For the second year in a row, metastatic melanoma (MM) research will be presented at the plenary session of the American Society of Clinical Oncology (ASCO) Annual meeting. Last year, the results of the second-line phase 3 data on the immunotherapy ipilimumab for MM, called the 020 trial, were presented in the plenary session.
This year, two of the five plenary session presentations feature MM clinical results. One will be the long-awaited result of the 024 phase 3 clinical trial comparing the treatment of ipilimumab and the chemotherapy DTIC versus DTIC alone in treatment-nave MM patients (Abstract LBA5, Sunday June 5, 3:30pm Plenary). The second will be a phase 3 trial that compares the BRAF-inhibitor vemurafenib (RG7024/PLX4032) to DTIC in treatment-naive MM patients (Abstract LBA4, Sunday June 5 Plenary). Melanoma is the most serious and aggressive form of skin cancer. If it is recognized and treated early, it is almost always curable, but if it is not, the cancer can advance and spread to other parts of the body, making it very difficult to treat. Prior to March 2011, the only two treatment options approved for MM were chemotherapy and the highly-toxic interleukin-2 (IL-2). Because chemotherapy has a short and non-durable response and IL-2 is only suitable for younger and generally healthy patients (and only shows a response in ~5-10% of patients) most MM patients go on clinical trials for new treatments.
The current survival time for patients with metastatic melanoma is approximately 6 to 9 months. While melanoma accounts for about 5 percent of skin cancer cases, it causes 3 times as many deaths as non-melanoma skin cancers annually, and killed approximately 8,700 people in the US in 2010. Additionally, the incidence of melanoma has increased ten-fold over the past 50 years. The rapid increase of advanced stage melanoma is occurring worldwide and at a faster rate than any other cancers except lung cancer in women.
The good news, however, is the surge in the development of novel and promising treatments that have been made possible mostly due to an evolving molecular model of the disease.
While ipilimumab (YERVOY) data from the 024 trial is being featured at ASCO, ipiilimumab was approved by the FDA on March 25, 2011 based on the results of the 020 trial data presented at the plenary session of the ASCO 2010 meeting and published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1003466). Ipilimumab is now broadly approved as a monotherapy for both treatment-nave and previously treated patients. The drug is the first to show a significant overall survival benefit in a phase 3 clinical trial. Patient survival at 1 year was 46% in the ipilimumab arm compared to 25% in a vaccine arm that was essentially equivalent to a placebo in the 020 trial. At 2 years, survival was 24% compared to 14% for the vaccine arm.
Ipilimumab aims to boost the patient’s immune system to fight the cancer systemically in the body. The drug is infused into patients in an out-patient setting every 3 weeks and is a monoclonal antibody against the cytotoxic T- lymphocyte antigen-4 (CTLA-4). Data so far show that ipilimumab shows a response in 10-20% of patients. Unique to this type of therapy, patients that respond to treatment have a durable response that lasts for years.
The important outcomes of the 024 trial will be the improvement in median overall survival as well as the long-term survival difference between the two treatment arms. The main question here is whether adding chemotherapy to ipilimumanb will significantly change the survival and durability of survival in first-line patients. Equally important will be the safety profile of the ipilimumab-chemotherapy combination and whether the increased dosage in this trial compared with the 020 trial will increase the immune-related side effects.
The second treatment that will be featured at the ASCO 2011 plenary session for MM is vemurafenib. Vemurafenib is a first-in-class oral targeted therapy that inhibits a mutated form of the BRAF protein, BRAFV600E. Approximately 40-50% of MM patients harbor this mutation and clinicians now systematically test for this mutation before deciding on potential treatment options.
On May 11, 2011, Roche, which makes vemurafenib, announced that it had submitted a New Drug Application to both the FDA as well as the European Medicines Agency (EMA). The indication is BRAF V600 mutation positive MM patients. Roche also concurrently submitted its diagnostic test to test for the presence of the mutation in eligible patients. The submission is based on the phase 3 BRIM3 trial that will be presented at ASCO as well as the phase 2 trial, BRIM2. The FDA’s decision is expected by the end of 2011.
The BRIM2 trial results were presented in November 2010 at the International Society for Melanoma Research in Sydney, Australia. The data showed that the drug shrank tumors in more than half of the previously treated patients on the therapy. Patients taking vemurafenib lived a median 6.2 months without disease progression (median progression-free survival or PFS) while typically the PFS for this population is only ~2 months.
The availability of both ipilimumab and vemurafenib offer MM patients new options for treatment. Because ipilimumab is now widely approved, it is available nationwide at both research hospitals as well as smaller centers. Ipilimumab use, unlike vemurafenib, is not restricted by the molecular make-up of the patient’s tumor. Ipilimumab gives MM patients a chance at a durable response, although the current rate of response, based on clinical trial results, is not greater than 20%. The treatment comes with toxicities that correlate well with a patient’s response to the treatment. The toxicity profile includes autoimmune reactions of the skin and the gut, as well as liver and endocrine reactions. Due to these toxicities, which can be up to grade 3 and 4 in severity. the FDA has issued a “black-box” warning for the medication. According to research clinicians well-versed in treating patients with ipilimumab, the toxicities are different than those experienced with chemotherapy agents but are manageable with both education and vigilance by both the patient and caregivers.
Vemurafenib is targeted at the 40-50% of patients that harbor the V600E BRAF mutation in their tumors. It acts quickly to shrink tumors and has less toxicity compared to immunotherapy. The side effects include rash, joint pain, photosensitivity and hair loss. One concerning side effect, however, is the frequency of cutaneous squamous cell carcinoma (cSCC), a type of cancer that occurred in 26% of patients on the phase 2 trial. The cSSCs are lesions that are excisable and did not prevent patients from continued treatment. The problem with vemurafenib is that most patients acquire resistance to the drug and require subsequent treatment. The survival data as well as the frequency of progression will be the key to the BRIM3 data.
GSK1120212, GSK2118436 Combination
GSK2118436 (GSK436) is another BRAF inhibitor that is a highly selective BRAF mutant inhibitor. It is being tested in MM patients that harbor any of the BRAF V600E, K, or R mutations. Among BRAF mutations, the V600E mutation accounts for ~80%, while the K mutation accounts for ~15% of BRAF mutations in MM. Phase 1 and 2 trials have shown clinical activity, minimal toxicity, and a potentially exciting activity in MM patients with brain metastases. GlaxoSmithKline is developing the agent as a monotherapy and as a combination therapy with a MEK1/2 inhobitor, GSK1120212.
One of the major signaling pathways implicated in melanoma development is the mitogen-activated protein kinase (MAPK) pathway, which includes the BRAF and MEK. A combination treatment may be promising in order to prevent the resistance/relapse seen in the BRAF monotherapy trials. Data from the combination phase 1/2 trial will be presented Clinical Science Symposium at ASCO on Monday June 6th (Abstract #CRA8503 2:15-2:30 pm).
With the development of these and other novel MM treatments, the field is moving in the direction of combination therapies that may include combination immunotherapy and targeted treatments (ipilimumab and vemurafenib for example) as well as 2-combination and 3-combination targeted therapies in order to inhibit multiple mutated pathways in tumor cells. The results presented at ASCO highlighted here as well as others will provide another stepping stone in the challenge of developing sate and reliable treatments for melanoma patients based on solid science and clinical trial data.