Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced ...gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. In this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab.
The subjects of this study were AGC patients received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups.
Of the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3-407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that number of metastatic sites ≥2 (HR = 2.15; 95% CI, 1.02 to 4.54), high ALP level (HR = 2.50; 95% CI, 1.27 to 4.54), and absence of irAEs (HR = 9.54, 95% CI, 3.34 to 27.30 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). There were no grade 4 or 5 adverse events related to nivolumab.
Development of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.
Trifluridine/tipiracil (TFTD), with or without bevacizumab (Bev), and regorafenib are salvage chemotherapy options for metastatic colorectal cancer (mCRC). Here, we examined the influence of ...precedent drug on the efficacy of subsequent drug.
The subjects were patients with mCRC who received salvage chemotherapy with TFTD (with/without Bev) followed by regorafenib (TFTD→Rego group/TFTD+Bev→Rego group), or reverse sequence (Rego→TFTD group) at the National Cancer Center Hospital between November 2013 and December 2020. The overall survival (OS), progression-free survival (PFS), disease control rate (DCR), tumor growth rate (TGR), and tumor growth kinetics (TGK) in the first evaluation were assessed in the three groups.
A total of 69 patients, including 27 in the TFTD→Rego group, 13 in the TFTD+Bev→Rego group, and 29 in the Rego→TFTD group, were identified. There were no significant differences in the OS among the three groups, and in the PFS and DCR between the precedent and subsequent therapies in any of the groups. The median TGR (%/month) and TGK (mm/month) in the precedent→subsequent therapy were 50.9→32.7 (p = 0.044) and 8.76→7.79 in the TFTD→Rego group, 25.4→36.1 and 7.49→9.92 in the TFTD+Bev→Rego group, and 40.8→24.4 (p = 0.027) and 8.02→7.20 in the Rego→TFTD group, respectively.
In crossover use of TFTD with/without Bev and regorafenib, both agents showed similar efficacy in terms of the conventional parameters, but the differences observed in the TGR and TGK might suggest some influence of prior regorafenib treatment on the efficacy of subsequent TFTD therapy, and vice versa.
Background
Because standard chemotherapy for advanced gastric cancer consists of oral fluoropyrimidines plus platinum as first-line therapy, with paclitaxel plus ramucirumab as the second line, ...irinotecan is usually positioned as third-line chemotherapy in clinical practice in Japan.
Methods
A retrospective evaluation was conducted to determine the efficacy and safety of irinotecan as third-line chemotherapy for advanced gastric cancer in patients refractory or intolerant to fluoropyrimidines, platinum, and taxanes.
Results
Between February 2008 and December 2013, 52 patients received third-line irinotecan monotherapy. Among the 32 patients with measurable lesions, 1 patient achieved a confirmed partial response and 6 patients had stable disease. The overall response rate was 3% and the disease control rate was 22%. Median progression-free survival was 2.3 months 95% confidence interval (CI), 1.8–2.8 and median overall survival was 4.0 months (95% CI, 2.6–5.3). The most common adverse events of grade 3 severity or higher were neutropenia (27%), febrile neutropenia (12%), anorexia (12%), and diarrhea (6%). Although no treatment-related deaths occurred, 2 patients (4%) died of disease progression within 30 days after the last administration of irinotecan.
Conclusion
Irinotecan monotherapy appears to be tolerated but was shown to have modest activity as third-line chemotherapy for advanced gastric cancer.
Summary
Background
Ramucirumab (RAM) plus solvent-based (sb)-paclitaxel (PTX) is the standard second-line chemotherapy for advanced gastric cancer (AGC). The subset analysis of the ABSOLUTE trial, ...which confirmed non-inferiority of weekly nanoparticle albumin-bound (nab)-PTX to weekly sb-PTX, suggested that nab-PTX might have better efficacy than sb-PTX in patients with peritoneal metastasis. We retrospectively evaluated the efficacy and safety of RAM plus sb-PTX and nab-PTX in patients with peritoneal metastasis of AGC.
Methods
AGC patients who received RAM plus sb-PTX or nab-PTX as second-line chemotherapy from June 2015 to February 2019 were included in the study. Overall survival (OS), progression-free survival (PFS), response rate, and safety were assessed.
Results
A total of 128 patients were included in this study (93 in the RAM plus sb-PTX group and 35 in the RAM plus nab-PTX group). PFS was 4.1 months in the RAM plus sb-PTX group and 4.6 months in the RAM plus nab-PTX group (HR 0.90; 95%CI 0.58–1.41,
p
= 0.643). OS was 8.9 months in the RAM plus sb-PTX group and 11.4 months in the RAM plus nab-PTX group (HR 0.95; 95%CI 0.56–1.62,
p
= 0.847). A total of 62 and 31 patients had peritoneal metastasis in the RAM plus sb-PTX and the RAM plus nab-PTX groups, respectively. RAM plus nab-PTX showed a slightly longer survival compared to RAM plus sb-PTX in patients with peritoneal metastasis (PFS 5.8 vs 3.5 months, HR 0.66; 95% CI 0.40–1.10,
p
= 0.109).
Conclusion
This study suggests that RAM plus nab-PTX might be a more effective treatment for peritoneal metastasis of AGC.
