Advances in melanoma therapy

The increasing incidence of melanoma and ever younger age of the patients determined the world of science to find effective drugs. Some are already on the market, others are under investigation.

- Each year in Europe, there has been a 68 thousand. new cases of metastatic melanoma, more than 20 thousand. patients die. It is barely 4 percent. incidence among all skin cancers, but accounts for 80 percent. deaths - said Axel Hoose, responsible for the department of immunology and oncology, Bristol Myers Squibb Company, at a press conference organized as part of this year's European Oncology Multidisciplinary Congress in Stockholm (23-27 September 2011.). 


Cancer 
 youth

In countries such as Great Britain takes on epidemic proportions. Drastically reduces the average age of the patients. Melanoma is the most common cancer among 20th years old. In Poland, for the time being in the second ten most common cancers.

- This shows the difference in the determination to fight the disease - summarizes the epidemiology of cancer Piotr Rutkowski, director of Cancer Soft Tissue Clinic, Bone and Czerniaków Free Society:

- Just look at the growing number of sessions devoted to this type of cancer in the international oncology meetings. 
 
 The metastatic melanoma has come to be loud at last year's ASCO information due to the progress in this area has not been seen since the 70s these.


Long-term survival

In 2010, the magazine published the NEJM study ipilimumabu (Bristol Myers Squibb). The drug is a human monoclonal antibody that blocks CTLA-4 antigen and the immune system to be active in the fight against melanoma cells.
 


In March 2011, FDA registered drug as monotherapy for the treatment of patients in stage III and IV disease. In July, ipilimumab was registered by the EMA. 
 


The three-arm randomized phase III trial randomized patients with unresectable melanoma of the III and stage IV, in which the disease had progressed after treatment system, compared ipilimumab glycopeptide vaccine (gp100). 
 


676 patients were randomized to three groups in a 3:1:1 ratio: ipilimumab (at a dose of 3 mg kg of body weight in cycles every 3 weeks for a total of four cycles) with the addition of gp100 vaccine (403 patients), ipilimumab alone at the same dose (137) and gp100 monotherapy (136).

Median survival in these groups were 10, 10.1 and 6.4 months. When it comes to overall survival, drug prolongs survival two of the patients compared to standard therapy. There is also fourth year survival. (Improved Survival with Ipilimumab in Patients with Metastatic Melanoma, NEJM, 2010).

Immukoonkologia without targeted selection 


The genetically targeted therapies can be selected patients who respond to treatment - The treatment of isolated molecularly targeted group of patients in whom the target of the drug. For now, unfortunately there are no known predictors of treatment immunotherapy, work in progress - says prof. Rutkowski. 


On the basis of currently available clinical data treatment according to European ipilimumabem indications registration must first be considered in patients: 


• Diagnosed with melanoma of the skin or mucous membranes in unresectable stage III or IV,
• After previous unsuccessful treatment system (based on dacarbazine), up to 2 lines of therapy for systemic therapy or intolerance,
• No metastasis to the brain or of asymptomatic brain metastases in good performance status (0/1 according to the criteria of ECOG - Eastern Cooperative Oncology Group, which allows the scale to determine the general condition and quality of life of patients with cancer). 
 


Single therapy

In the U.S., a 4-dose administration of ipilimumabu will cost 120 thousand. dollars. According to Valentino Confalone of BMS, in Europe the cost of therapy did not exceed 84 thousand. euro. That's a lot, but he says, on the therapy must take into account factors: overall survival, which gives the drug and, above all, his one-time application.


In this section draws attention to the prof. Rutkowski: - It is a single cycle of treatment, in contrast to molecularly targeted therapy in which treatment can be chronic, even several years, which somehow balances the costs ipilimumabu. Of course, that the clinical benefit of treatment ipilimumabem concern a limited number of patients who still have a long answer.

The professor notes the opportunities offered by law to negotiate the reimbursement price of the product: - In case of acceptance of the proposed price of the drug treatment program should be subject to negotiation with the Ministry of Health and National Health Fund, as was the case with other biologics.

Clinical Dilemmas

Immunoonkologia is just one of the directions of the fight against melanoma. In about half of the patients the disease is caused by a change in one of the amino acids in the protein molecule encoded by the oncogene BRAF. Therapy involves the use of BRAF kinase inhibitors, which counteract the action of this protein. 


This year we started two Phase III inhibitors, which act on melanoma cells with mutated BRAF gene (GSK). In August this year. FDA approved vemurafenib (Roche) in the first line treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutation present.
 


Oncologists were given a tool in the form of new drugs before becoming a clinical problem that therapy should be the drug of first choice in patients with BRAF mutation?

- This is not resolved - in patients with melanoma with a known mutation of BRAF and symptoms of cancer would suggest starting therapy with inhibitors of BRAF. For patients in the full state of efficiency, without signs of cancer - probably ipilimumab, taking into account its long-term effects in some patients and the fact that emergence of resistance to BRAF inhibitors - says prof. Rutkowski.

- In view of the fact that BRAF inhibitors in selected patients with advanced melanoma (BRAF mutation was confirmed) cause in the short term response and tumor control in most patients undergoing treatment, while the duration of response is limited due to the emergence of resistance mechanisms (median duration of response of 6.7 months),

This will probably be the drug of choice in symptomatic patients with high tumor mass prior to treatment ipilimumabem (sequential therapy), or be the subject of future studies in combination therapy (with ipilimumabem or MEK inhibitors) - he adds.

Phase I combination therapy and ipilimumambu vemurafenibu already started. We are also planning a direct comparison of the registered dose ipilimumabu with higher doses (5 and 10 mg / kg).