Although comprehensive genomic profiling (CGP) tests have been covered under the Japanese national health insurance program since 2018, the utility and issues of CGP tests have not been clarified. We retrospectively reviewed 115 patients with incurable pancreatic cancer (IPC) who underwent CGP tests in a Japanese cancer referral center from November 2019 to August 2021. We evaluated the results of CGP tests, treatments based on CGP tests, and survival time. Eight cases (6.9%) were diagnosed as tumor mutation burden-high (TMB-H) and/or microsatellite instability-high (MSI-H). The gene mutation rates of KRAS/TP53/CDKN2A/SMAD4 were 93.0/83.0/53.0/25.2%, respectively. Twenty-five patients (21.7%) had homologous recombination deficiency (HRD)-related genetic mutations. Four patients (3.5%) having TMB-H and/or MSI-H were treated with pembrolizumab, and only two patients (1.7%) participated in the clinical trials. Patient characteristics were not significantly different between patients with and without HRD-related gene mutations. The median OS was significantly longer in the HRD (+) group than in the HRD (−) group (749 days vs. 519 days, p = 0.047). In multivariate analysis, HRD-related gene mutation was an independent prognostic factor associated with favorable OS. CGP tests for patients with IPC have the potential utility of detecting HRD-related gene mutations as prognostic factors as well as a therapeutic search.

Purpose: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin and has shown preliminary efficacy in the treatment of gastric cancer. Study 120, a phase Ib/II open-label study, assessed efficacy and safety of E7389-LF in combination with nivolumab, a programmed cell death (PD)-1 inhibitor. This report focuses on the gastric cancer cohort within the expansion phase. Patients and Methods: Eligible patients had unresectable, measurable gastric cancer, progression following a platinum drug plus fluoropyrimidine (1L), and a taxane-containing regimen (2L). The primary objective of the expansion phase was objective response rate, secondary objectives included safety and PFS, and exploratory objectives included overall survival and biomarker evaluation. Patients received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks, both as intravenous infusions. Tumor responses were assessed every 6 weeks by the investigators per RECIST v1.1. Plasma and tumor biomarkers were assessed. Results: In the 31 patients who received E7389-LF in combination with nivolumab, the objective response rate was 25.8% [confidence interval (CI), 11.9–44.6]. The median progression-free survival was 2.69 months (95% CI, 1.91–2.99) and median overall survival was 7.85 months (95% CI, 4.47–not estimable). The most common treatment-related TEAE of any grade were neutropenia (77.4%), leukopenia (74.2%), and decreased appetite (51.6%). E7389-LF in combination with nivolumab significantly increased CD8-positive cells at C2D1 (P = 0.039), and six of seven vascular markers and four IFNγ-related markers showed increases from C1D1. Conclusions: Promising antitumor activity was observed with E7389-LF in combination with nivolumab in patients with gastric cancer, and no new safety signals were observed, compared with either monotherapy.

Background/Aim: No prospective study has evaluated salvage chemotherapy with capecitabine plus oxaliplatin (XELOX) in patients with gastric cancer who are resistant to or intolerant of cisplatin. Patients and Methods: This multicenter, open-label, single-arm, phase II study was conducted at six centers in Japan, enrolling patients with metastatic or advanced gastric cancer resistant to or intolerant of fluoropyrimidine, cisplatin, taxane, and irinotecan. Capecitabine 1,000 mg/m² was administered orally twice daily for 14 days, followed by a 7-day rest period. Oxaliplatin 130 mg/m² was administered intravenously on day one. The primary endpoint was disease control rate (DCR). Secondary endpoints included response rate (RR), progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), and safety. Results: The study was terminated prematurely due to poor accrual, with 12 patients enrolled. Eight patients demonstrated resistance to prior cisplatin, while four experienced unacceptable toxicity. The median age was 64 years, and eight were male. Four, six, and two patients had Eastern Cooperative Oncology Group performance status 0, 1, and 2, respectively. Among 10 evaluable patients, DCR was 90%, with an RR of 30%. Median PFS, TTF, and OS were 4.2 months [95% confidence interval (CI)=1.4-5.3], 4.1 months (95%CI=1.4-4.4), and 7.1 months (95%CI=2.3-10.1), respectively. The most frequently reported grade 3-4 adverse events were fatigue (20%) and hypokalemia (20%). No treatment-related deaths occurred. Conclusion: Salvage chemotherapy with XELOX may offer clinical benefits for patients with metastatic or advanced gastric cancer resistant to or intolerant of cisplatin.

