the first 15 pts received at least two months of treatment. The trial is flanked by a large translational program including immunoprofiling to determine and correlate the respective immune response signatures with clonal dynamics. Recruitment has started in March 2018. Overall 40 German sites are planned. Conclusion: The INTEGA trial will determine the feasibility and efficacy of trastuzumab and nivolumab in combination with either mFOLFOX6 or ipilimumab in 1^st line HER2+ EGA. The translational research program will shed light on the potential mode of action of these novel combinations.

Clinical trial identification

NCT03409848.

Legal entity responsible for the study

AIO-Studien-gGmbH.

Funding

BMS.

Editorial Acknowledgement

Disclosure

E. Goekkurt: Advisory board: Sanofi, Merck, BMS, MSD, Servier, Sirtex, Pfizer, Lilly; Speakers fees: Servier, MSD, BMS. M. Binder: Travel expanses: BMS, Hexal; Advisory board: Roche, BMS, MSD, Hexal, Takeda, Celgene, AbbVie; Speakers fees: Chugai, Roche, BMS, Janssen-Cilag, Hexal, Sanofi, Celgene, AstraZeneca. S. Lorenzen: Advisory board: Sanofi, Merck, BMS, MSD, Servier, Lilly, Roche; Speakers fees: Servier, Roche, BMS, Lilly. P.C. Thuss-Patience: Advisory board: Merck, Roche, Lilly, Pfizer, MSD, BMS, Nordic. S-E. Al-Batran: Advisory board, speakers fees: BMS. A. Hinke: Honoraria: Roche S. Hegewisch-Becker: Advisory board: Lilly, BMS, Merck. C. Bokemeyer: Research funding: German Cancer Aid, Sanofi, Roche, Merck, GBA Innovationfond, BMS; Honoraria: Merck, Sanofi, Roche, Bayer, BMS, Servier, AstraZeneca; Advisory board: Lilly/ImClone, Mundipharma, Hexal, Bayer Schering, Sanofi, Merck. Travel, accommodations, expenses: Merck Serono, Sanofi, Pfizer, BMS. A. Stein: Research funding: German Cancer Aid, Sanofi, Roche, Merck, GBA Innovationfond, BMS; Advisory board: Sanofi, Amgen, Merck, Roche, BMS, MSD, Servier, Sirtex; Speakers fees: Sanofi, Merck, Roche, Servier, Bayer, Lilly. All other authors have declared no conflicts of interest.