This multicenter, randomized, open-label phase III trial (planned enrollment: 700 patients) was conducted to test the hypothesis that single-agent sunitinib improves progression-free survival (PFS) ...compared with capecitabine as treatment for advanced breast cancer (ABC). Patients with HER2-negative ABC that recurred after anthracycline and taxane therapy were randomized (1:1) to sunitinib 37.5 mg/day or capecitabine 1,250 mg/m² (1,000 mg/m² in patients >65 years) BID on days 1-14 q3w. The independent data-monitoring committee (DMC) determined during the first interim analysis (238 patients randomized to sunitinib, 244 to capecitabine) that the trial be terminated due to futility in reaching the primary endpoint. No statistical evidence supported the hypothesis that sunitinib improved PFS compared with capecitabine (one-sided P = 0.999). The data indicated that PFS was shorter with sunitinib than capecitabine (median 2.8 vs. 4.2 months, respectively; HR, 1.47; 95% CI, 1.16-1.87; two-sided P = 0.002). Median overall survival (15.3 vs. 24.6 months; HR, 1.17; two-sided P = 0.350) and objective response rates (11 vs. 16%; odds ratio, 0.65; P = 0.109) were numerically inferior with sunitinib versus capecitabine. While no new or unexpected safety findings were reported, sunitinib treatment was associated with higher frequencies and greater severities of many common adverse events (AEs) compared with capecitabine, resulting in more temporary discontinuations due to AEs with sunitinib (66 vs. 51%). The relative dose intensity was lower with sunitinib than capecitabine (73 vs. 95%). Based on these efficacy and safety results, sunitinib should not be used as monotherapy for patients with ABC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
BACKGROUND: We conducted a phase I/II clinical trial to evaluate the efficacy of eribulin and olaparib in a tablet form (EO study) for triple-negative breast cancer (TNBC) patients. We hypothesized ...that somatic BRCA mutations and homologous recombination repair (HRR)-related gene alterations might affect efficacy. METHODS: Our analyses identified mutations in HRR-related genes and BRCA1/2, and we subsequently evaluated their association to response by the EO study participants. Tissue specimens were obtained from primary or metastatic lesion. Tissue specimens were examined for gene mutations or protein expression using a Foundation Medicine gene panel and immunohistochemistry. RESULTS: In the 32 tissue specimens collected, we detected 33 gene mutations, with the most frequent nonsynonymous mutations found in TP53. The objective response rates (ORRs) in patients with and without HRR-related gene mutation were 33.3% and 40%, respectively (P = .732), and the ORRs in patients with and without somatic BRCA mutations were 60% and 33.3%, respectively (P = .264), with the ORR numerically higher in the somatic BRCA-mutation group but not statistically significant. There was no correlation between immunohistochemistry status and response or between BRCA status or HRR-related gene mutation and survival. Immunohistochemical analysis indicated that EGFR-negative patients had a tendency for better progression-free survival (log-rank P = .059) and significantly better overall survival (log-rank P = .046); however, there was no correlation between the status of other immunohistochemistry markers and survival. CONCLUSION: These findings suggested somatic BRCA mutation and EGFR-negativity as a potential biomarker for predicting the efficacy of eribulin/olaparib combination therapy. (UMIN000018721).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Anticipatory chemotherapy-induced nausea and vomiting (CINV) is a conditioned response influenced by the severity and duration of previous emetic responses to chemotherapy. We aimed to ...evaluate the efficacy of non-pharmacologic interventions for anticipatory CINV among patients with cancer.
Methods
We conducted a systematic search in databases, including PubMed, the Cochrane Library, CINAHL, and Ichushi-Web, from January 1, 1990, to December 31, 2020. Randomized controlled trials, non-randomized designs, observational studies, or case–control studies that utilized non-pharmacological therapies were included. The primary outcomes were anticipatory CINV, with an additional investigation into adverse events and the costs of therapies. The risk-of-bias for each study was assessed using the Cochrane risk-of-bias tool, and meta-analysis was performed using Revman 5.4 software.