Background: FOLFIRI (5-FU + leucovorin + irinotecan) plus ramucirumab is one of the standards in second-line metastatic colorectal cancer (CRC) patients progressing after treatment with oxaliplatin/fluoropyrimidine with bevacizumab, but there is no evidence on its efficacy without prior bevacizumab. Moreover, VEGF-D has not been confirmed as a predictive biomarker for ramucirumab’s efficacy, either. Methods: The RAINCLOUD study was a multicenter, single-arm, phase II trial conducted in Japan. Patients with recurrent CRC pretreated with fluoropyrimidine and oxaliplatin without bevacizumab were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints measured were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 48 patients were enrolled from 15 sites between September 2017 and September 2020. Their median age was 63.5 years (25~77), 20.1% had a right-sided tumor, and 68.8% had RAS-mutant cancer. The median PFS was 8.9 months (90% CI: 6.3–11.8), so the primary endpoint was met. Their median OS and ORR were 22.3 months (95% CI: 17.4-NA) and 41.7% (95% CI: 4.9–7.6), respectively. An incidence of grade 3/4 adverse events that reached over 5% applied to neutropenia (44%), leucopenia (10%), and hypertension (8%). In the biomarker analysis, the serum VEGF-D levels post-treatment were higher than those pre-treatment, but the PFS in those with high VEGF-D levels trended towards being worse than that in those with low VEGF-D (7.6M/5.6M (p = 0.095; HR: 0.56)). Instead, those with low TSP-2 had a better PFS than those with high TSP-2 (7.5M/4.3M (p = 0.022; HR: 0.45)). Conclusions: Our data suggested that FOLFIRI plus ramucirumab was effective and tolerable for CRC refractory to fluoropyrimidine and oxaliplatin without anti-angiogenesis. Serum VEGF-D levels may not be predictive but TSP-2 may be a potential prognostic biomarker for ramucirumab’s efficacy.

Background: Advanced gastric cancer patients with severe peritoneal metastases, defined as massive ascites throughout the abdominal cavity and/or inadequate oral intake requiring intravenous infusion support, have been excluded from pivotal clinical trials. Methods: This phase II trial evaluated mFOLFOX6 in HER2-negative, chemotherapy-naive advanced gastric cancer patients with severe peritoneal metastases. The primary endpoint was overall survival (OS); secondary endpoints included ascites response rate among patients with massive ascites and oral intake improvement rate. A sample size of 50 was planned to detect a median OS of 9 months, with a threshold of 6 months (one-sided α = 0.05; β = 0.2). A prespecified individual patient data comparative analysis was performed using data from patients treated with 5-fluorouracil/l-leucovorin (FL) or FL plus paclitaxel (FLTAX) in JCOG1108/WJOG7312G. Results: Among 51 patients, Eastern Cooperative Oncology Group performance status was 0/1/2 in 3/40/8 patients. Median OS and progression-free survival were 7.4 (lower limit of one-sided 95% confidence interval [CI], 6.5) and 3.8 months, respectively. Among 25 patients with massive ascites, the ascites response rate was 36%. Of 33 patients with inadequate oral intake, 46% achieved improved oral intake. The most frequent grade 3–4 adverse event was neutropenia (51%), and febrile neutropenia occurred in one patient (2%). No treatment-related deaths occurred. In propensity score-weighted analysis, OS hazard ratios with mFOLFOX6 versus FL and FLTAX were 0.76 (95% CI 0.56–1.03) and 0.87 (95% CI 0.64–1.18), respectively. Conclusions: mFOLFOX6 was tolerable and may be a treatment option for advanced gastric cancer patients with severe peritoneal metastases. Clinical trial registration: jRCTs041180007.

Supplementary Fig S3. Percent change in biomarkers at C1D8 (A) and C2D8 (B), pharmacodynamic changes in plasma biomarkers from C1D1 (C), and dichotomized analysis of plasma biomarker levels and PFS (D)