A phase IB study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma.

Abstract

8594 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of lenvatinib partial responses were observed in melanoma as well as thyroid, endometrial, and renal cancers. Methods: Patients (pts) with stage 4 or unresectable stage 3 melanoma were treated in sequential cohorts of escalating doses of lenvatinib by continuous once daily dosing and temozolomide (TMZ) days 1-5 every 28 days. Cohort 1: lenvatinib 20mg, TMZ 100 mg; cohort 2: lenvatinib 24 mg, TMZ 100 mg; cohort 3: lenvatinib 24 mg, TMZ 150 mg. Adverse events were recorded according to CTCAE v3.0 and tumor response assessed according to RECIST 1.0. Results: 32 pts were treated: cohort 1: 6 pts, cohort 2: 4 pts, cohort 3: 22 pts. Demographics: median age: 58; males: 63%. Dose limiting toxicities occurred in 0/6 pts in cohort 3 leading to cohort expansion to a total of 22 pts to enable more extensive assessment of toxicity and a preliminary estimate of efficacy. The most common treatment related adverse events in the cohort 3 were fatigue: 50% (gr3: 9%), hypertension: 50% (gr3: 9%), proteinuria: 50% (no gr3), vomiting: 46% (no gr3), hypothyroidism: 46% (no gr3), anorexia: 41% (no gr3), nausea: 41% (no gr3), diarrhea: 36% (gr3: 5%), thrombocytopenia: 32% (no gr3). No treatment-related gr4 events were reported in these categories. The best overall responses per RECIST were partial responses: 5/22 (23%) for cohort 3 pts and 6/32 (19%) for all pts treated at all dose levels. Six-month progression free survival (PFS) rate was 37% and median PFS was 5.4 months. PK/PD analysis and correlation of response with genetic mutational status (BRAF mutations in 31% pts; NRAS mutations in 19% pts) will be presented. Conclusions: Lenvatinib 24 mg once daily in combination with TMZ 150 mg days1-5 every 28 days was given without apparent worsening of either lenvatinib or TMZ related toxicities. Modest clinical efficacy for this combination was observed.

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

“…This PFS compares favourably with clinical trial data for paclitaxel/carboplatin without axitinib (median PFS=4.1–4.5 months) ( Hauschild et al , 2009 ; Kottschade et al , 2011 ; Kim et al , 2012 ) and to axitinib monotherapy (median PFS=3.9 months) ( Fruehauf et al , 2011 ). The median PFS also compares favourably with combination of VEGF-targeted agents with chemotherapy such as carboplatin and paclitaxel with bevacizumab (median PFS=5.6 months) ( Kim et al , 2012 ), nab-paclitaxel with bevacizumab (median PFS=4 months) ( Spitler et al , 2015 ), and lenvatinib with oral temozolomide (median PFS=5.4 months) ( Hong et al , 2012 ). Somewhat surprisingly, the median PFS of axitinib with paclitaxel/carboplatin exceeds the median PFS of several new agents approved for metastatic melanoma within the past 3 years: vemurafenib (median PFS=5.3 months) ( Chapman et al , 2011 ), dabrafenib (median PFS=5.1 months) ( Hauschild et al , 2012 ), and ipilimumab (median PFS<3 months) ( Hodi et al , 2010 ; Robert et al , 2011 ).…”

Lenvatinib and Palbociclib

“…Central Nervous System: Headache 26% to 27%, 17,18 (grade 3 or 4) 1% to 3%. 17,18 C. Constitutional: Dysphonia 24% to 27%, 17,18 (grade 3 or 4) 1% 18 ; fatigue 42% to 100%, 10,11,13,[15][16][17][18] (grade 3) 5% to 13%, 11,13,15,16 (grade 3 or 4) 9% to 42% 17,18 ; weight loss 32% to 46%, 13,15,18 (grade 3) 3% to 4%, 13,15 (grade 3 or 4) 10%. 18 D. Dermatologic: Alopecia 11% 18 ; rash 16% to 50%, 10,18 (grade 3 or 4) 0.4%.…”

“…18 E. Endocrine/Metabolic: Hypocalcemia 7%, 18 (grade 3 or 4) 3% 18 ; hypothyroidism 46%. 11 F. Gastrointestinal: Anorexia 35% to 50%, 10,11,13,[16][17][18] (grade 3) 2% to 5%, 13,15,16 (grade 3 or 4) 5% 18 ; constipation 15% to 50%, 10,18 (grade 3 or 4) 0.4% 18 ; diarrhea 35% to 59%, 10,11,13,[15][16][17][18] (grade 3) 5%, 11,13,15,16 (grade 3 or 4) 2% to 8% 17,18 ; dysgeusia 17% 18 ; dyspepsia 10% 18 ; mucosal inflammation 100% 10 ; nausea 32% to 50%, 10,11,[16][17][18] (grade 3) 3%, 16 (grade 3 or 4) 2% to 3% 17,18 ; stomatitis 36%, 18 (grade 3 or 4) 4% 18 ; vomiting 28% to 50%, 10,11,18 (grade 3) 2%, 17 (grade 3 or 4) 2% 18 ; xerostomia 14%, …”

“…18 L. Pulmonary: Dyspnea 50%, 10 (grade 3 or 4) 9% 19 ; embolism (grade 3 or 4) 3%. 18 M. Renal: Proteinuria 26% to 58%, 11,13,15,17,18 (grade 3) 2% to 7%, 13,15 (grade 3 or 4) 4% to 10%. 17,18 DOSE ADJUSTMENT A. Hepatic 1.…”