Integrating trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy (CT) of HER-2+gastric cancer (GC) - subgroup analyses of EORTC 1203 "INNOVATION", a collaboration with KCSG and DUCG

10-20% of GC are HER-2 positive. The role of perioperative anti-HER2-directed treatment is yet undefined. This randomized, open-label phase II-trial investigated the benefit of combining T or T/P in combination with perioperative CT for HER-2-positive GC and EGJC. Between 2015 and 2021,172 of a planned 215 patients (pts) with centrally confirmed, positive HER-2 status and resectable GC or EGJC (UICC TNM stages Ib-III) were included. Recruitment was prematurely terminated due to slow accrual. Pts were randomized 1:2:2 to: Arm A (CT alone) (35 pts); Arm B (CT+ T [8mg/kg, followed by 6mg every 3 weeks]) (67 pts); Arm C (CT + T+ P [840mg every 3 weeks]) (70 pts). CT was initially cisplatin (80 mg/m2 d1) and capecitabine (2 x 1000 mg/m2/d d1) for 3 cycles before and after surgery. After publication of the FLOT-4 study, the protocol was amended to four cycles FLOT pre- and postoperatively, with FOLFOX or CAPOX as alternative for pts ineligible for FLOT. In the experimental arms, T and P were continued beyond CT at the same dose for a total of 17 cycles. Major pathological response rate (mpRR), determined by central review was the primary endpoint. The study was designed to have 80% power to detect an increase in mpRR from 25% with CT to 45% with CT+T+P or CT+T with a one-sided alpha of 10%. Possible heterogeneity of odds ratios (ORs) for mpRR between CT and CT+T+P or CT+T arms was investigated across chemotherapy regimen and other factors. Out of 172 pts randomized, 161 eligible pts started their allocated treatment (per protocol population). Cisplatin+capecitabine was administered in 42.2%, and FLOT in 46.6% of patients. In Arm A:B:C, 90.9%, 92.2% and 81.3% completed neoadjuvant treatment. Major reason for treatment discontinuation was toxicity (70%). Surgery was performed in 84.8%, 98.4%, 92.2% pts in Arm A:B:C. R0 resection rates were 83.9%, 90.3% and 85.9%. Results of central pathology review of mpRR are available for 126 out of 150 operated pts (84.0%). MpRR was 23.3%, 37.0%, 26.4% in Arm A:B:C. The increase of 3.1% (80% CI: [-9.5%, 15.7%], one-sided p=0.378) in Arm C vs. A was not statistically significant. The increase in Arm B vs. A was 13.7% (80% CI: [0.7%,26.7%], one-sided p=0.099). Overall MpRR in all three arms was increased from 13.3% before the amendment to 42.9% thereafter (OR 4.87, p= 0.0004). MpRR was 33.3%, 53.3% and 37.9% in Arm A:B:C after amendment (OR 2.29 for CT+T vs CT; OR 1.22 for CT vs CT+T+P) while, in contrast, it was 8.3%, 16.7% and 12.5% before the amendment (OR 2.20 for CT+T vs CT; OR 1.57 for CT vs CT+T+P). ORs for mpRR between CT and CT+T or CT+T+P were consistent across investigated subgroups. The primary endpoint analysis did not meet the pre-specified criteria of efficacy for the combination of CT+T+P. However, CT+T showed interesting response rates, especially with FLOT as CT backbone. Follow-up data, including progression free-, overall survival is necessary to define the clinical value of this regimen.