PACMEL: A phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel

Coupe, Nicholas; Corrie, Pippa; Hategan, Mirela; Larkin, James; Gore, Martin; Gupta, Avinash; Wise, Adelyn; Suter, Sam; Ciria, Cristian; Love, Sharon; Collins, Linda; Middleton, Mark R.

doi:10.1016/j.ejca.2014.11.018

Cited by 23 publications

(16 citation statements)

References 30 publications

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“…Several groups have previously shown that treatment with a MEKi can enhance paclitaxel-driven cell death in vitro and in vivo (48–50). Multiple clinical trials are currently underway in advanced solid tumors, such as melanoma and non-small cell lung cancer, testing combinations of taxanes and the MEK inhibitor Trametinib (51). …”

Section: Discussionmentioning

confidence: 99%

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer

Oudin

Barbier

Schäfer

et al. 2017

Molecular Cancer Therapeutics

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Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA, particularly its invasive isoform, MENAINV, are established drivers of metastasis. MENAINV expression is significantly correlated with metastasis and poor outcome in human breast cancer patients. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENAINV confer resistance to the taxane paclitaxel, but not to the widely used DNA damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENAINV-driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by co-treatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance.

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Section: Discussionmentioning

confidence: 99%

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer

Oudin

Barbier

Schäfer

et al. 2017

Molecular Cancer Therapeutics

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“…The tubulin polymerization stabilizer paclitaxel was given intravenously at 80 mg/m 2 on days 1, 8, and 15 every 4 weeks in combination with trametinib (2 mg po daily) [9]. The combination was well tolerated, and among eight NRAS mutant patients, there were a 50% PR rate and a 75% DCR.…”

Section: Discussionmentioning

confidence: 99%

Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients

et al. 2017

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This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy.Key pointsDigoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.

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“…In this small group, promising PFS and overall survival rates were observed in patients with melanoma lacking the BRAF V600 mutation. 19 …”

Section: Efficacy Studiesmentioning

confidence: 99%

Trametinib: a MEK inhibitor for management of metastatic melanoma

Ługowska¹,

Koseła-Paterczyk²,

Kozak³

et al. 2015

OTT

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This review presents the current data on the efficacy and safety of the selective mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in patients with metastatic BRAF V600-positive melanoma. The pharmacological, safety, and efficacy data come from the Phase I, II, and III studies of trametinib monotherapy, as well as those in combination with the BRAF inhibitor dabrafenib. The most common adverse effects of trametinib therapy are rash, dermatitis, diarrhea, and fatigue. The Phase III METRIC study showed significant improvement in overall survival and progression-free survival in favor of trametinib over standard dacarbazine or paclitaxel chemotherapy. Therefore, trametinib was approved by the US Food and Drug Administration and European Medicines Agency as a single agent for the treatment of patients with V600E-mutated metastatic melanoma. Progression-free survival and response rates for trametinib monotherapy were lower than those noted with BRAF inhibitors. The second step in developing trametinib was to use the combination of trametinib with the BRAF inhibitor, eg, dabrafenib, to postpone the progression on MEK or BRAF inhibitors. The recently published data showed significant improvement in overall survival and progression-free survival in favor of the combination of trametinib and dabrafenib over vemurafenib therapy or dabrafenib alone, with good tolerance. The US Food and Drug Administration has approved the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma, and their use seems to be currently the best approach. While BRAF-MEK inhibition is a standard, molecular targeted therapy in BRAF-mutated melanomas, its future utility has to be established in the rapidly changing landscape of immunotherapeutics.

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PACMEL: A phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel

Cited by 23 publications

References 30 publications

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer

Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients

Trametinib: a MEK inhibitor for management of metastatic melanoma

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