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Supplementary Data 3 & 4

Purpose:HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988).Patients and Methods:A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 μg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1.Results:IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses.Conclusions:IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 μg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.

Supp. Table 1; Supp. Table 2; Supp. Table 3 A,B; Supp. Table 4; Supp. Table 5; Supp. Table 6; Supplementary Data 1; Supplementary Data 2

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812–21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781

Background: HER2/neu is overexpressed in 15-25% of gastric cancer patients and associated with poor prognosis. Alternative treatments to monoclonal antibodies are needed due to cost and global availability issues of mAbs. Thus a B-cell peptide vaccine (IMU-131) was developed, consisting of 3 fused B-cell epitopes (p467) from the HER2/neu extracellular domain coupled to CRM197 applied with the adjuvant Montanide. The current study evaluated the optimal and safe vaccine dose leading to immunogenicity and clinical responses. Material & Methods: In an open-label multicenter Phase Ib trial in SE-Asia and Eastern Europe, 14 patients with HER2/neu overexpressing (++/+++) gastric or gastroesophageal junction adenocarcinoma were recruited to receive 3 injections of IMU-131 (days 0, 14, 35) in combination with chemotherapy (CT) every 21 days. Dose escalation with 10 µg, 30 µg and 50 µg was performed in 3 cohorts. Safety, immunogenicity and clinical responses were evaluated. Results: No SAEs related to administration of IMU-131 were reported. Eleven of 14 patients were evaluable for vaccine-specific immune responses and 10 for tumor growth assessment. Higher p467- and Her-2 specific IgG levels were observed in cohort 2 (30 µg/dose) compared to cohort 1 (10 µg/dose). Two of five patients in cohort 2 showed minimal antibody titers. In contrast, all patients in cohort 3 (50µg/dose) responded to the vaccine with equally high antibody levels. Response rate was an exploratory endpoint and of 10 evaluable patients, 5 patients showed partial response and 4 patients showed stable disease. In cohort 3 the high antibody levels correlated with clinical response, while in cohort 2 only moderate correlations between humoral and clinical responses were observed. In cohort 1 partial response did not correlate with Ab levels, but rather with a high percentage of CD8 T-cells and increased inflammatory cytokine levels (high IFN-γ and TNF-α/IL-10 ratio). Conclusions: The vaccine was well tolerated and safe with antibody responses at the highest dose (50 µg) showing a strong correlation with clinical responses. Thus, a dose of 50 µg was recommended for further evaluation in Phase II, featuring two arms of either IMU 131 plus CT or CT alone. We propose that this vaccine might be of significant medical benefit and further trials are warranted. Citation Format: Ursula Wiedermann, Erika Garner-Spitzer, Yee Chao, Iurie Bulat, Arunee Dechaphunkul, Wichit Arpornwirat, Chaiyut Charoentum, Chia-Jui Yen, Thomas Cheung Yau, Marina Maglakelidze, Suebpong Tanasanvimon, Jedzada Maneechavakajorn, Aumkhae Sookprasert, Li-Yuan Bai, Wen-Chi Chou, Teerapat Ungtrakul, Christoph C. Zielinski, Leslie Chong, Nick Ede, Anthony J Good. A Phase Ib open label multicenter study with a HER2/neu peptide vaccine administered with cisplatin and 5-fluorouracil or capecitabine chemotherapy shows safety, immunogenicity and clinical response in patients with HER2/Neu overexpressing advanced cancer of the stomach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT059.