1422MO Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-low, advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Results of the exploratory cohorts in the phase II, multicenter, open-label DESTINY-Gastric01 study

Abstract

Background: Perioperative FLOT is a standard of care for resectable, esophagogastric adenocarcinoma (EGA). This trial evaluates the addition of trastuzumab (tras) and pertuzumab (per) to FLOT for HER2-positive patients (pts).Methods: PETRARCA is a multicenter, randomized, investigator initiated trial planned as a phase II/III study. We report the phase II part of this trial. Pts with HER2+ resectable EGA (! cT2 or cN+) were randomized 1:1 to 4 pre-and post-operative cycles of FLOT (Docetaxel 50 mg/m 2 ; Oxaliplatin 85 mg/m 2 ; Leucovorin 200 mg/m 2 ; 5-FU 2600 mg/m 2 , q2w) (Arm A) or the same regimen with tras 8/6 mg/kg and per 840 mg q3w, followed by 9 cycles tras/per (arm B). Primary endpoint for the phase II part was the rate of pathological complete remission (pCR). Main secondary endpoints were DFS, OS and safety.Results: The trial closed prematurely and did not proceed to phase III. In total, 81 pts were randomized (A, 41; B, 40). Baseline characteristics were balanced (overall, male 79%; median age 60; cT3/T4 86%; cN+ 85%; GEJ 75%). 93% in arm A and 90% in arm B completed pre-OP treatment as planned. More pts had at least one dose modification in arm B (A, 44%; B, 70%). pCR rate was significantly improved with tras/per (A, 12%; B, 35%; p ¼ 0.02). Likewise, the rate of pathological lymph node negativity was higher with tras/per (A, 39%; B, 68%). R0-resection rate (A, 90%; B, 93%) and surgical morbidity (A: 43%; B, 44%) were comparable. Moreover, in-house mortality was equal in both arms (overall 2.5%). Median DFS was 26 months in arm A and not yet reached in arm B (HR 0.58, p ¼ 0.14). After a median follow-up of 22 months median OS was not yet reached. DFS and OS rates [with 95% CI] at 24 months were 54% [38-71%] and 77% [63-90%] in arm A and 70% [55-85%] and 84% [72-96%] in arm B, respectively. More ! grade 3 adverse events were reported with tras/per (75% vs. 85%), especially diarrhea (5% vs. 41%) and leukopenia (13% vs 23%).Conclusions: The addition of tras/per to perioperative FLOT significantly improved pCR and nodal negativity rates in pts with Her2+ resectable EGA at the price of higher rates of diarrhea and leukopenia. Subgroup analyses will be presented.

Trastuzumab deruxtecan for the treatment of patients with HER2-positive gastric cancer

“…The median PFS was 4.4 and 2.8 months, and the median OS was 7.8 and 8.5 months, respectively. 35 The adverse events observed were generally manageable and comparable to those observed in previous studies and in the DESTINY-Gastric01 primary cohort. 20 These results suggest that IHC status might be important for predicting the efficacy of T-DXd, but they also suggest that T-DXd has some clinical activity against T-DXd for HER2-low gastric cancer.…”

Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

“…Although the DESTINY-Gastric01 has represented an important step forward, the results of this phase II study have raised some controversies in the GC medical community. In fact, the magnitude of benefit seemed pronounced in the IHC 3+ population while the ORR, PFS, and OS benefit was not confirmed in IHC 2+ or ISH-positive GC patients, where a lower response rate was observed [ 23 , 37 ]. In addition, the study presented limited ethnic diversity, with all patients enrolled in Asian countries; lastly, the safety profile of T-Dxd needs to be considered, since the 10% of patients of the experimental arm experienced interstitial lung disease, although most were defined as grade II.…”

“…In addition, the study presented limited ethnic diversity, with all patients enrolled in Asian countries; lastly, the safety profile of T-Dxd needs to be considered, since the 10% of patients of the experimental arm experienced interstitial lung disease, although most were defined as grade II. As such, a careful risk-benefit assessment should be performed in presence of underlying lung injury [ 23 , 37 ].…”

Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

“…The efficacy of T-DXd was also evaluated in two HER2-low gastric cancer exploratory cohorts, including patients with IHC 2+/ISH− (cohort 1, n = 20), or IHC 1+ (cohort 2, n = 24) [ 32 ]. In cohort 1, confirmed ORR was 26.3%, with confirmed DCR of 89.5%.…”