Results
Of the 107 studies identified, six met the inclusion criteria. Three types of non-pharmacological treatments were identified: systematic desensitization (
n
= 2), hypnotherapy (
n
= 2), and yoga therapy (
n
= 2). Among them, systematic desensitization significantly improved anticipatory CINV as compared to that in the control group (nausea: risk ratio RR = 0.60, 95% confidence interval CI = 0.49–0.72,
p
< 0.00001; vomiting: RR = 0.54, 95% CI = 0.32–0.91,
p
= 0.02). However, heterogeneity in outcome measures precluded meta-analysis for hypnotherapy and yoga. Additionally, most selected studies had a high or unclear risk of bias, and adverse events were not consistently reported.
Conclusions
Our findings suggest that systematic desensitization may effectively reduce anticipatory CINV. However, further research is warranted before implementation in clinical settings.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
The Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis 2023 was extensively revised to reflect the latest advances in antineoplastic agents, antiemetics, and ...antineoplastic regimens. This update provides new evidence on the efficacy of antiemetic regimens.
Methods
Guided by the Minds Clinical Practice Guideline Development Manual of 2017, a rigorous approach was used to update the guidelines; a thorough literature search was conducted from January 1, 1990, to December 31, 2020.
Results
Comprehensive process resulted in the creation of 13 background questions (BQs), 12 clinical questions (CQs), and three future research questions (FQs). Moreover, the emetic risk classification was also updated.
Conclusions
The primary goal of the present guidelines is to provide comprehensive information and facilitate informed decision-making, regarding antiemetic therapy, for both patients and healthcare providers.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background Previously, we reported the clinical outcomes of the combination of anti-PD-1 Ab, cyclin-dependent kinase 4/6 inhibitors, and endocrine therapy (ET) in patients with ER ...positive/HER2 negative advanced breast cancer in SABCS2020; biomarker analysis has been performed to provide insight into the hepatotoxicy frequently observed in the study. Methods Subjects received 240 mg nivolumab IV on days 1 and 15, 150 mg abemaciclib PO twice daily, and either 500 mg fulvestrant (FUL) on days 1, 15, 29, and every 4 weeks thereafter (FUL cohort) or 2.5 mg letrozole (LET) once daily (LET cohort). The primary endpoint was objective response rate and secondary endpoints included toxicity evaluated in the CTCAE along with an exploratory endpoint as related to the biomarker analysis. Archival tumor tissues were collected before study entry and blood and stool samples were collected at baseline and on cycle3 day1. Tumor tissues were subjected to IHC analysis and RNA sequencing followed by subtyping using NGS. High throughput cytokine analysis using ELISA-based assay were performed with serum samples and cell sorting analysis of PBMC was performed with FACS. Results From June 2019 to December 2019, 17 subjects were enrolled (FUL cohort n = 12, LET cohort n = 5). The study was prematurely closed due to safety concerns such as hepatotoxicity and interstitial lung disease. AEs ≥ Grade 3 were observed in 91.7% and 100% of patients in the FUL and LET cohorts, respectively. The most frequent AEs ≥ Grade 3 were elevated liver function tests (LFT; FUL cohort: 50.0%, LET cohort: 60.0%). Serum cytokine analysis from the subjects with severe hepatotoxicity indicated cytokine storm with elevations of sCD30/TNFRSF8, IL-11, -34, Pentraxin-3, sTNF-R1, -R2, TSLP, which was supported by the findings of reduction of effector regulatory T cells in PBMC. IHC study in liver biopsy from three subjects with the toxicity revealed infiltration of CD8+ T cells and FOXP3+ T reg into the liver, suggesting the immune related liver injury upon the treatment with nivolumab and abemaciclib. HLA typing was performed in the 17 patients but no association between HLA type and ILD or hepatotoxicity were observed. Conclusions The frequent and severe immune related hepatotoxicity induced by the combination of anti-DD-1 and CDK 4/6 inhibitors might have been an immune-boosting therapy as suggested in the preclinical studies. This study was supported by the Ono Pharmaceutical Co., LTD. The registration number of the study is UMIN000036970.
Citation Format: Junji Tsurutani, Jun Masuda, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kiyoshi Yoshimura, Chiyo K. Imamura, Sakiko Miura, Toshiko Yamochi, Kenichi Yoshimura, Toshimi Takano, Hidetaka Kawabata. Biomarker analysis of hepatotoxicity in a Phase II study of nivolumab, abemaciclib and endocrine therapy in patients with HR-positive, HER2-negative breast cancer: WJOG11418BTR NEWFLAME_TR abstract. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-08.
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