BRAF-Validated Target in Metastatic Melanoma.

Konference: 2011 XXXV. Brněnské onkologické dny a XXV. Konference pro sestry a laboranty

Kategorie: Maligní melanom a nádory kůže

Téma: Chemoterapie, biologická a hormonální terapie

Číslo abstraktu: 003

Autoři: Igor Puzanov


Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results come from treating melanoma as a single homogeneous disease [1,2]. Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/threonine kinase was described as present in over 50 % of all melanomas [3]. The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through MAP kinase pathway [4]. The frequency and specificity of this mutation (95 % at V600E of BRAF) suggested its potential as a target for therapy.

Recent data with PLX4032/RO5185426 provide first evidence that therapy targeting tumors containing activating V600EBRAF mutations can induce significant tumor regression in patients with melanoma. PLX4032/RO5185426 is a novel oral small molecule with selective inhibition of the oncogenic V600E mutant BRAF kinase among 70 kinases screened with preclinical in vivo and in vitro activity. Data presented at the 2009 American Society of Clinical Oncology meeting showed unprecedented antitumor activity in V600E BRAF mutant tumors in Phase I dose escalation study [5]. Fifty-five patients were enrolled, including those with metastatic melanoma (n = 49), thyroid (n = 3), rectal (n = 1), or ovarian carcinoma (n = 1). Dose-limiting toxicities included fatigue, myalgias, and rash in three of five patients at 1120 mg twice daily. Squamous cell carcinoma of the skin, keratoacanthoma type, was seen in 23 % of patients. Doses at or above 240 mg orally twice daily with a microprecipitated bulk powder formulation were able to deliver blood levels in or well above the range effective in preclinical models.

Results in the V600E BRAF melanoma patients (n = 16) at doses greater than 240 mg orally twice daily showed 10 partial responses and one complete response, with nine being confirmed with regression of liver, lung, and bone metastasis. Positron emission tomography results from baseline and at day 15 showed remarkable reduction in glucose uptake in most patients. Some patients had symptomatic improvement within days of starting treatment. The MTD was selected at 960 mg twice daily. Median progression-free survival (PFS) in this cohort was approximately 8.5 months. An extension cohort of 32 melanoma patients treated at the MTD of 960 mg twice daily was then enrolled [6]. The median age was 52 years, 74 % having M1c disease, 45 % Eastern Cooperative Oncology Group (ECOG) performance status 0, 55 % ECOG performance status 1, and 39 % given three or more prior therapies for metastatic disease. Drug-related toxicities were seen in more than 10 % of the extension cohort and included rash (68 %), arthralgias (48 %), photosensitivity (42 %), fatigue (32 %), cutaneous squamous cell carcinoma (keratoacanthoma type; 23 %), pruritus (23 %), palmar-plantar dysesthesia (23 %), nausea (19 %), alopecia (16 %), and hyperbilirubinemia (13 %). To date, this cohort of V600E BRAF-mutated melanoma patients treated with PLX4032 at MTD of 960 mg twice daily showed an overall RECIST (Response Evaluation Criteria in Solid Tumors) objective response in 26/32 patients (81 %), with two complete responses as compared to a historical experience of 10 % to 15 % OR with conventional drugs. Toxicity was manageable at 960 mg twice daily. The median PFS has been 8.01 months. with median overall survival not yet reached A Phase 2 trial of PLX4032 in 120 previously treated V600E BRAF-mutated patients, has finished accrual in the United States and Australia, PFS and OR were selected as primary endpoints.

A Phase 3 front-line randomized trial of PLX4032 or dacarbazine chemotherapy in 650 patients with V600E-mutated melanoma has opened worldwide in January 2010 with OS as primary endpoint. The development of cutaneous squamous cell carcinomas, keratoacanthoma type, occurred in up to 30 % of patients treated at the phase 2 dose. They were mostly easily treated with local therapy, have not shown any metastatic potential and generally regressed upon dose interruption. Recent published data demonstrates that selective BRAF inhibitors can activate the MAP kinase pathway in vitro in cells that lack a BRAF mutation [7,8,9]. This finding may pertain to some of the toxicities observed with PLX4032. Ongoing studies should bring insights to the molecular pathways active in development of these skin lesions and potentially help in development of the next generation of BRAF inhibitors.

These results represent the first example of successful targeting of an intracellular signaling molecule that harbors an activating mutation. The ongoing Phase III trial should provide answer whether this approach leads to improved overall survival in comparison to standard chemotherapy.


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Datum přednesení příspěvku: 21. 4. 2011