Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with <i><scp>BRAF</scp></i> V600 mutation‐positive advanced cutaneous melanoma

Yamazaki, Naoya; Tsutsumida, Arata; Takahashi, Akira; Namikawa, Kenjiro; Yoshikawa, Shusuke; Fujiwara, Yutaka; Kondo, Shunsuke; Mukaiyama, Akihira; Zhang, Fanghong; Kiyohara, Yoshio

doi:10.1111/1346-8138.14210

Cited by 21 publications

(19 citation statements)

References 28 publications

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“…Drug sensitivity was evaluated based on plasma concentration. In summary, the maximum human plasma concentrations of each inhibitor when used in combination with other drugs were reported to be 32.5 ng/mL (approximately 0.053 μmol/L, trametinib) and 35.2 ng/mL (approximately 0.076 μmol/L, taselisib) . According to these results, we classified drug sensitivity into 3 groups based on the IC 50 .…”

Section: Methodsmentioning

confidence: 99%

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

et al. 2018

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Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.

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Section: Methodsmentioning

confidence: 99%

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

et al. 2018

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“…Although its safety and efficacy in Japanese patients have been demonstrated in a Japanese phase 1/2 clinical trial, the results were based on only 12 subjects. 11 and the data are thus insufficient. We have therefore conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients in a clinical setting.…”

Section: Introductionmentioning

confidence: 99%

“…However, almost all of the evidence published on dabrafenib and trametinib combination therapy has been obtained from clinical trials of Caucasian patients with melanoma. Although its safety and efficacy in Japanese patients have been demonstrated in a Japanese phase 1/2 clinical trial, the results were based on only 12 subjects . and the data are thus insufficient.…”

Section: Introductionmentioning

confidence: 99%

Real‐world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma

Takahashi¹,

Namikawa²,

Nakano³

et al. 2019

The Journal of Dermatology

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We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma in real‐world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation‐positive advanced melanoma in our hospital (26 men and 24 women, aged 21–86 years, inclusive; median age, 53 years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression‐free survival (PFS) was 12 months, and median overall survival (OS) was 23 months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long‐term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study.

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“…Vemurafenib monotherapy was approved in Japan in December 2014. Subsequently, a phase I/II trial of dabrafenib plus trametinib combination therapy was carried out on 12 patients with advanced melanoma [ 29 ]. The overall response rate was 83%, and the most common adverse event (AE) was pyrexia, which was observed in 75% of the participants.…”

Section: Introductionmentioning

confidence: 99%

Targeted Therapy and Immunotherapy for Melanoma in Japan

Namikawa¹,

Yamazaki²

2019

Curr. Treat. Options in Oncol.

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Opinion statementMelanoma has several clinically and pathologically distinguishable subtypes, which also differ genetically. Mutation patterns vary among different melanoma subtypes, and efficacy of immune-checkpoint inhibitors differs depending on the subtype of melanoma. In spite of the recent revolution of systemic therapies for advanced melanoma, access to innovative agents is still restricted in many countries. This review article aimed to describe the epidemiology and current status of systemic therapies for melanoma in Japan, where melanoma is rare, but access to innovative agents is available. Acral and mucosal melanomas, which are common in Asian populations, predominantly occur in sun-protected areas and share several biological features. Both the melanomas harbor KIT mutation in approximately 15% of the cases; BRAF or NRAS mutation is found in approximately 10–15% of acral melanoma, but these mutations are less frequent in mucosal melanoma. Combined use of BRAF and MEK inhibitors is one of the standards of care for patients with advanced BRAF-mutant melanoma. In patients with melanoma harboring KIT mutation in exon 11 or 13, KIT inhibitors can be a treatment option; however, none of them have been approved in Japan. Immune-checkpoint inhibitors are expected to be less effective against acral and mucosal melanomas because their somatic mutation burden is lower than those in non-acral cutaneous melanomas. A recently completed phase II trial of nivolumab and ipilimumab combination therapy in 30 Japanese patients with melanoma, including seven with acral and 12 with mucosal melanoma, demonstrated an objective response rate of 43%. Regarding oncolytic viruses, canerpaturev (C-REV, also known as HF10) and talimogene laherparepvec (T-VEC) are currently under review in early phase trials. In the adjuvant setting, dabrafenib plus trametinb combination, nivolumab monotherapy, and pembrolizumab monotherapy were approved in July, August, and December 2018 in Japan, respectively. However, most of the adjuvant phase III trials excluded patients with mucosal melanoma. A phase III trial of adjuvant therapy with locoregional interferon (IFN)-β versus surgery alone is ongoing in Japan (JCOG1309, J-FERON), in which IFN-β is injected directly into the site of the primary tumor postoperatively, so that it would be drained through the untreated lymphatic route to the regional node basin. After the recent approval of these new agents, the JCOG1309 trial will be revised to focus on patients with stage II disease. In conclusion, acral and mucosal melanomas have been treated based on the available medical evidence for the treatment of non-acral cutaneous melanomas. Considering the differences in genetic backgrounds and therapeutic efficacy of immunotherapy, specialized therapeutic strategies for these subtypes of melanoma should be established in the future.

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Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Cited by 21 publications

References 28 publications

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

Real‐world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma

Targeted Therapy and Immunotherapy for Melanoma in Japan

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