The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial

• Published in: British journal of cancer 2015-04, Vol.112 (8), p.1326-1331
• Main Authors: Algazi, A P, Cha, E, Ortiz-Urda, S M, McCalmont, T, Bastian, B C, Hwang, J, Pampaloni, M H, Behr, S, Chong, K, Cortez, B, Quiroz, A, Coakley, F, Liu, S, Daud, A I
• Format: Article
• Language: English
• Subjects: 692/308/2779/109/1941; 692/699/67/1059/99; 692/699/67/1813/1634; 692/700/565/1436/1437; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Axitinib; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carboplatin - administration & dosage; Carboplatin - adverse effects; Clinical Study; Dideoxynucleosides; Drug Resistance; Epidemiology; Female; Humans; Imidazoles - administration & dosage; Imidazoles - adverse effects; Indazoles - administration & dosage; Indazoles - adverse effects; Male; Melanoma - diagnostic imaging; Melanoma - drug therapy; Melanoma - genetics; Middle Aged; Molecular Medicine; Oncology; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Positron-Emission Tomography - methods; Prospective Studies; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Proto-Oncogene Proteins B-raf - genetics; Radiography; Treatment Outcome
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.541

Background: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. Methods: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0–1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1–14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m −2 ) was administered on day 1 starting with cycle 2. 3′-Deoxy-3′- 18 F-fluorothymidine ( 18 F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. Results: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing 18 F-FLT-PET scans showed increases (23–92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF V600E/K patients had significantly worse PFS than patients without these mutations. Conclusions: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3′-Deoxy-3′- 18 F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.