Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK.

Abstract

4003 Background: DANTE evaluates atezolizumab in the perioperative treatment of resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with FLOT. Here, we report interim results. Methods: DANTE is a multicenter, investigator-initiated, phase IIb trial. Patients (pts) with resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N+) were randomized to receive 4+4 cycles of periop. FLOT chemotherapy (arm B) or the same regime with additional atezolizumab at 840 mg, q2w, followed by atezolizumab monotherapy for 8 cycles at 1200 mg, q3w (arm A). The primary endpoint is progression-free survival. The secondary endpoints surgical outcome (pTNM, R0 resection rate and periop. morbidity/mortality), path. regression and safety are reported here. TNM stage was evaluated by local pathologists and path. regression (Becker-Classification) by local and central pathologists. PD-L1 and MSI status were centrally evaluated. Results: In total, 295 pts were randomized (A, 146; B, 149) with baseline characteristics as follows: median age 61y, male 74%, intestinal type 42%, GEJ 61%, cT3/4 77%, N+ 78%. Twenty-five pts (8.5%) were MSI; 50% had PD-L1 CPS ≥1, 23% PD-L1 CPS ≥5 and 15% PD-L1 CPS ≥10. Pre-op FLOT cycles were completed in 93% of pts and post-op cycles in 43% of pts, with no difference between arms. Surgical morbidity (A, 45%; B, 43%) and mortality (overall 2.5%) were comparable between arms, as were R0-resection rates (arm A, 92% vs. arm B, 91%). Downsizing favored arm A vs B (pT0, 23% vs 15%; pN0, 68% vs 54%). Increases in path. regression rates were seen, particularly with higher PD-L1 expression (Table). Conclusions: The analysis shows beneficial effects of atezolizumab combined with FLOT vs FLOT alone on path. stage and path. regression that seem to be more pronounced with higher PD-L1 expression. Sponsor: Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest. EudraCT: 2017-001979-23. Clinical trial information: NCT03421288. [Table: see text]

The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction

“…Recently, the randomized DANTE trial reported the interim results of neoadjuvant atezolizumab plus chemotherapy in 146 patients with resectable esophagogastric adenocarcinoma. Compared with our study, DANTE also reported a lower pCR rate (25% in the FAS), but a slightly higher MPR rate (49% in the FAS) 18 . Considering the single-arm design of our study with small sample size, a large-scale randomized controlled trial is warranted to validate camrelizumab plus concurrent chemoradiotherapy in patients with gastric cancer.…”

“…The median number of lymph nodes resected was 28 (range, 6-51). The median length of postoperative hospital stay was 8 days (range, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Three patients did not undergo gastrectomy because one had progressive disease, one refused surgery, and one was deemed uncurable due to liver metastases during surgical exploration.…”

“…Given the success of immunotherapy plus chemotherapy in the first-line setting, neoadjuvant therapy containing PD-1/PD-L1 blockade has been investigated in gastric adenocarcinoma [13][14][15][16][17][18] , with a hypothesis of the promotion of systemic antitumor immunity, derived from the activation of tumor-specific T cells within the tumor microenvironment, and the enhancement of antigen presentation from the dendritic cell to the tumor-specific T cells 19 . Additionally, chemoradiotherapy might increase the expression of PD-1/PD-L1 in tumor cells and improve the efficacy of immunotherapy in PD-L1-negative or microsatellite-stable patients 20 .…”

The Role of Surgery in the Management of Gastric Cancer: State of the Art

“…Finally, for patients who have good to moderate performance status, the suggested perioperative regimen is fluorouracil and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) [ 13 ]. Ongoing trials are testing the addition of immune checkpoint inhibitors to the FLOT regimen for mismatch repair-deficient tumors that express programmed death-ligand 1, such as pembrolizumab in the KEYNOTE-585 trial [ 102 ], etezolizumab in the DANTE study [ 103 ], and durvalumab [ 104 ]. Moreover, ongoing studies are investigating the addition of trastuzumab to a current chemotherapy regimen in a perioperative setting for patients with ERBB2 (HER2 or HER2/neu)–positive tumors [ 105 ].…”

Immune checkpoint inhibitors in resectable gastroesophageal cancers - a review

“…However, the difference was much higher in higher PD-L1 CPS groups as well as the MSI-H subgroup. 44 …”