Interim safety and clinical activity in patients (pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab (R) plus durvalumab (D).

Abstract

92 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This global phase 1 trial evaluates the combination of R (anti-VEGFR2) and D (anti-PD-L1) in pts with G/GEJ by simultaneously targeting these two processes. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02572687) enrolled pts with confirmed G/GEJ adenocarcinoma with prior progression on 1 or 2 lines of systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. PD-L1 expression was assessed using the SP-263 IHC; MSI status was determined using PCR. Enrolled pts received R (8 mg/kg IV) and D (750 mg IV) every two weeks on a 28-day cycle. Primary objective was to assess safety and tolerability of R+D; preliminary efficacy was also examined. Results: As of 26-May-2017, 29 G/GEJ adenocarcinoma pts were treated. The median age was 55 y; 69% were male; 66% had ECOG PS of 1; 48% had PD-L1 ≥25% expression in tumor or immune cells, 3.5% were MSI-high; and 72% received study treatment as second line for advanced disease. Median duration of treatment was 2.5 mo for R and 3.0 mo for D. Treatment-emergent adverse events (TEAEs) occurred in 29 (100%) pts and 21 (72%) pts experienced grade 3/4 TEAEs, while treatment-related AEs (TRAE) occurred in 24 (83%) pts; none resulted in treatment discontinuation. Ten (35%) pts had grade 3 TRAEs, and no grade 4 or 5. All grade TRAEs occurring in ≥10% of pts were hypertension (34%), fatigue (31%), headache (24%), diarrhea (21%), pyrexia (10%) and decreased appetite (10%). Five pts (17%) reported a serious adverse event related to study treatment. Preliminary efficacy data (RECIST v1.1) showed 5 of 29 pts (17%) achieved a confirmed PR. Only 1 responding pt was MSI high. The overall response rate for pts with PD-L1 ≥25% was 36%. Median PFS was 2.6 mo (95% CI, 1.45 to 6.28). As of data cut-off, 6 pts (21%) remain on treatment. Conclusions: R+D generated no unexpected toxicity, and demonstrated antitumor activity in pts with previously treated advanced G/GEJ adenocarcinoma. Clinical trial information: NCT02572687.

Maintenance Avelumab Versus Continuation of First-Line Chemotherapy in Gastric Cancer: JAVELIN Gastric 100 Study Design

“…Across several studies, anti-PD-L1/PD-1 antibodies have shown clinical activity and durability of response in pretreated patients with advanced GC/GEJC and disease progression following chemotherapy [25][26][27][28][36][37][38], leading to regulatory approval of nivolumab in Japan for patients with advanced GC progressed after chemotherapy (based on a Phase III trial vs placebo) [27,39], and accelerated approval of pembrolizumab in the USA as 3L treatment for advanced PD-L1+ GC/GEJC (based on a large, Phase I, single-arm cohort) [26,40]. However, it has recently been reported that two randomized, Phase III trials of later-line treatment for GC/GEJC did not show superior OS with an anti-PD-1 or anti-PD-L1 antibody when compared directly with chemotherapy; this includes KEYNOTE-061 (NCT02370498), a trial of 2L pembrolizumab versus paclitaxel [41], and JAVELIN Gastric 300 (NCT02625623), a trial of 3L avelumab versus physician's choice of chemotherapy [42].…”

New therapeutic options opened by the molecular classification of gastric cancer

“…There are 4 phase Ib/II studies that are currently enrolling patients for treatment with durvalumab as single agent, or in combination with tremelimumab - a CTLA4 inhibitor (NCT02340975) or ramucirumab - a VEGFR-2 inhibitor (NCT02572687). Preliminary results from the last study, presented at the 2018 Gastrointestinal Cancers Symposium, suggests that blocking VEGFR-2 and the PD-1/PD-L1 pathway induces synergic antitumor effects[ 42 ].…”

Immune checkpoint inhibitor combination therapy for gastric cancer: Research progress (Review)

“…NCT02572687 is a phase Ia/b clinical trial of durvalumab combined with ramucirumab for the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma who failed first-line or multi-line treatment. The PRR was 17% (5/29), PFS was 2.6 months and OS was 6.4 months (Table III) (37).…”