Phase II trial of perioperative chemotherapy + avelumab in locally advanced gastroesophageal adenocarcinoma: Preliminary results.

Abstract

4046 Background: Perioperative chemotherapy improves cure rate in locally advanced gastroesophageal adenocarcinoma (GEA), and immune checkpoint inhibitors are active at the metastatic stage. This trial tests the hypothesis that the addition of avelumab to perioperative chemotherapy will increase the major pathologic response (MPR) rate in comparison with historical controls. Methods: Phase II study of avelumab + chemotherapy (docetaxel, cisplatin and 5-FU or mDCF) given every 2 weeks for 4 cycles before and after surgery. Main inclusion criteria: GEA, cT3 and/or cN+, M0, WHO PS 0-1. Main exclusion criteria: use of immunosuppressants, serious autoimmune disease, daily intake >10 mg prednisone. Staging studies: CT, PET-CT, endoscopic ultrasound, diagnostic laparoscopy. Surgical resection: D2 lymphadenectomy, en-bloc esophagectomy for type I/II gastroesophageal junction (GEJ) tumors. Aim of the study: MPR as defined as tumor regression grades 0-1 (modified Ryan scheme); as per hypothesis, this experimental regimen will result in a 20% rate of MPR, compared with 7% with chemotherapy alone. Simon 2-stage design: if less than 2 MPR are seen in the first 16 patients, the study will be closed. The study hypothesis cannot be rejected if at least 6 MPR are seen in the first 50 patients. All adverse effects are prospectively recorded per CTCAE guidelines in patients who have received at least one treatment cycle. Survival rates are calculated with Kaplan-Meier method. Preliminary results are presented since the study has met its primary endpoint. Results: Feb 2018-Feb 2020: 28 patients enrolled (25 M/3 F, age 45-78). Location: GEJ (23), stomach (5). Staging: cT3 (25), cT4 (1), cN+ (20). Biomarkers expression: mismatch repair (MMR) protein loss (3/28); PD-L1(clone 73-10) expression in 1% (TPS) or more of tumor cells seen in 12/28 samples, and >10% in 6 patients. Grade 3 toxicity: stomatitis (2/28); nausea (2/28); vomiting (1/28); diarrhea (1/28); hypothyroidism (1/28); arthralgia (3/28); neutropenia (1/28). Grade 4 toxicity: pneumonia (1/28); neutropenia (2/28). Postoperative 30-day mortality: 0%. One patient was excluded from efficacy analyses for M1 staging; 27 patients underwent surgery, 26 with R0 (96%). Six cases (22%) show MPR: 3 grade 0 (11%) and 3 grade 1 (11%) tumor regressions. No correlation was seen between MMR proteins or PD-L1 expression and tumor regression. With a median follow-up of 1.5 years (range 0.4-2.5), the disease-free survival rate is projected to be 0.92 (95% CI 0.83-1.00) at 12 months and 0.77 (95% CI 0.58-1.00) at 24 months. Conclusions: The combination of mDCF chemotherapy with Avelumab demonstrates a promising safety and activity profile. Ongoing laboratory investigations are underway to correlate our findings with tumor molecular features before exposure to treatment. Clinical trial information: NCT03288350.

Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer

“…Based on preliminary data, the neoadjuvant ICI-based therapy led to good outcomes in pathological responses, especially in MSI-H or PD-L1 positive patients. This was consistent with several recent phase I/II single-armed studies in the 2021 ASCO annual meeting, which used ICI plus chemotherapy to treat cT3-4 or N+ gastric cancer patients and achieved >90% R0 resection rates, 0-25% CPR, and 22-42% MPR [26][27][28][29][30][31] . Compared with these studies, our trial recruited patients with more advanced cancer, all being cT4N+, 56% initially unresectable cT4bN+, and 64% Lauren's diffused type patients.…”

Neoadjuvant immune checkpoint inhibitor in combination with chemotherapy or chemoradiotherapy in resectable esophageal cancer: A systematic review and meta-analysis

“…The selection process and reasons for study exclusion are shown in Figure 1. Among the 27 studies, 8 trials with 221 patients examined nICRT (14-21), 19 trials with 588 patients examined nICT (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Except one twoarms trial (33), all included studies were single-arm trials.…”

“…The frequently adopted RT dose in studies of nICRT was 41.4Gy in 23 fractions (4/8). The median patient age were 63 years (interquartile range [IQR], 62-64 years) and 62 years (IQR, 61-64) for patients receiving nICRT and nICT, respectively; and the median sample sizes were 26 participants (IQR, [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] and 28 participants (IQR, 20-41), respectively. The main characteristics and outcomes of studies are presented in Tables 1, 2.…”

Immunotherapy-Based Neoadjuvant Treatment of Advanced Microsatellite Instability–High Gastric Cancer: A Case Series

“…Our observations appear consistent with other small prospective trials reported to date in which ICIs have been incorporated into perioperative chemotherapy for molecularly unselected patients with GC. [32][33][34] Ongoing phase III trials randomizing patients with GC receiving perioperative chemotherapy to the addition of an ICI or placebo may validate acceptable toxicities. 35,36 Despite the dramatic responses to ICIs demonstrated in MSI-H tumors, the adoption of MSI/dMMR testing in the clinical setting remains a challenge.…”