Expression levels of insulin-like growth factor type 1 receptor (IGF-IR), epidermal growth factor receptor (EGFR), and HER2 expressions have been linked to clinical outcomes in several solid tumors. ...However, the clinical significance of these biomarkers in gastric cancer (GC) remains unclear. This study was designed to delineate the clinical implications of these three biomarkers in GC.
The study group comprised 87 patients who underwent gastrectomy at National Cancer Center Hospital and subsequently received chemotherapy for recurrent or residual tumors. Using immunohistochemical techniques, we analyzed the expressions of IGF-IR, EGFR, and HER2 on formalin-fixed paraffin-embedded specimens of surgically removed primary tumors.
IGF-IR expression (defined as >10% membranous staining) was found in 67 tumors (77%), EGFR expression in 55 (63%), and HER2 expression in 16 (18%). Positive coexpression of IGF-IR and EGFR was found in 48 tumors (55%), that of IGF-IR and HER2 in 16 (18%), and that of EGFR and HER2 in 13 (15%). Multivariate survival analysis showed that IGF-IR-positive expression hazard ratio (HR) 2.14, 95% confidence interval (95% CI) 1.20-3.82; P = 0.01, performance status 1 or 2 (HR 1.83, 95% CI 1.15-2.91; P = 0.01), and diffuse type tumors (HR 1.71; 95% CI 1.08-2.70; P = 0.02) were significant predictors of poor survival.
IGF-IR expression in surgical GC specimens, poor performance status, and diffuse type tumors are significant predictors of poor outcomes in patients with GC. Our data suggest that anti-IGF-IR strategies may prove valuable in such patients.
...the Advanced Medical Care B system, which is similar to the Medicare Clinical Trial Policy system in the USA, under which unapproved or off-label drugs are used in a clinical trial setting with ...health insurance coverage for the routine medical care cost--the so-called mixed medical treatment system--a plausible measure that can provide patients with a chance to participate in clinical trials of unapproved or off-label oncology drugs.
Metabolic reprogramming, including the Warburg effect, is a hallmark of cancer. Indeed, the diversity of cancer metabolism leads to cancer heterogeneity, but accurate assessment of metabolic ...properties in tumors has not yet been undertaken. Here, we performed absolute quantification of the expression levels of 113 proteins related to carbohydrate metabolism and antioxidant pathways, in stage III colorectal cancer surgical specimens from 70 patients. The Warburg effect appeared in absolute protein levels between tumor and normal mucosa specimens demonstrated. Notably, the levels of proteins associated with the tricarboxylic citric acid cycle were remarkably reduced in the malignant tumors which had relapsed after surgery and treatment with 5‐fluorouracil‐based adjuvant therapy. In addition, the efficacy of 5‐fluorouracil also decreased in the cultured cancer cell lines with promotion of the Warburg effect. We further identified nine and eight important proteins, which are closely related to the Warburg effect, for relapse risk and 5‐fluorouracil benefit, respectively, using a biomarker exploration procedure. These results provide us a clue for bridging between metabolic protein expression profiles and benefit from 5‐fluorouracil adjuvant chemotherapy.
Using absolute quantification of protein levels, we identified that the behavior of Warburg effect‐related proteins was strongly associated with relapse prediction and the therapeutic indication of uracil‐tegafur (UFT)‐adjuvant therapy.
Background In clinical practice, the same chemotherapeutic agents are occasionally reused (re-challenge) after failure of all available standard chemotherapy options for metastatic colorectal cancer ...(mCRC). However, the benefits of re-challenge chemotherapy (Re-Cx) are unclear. This retrospective study evaluated the efficacy of Re-Cx, focusing on the tumor growth rate (TGR). Methods The study included mCRC patients with measurable lesions who received Re-Cx from November 2011 to October 2018 at National Cancer Center Hospital. Re-Cx was defined as re-administration of agents which had been used in prior lines of chemotherapy and discontinued due to disease progression. We compared the TGR immediately after initiating Re-Cx regimens with that observed at the time of disease progression during prior chemotherapy (Prior-Cx) immediately before Re-Cx. Results Of the 25 patients who received Re-Cx, five patients received two Re-Cx regimens. Therefore, a total of 30 cases of Re-Cx were analyzed in this study. The regimens of Re-Cx were oxaliplatin based (19 cases), irinotecan based (8 cases), and others (3 cases). Although the objective response rate to Re-Cx was 0%, the disease control rate was 60% (18 cases), and 40% (12 cases) showed some tumor shrinkage. We compared the effects of Re-Cx and Prior-Cx by the TGR and found that the TGR of Re-Cx was slower than that recorded in Prior-Cx in 26 of 30 cases (87%). In particular, the ratio of% TGR <0, which indicates tumor shrinkage, was obtained in 13 of 30 cases (43.3%). The median progression-free survival and overall survival after Re-Cx were 3.8 and 6.57 months, respectively. Conclusion We found that Re-Cx may have some anti-tumor efficacy as salvage treatment for mCRC and these results also suggested the clinical benefits of Re-Cx.
Background Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, ...there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project). Methods/Design This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021. Discussion A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities. Trial registration Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) ClinicalTrials.gov: NCT04962867 (registered July 15, 2021). Keywords: Fibroblast growth factor receptor, Gene fusion, Mutation, Amplification, Precision medicine
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