Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

By T. Eisen, T. Ahmad, K. Flaherty, M. Gore, S. Kaye, R. Marais, I. Gibbens, S. Hackett, M. James, L. Schuchter and 7 more. British Journal of Cancer, 2006

652 citations recorded by the source corpus.

The effects of sorafenib – an oral multikinase inhibitor targeting the tumour and tumour vasculature – were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with ⩾25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with ⩾25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had ⩾25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had ⩾25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e646e9d8dcc49b7dc984ff6ae8ee6682a3d084c5

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In Molecular Biology

1. C. Der
2. P. Roberts
3. S. Hagan
4. Walter Kolch
5. Oliver Rath
6. Vincent A. Miller
7. S. Lippman
8. Marc Ladanyi

In Oncology

1. Gregory Riely
2. Vincent A. Miller
3. M. Kris
4. Walter Kolch
5. C. Der
6. P. Roberts
7. William Pao

Citations in the corpus

• Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer (2007, background): “Although preclinical cell culture and mouse model analyses showed that continued expression of mutant B-Raf is critical for melanoma growth and tumorigenicity, phase II clinical trial analyses with sorafenib observed little or no antitumor activity when evaluated as monotherapy for advanced melanoma”
• Targeting the Mitogen-Activated Protein Kinase RAS-RAF Signaling Pathway in Cancer Therapy (2012, background): “Furthermore, although preclinical data showed that continued expression of mutant Braf is critical for melanoma growth and tumorigenicity, Phase II clinical trials with sorafenib (400 mg twice daily) showed only modest or no antitumor activity [78].”
• MAP kinase signalling pathways in cancer (2007, background): “monotherapy with Sorafenib is well tolerated but has little or no antitumour activity (Eisen et al., 2006).”
• Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. (2011, result): “This is an important observation, as the first clinical trials of RAF inhibitors in melanoma used sorafenib, which was found to be ineffective against the V600E mutant isoform.(30) There were too few patients with BRAF mutations to perform a comparison of the clinical characteristics and outcomes am”