Background Advanced melanoma patients have a poor prognosis (median survival-time of <9 months; 5-year survival-rate <5%). Neither of the 2 FDA-approved agents for the treatment of stage IV melanoma [Dacarbazine (DTIC) and Interleukin-2 (IL-2)] has resulted in an improved overall-survival, but a modest increase in tumour response-rate. Single-agent DTIC showed average response-rate of 10% and median response-duration of 5–6 months, being poly-chemotherapy never proven as superior to mono-chemotherapy. To improve such sober results, different DTIC-combinations have been proposed. Several melanoma in vitro models showed a transcriptional up-regulation of Vascular Endothelial Growth-Factor (VEGF) by DTIC, suggesting the combination of DTIC/anti-VEGF therapy as an intriguing exploiting path.
Aim Clinical benefit, response evaluation and duration as well as safety and feasibility of the combination DTIC/Bevacizumab in a group of chemotherapy-naive advanced melanoma pts, within a phase II study.
Patients and methods Between July 2006 – September 2009, 40 advanced melanoma patients underwent first-line chemotherapy as follows: DTIC (800 mg/mq q4w)+Bevacizumab (10 mg/kg q2w). Disease evaluation was performed at each access by physical examination and every 3 cycles by whole-body (wb) CT-scan, according to Recist criteria. Response rate, median TTP and safety were analyzed.
Results 36/40 patients were evaluable at the analysis-time, with 4 screening failures because of brain metastasis detection at the pre-study wb CT-scan (3pts) and bleeding risk (1pt). Male/Female=23/13; with a median age of the whole group of 57 years (Male 60 yr; Female 47 yr). PS 0/1=32/4. 6/36 pts (16.6%) developed partial response (PR), 13/36 pts (36.1%) stable disease (SD ≥24w=10 pts, 25.6%). 17/36 pts (47.2%) developed progressive disease (PD), defined respectively as Recist-criteria progression at the first CT-scan evaluation (8pts) or earlier clinical progression (ePD; 9pts). PR pts were on average older (65.7 yrs; range 46.3–74.1) than both SD (57.2 yrs; range 33.1–78.5) and PD pts (51.4 yrs; range 31.6–76.3). Median TTP was 6 mo (95% CI 2.8–12.6). Stratifying by M1-stage, PD-pts mostly belonged to the M1c-group (10/16). Furthermore, exploratory data analysis interestingly shows 42.2% clinical benefit (defined as PR+SD≥24w) and 16.5 months (95% CI 5–31.5) median survival. The treatment was well tolerated (most common AEs (8/39): mild hypertension & mucositis easily controlled by symptomatic therapy). Three SAEs were reordered: 2 major cardiac events and 1 allergic reaction to Bevacizumab at the first administration.
Conclusion Long-lasting response obtained in both SD and PR pts and mild side effects support DTIC/B as a promising combination in advanced MM pts. We are currently investigating whether the molecular pattern and gene profiling of each patient can predict responders vs non-responders to the DTIC/B combination.