Striking results from a study carried out by Roche and Plexxikon caused a significant splash a couple of weeks ago, and the data were remarkable not only because they were from a phase I study but because they were from a trial in melanoma, one of the hardest to treat cancers.
Patients in the trial responded so strongly to the companies’ experimental kinase inhibitor PLX4032 that it warranted a paper in the New England Journal of Medicine; an associated editorial described the findings as “remarkable”. The candidate is already in a phase III study with results due in 2014 but, unfortunately, whilst this agent looks like representing a significant step forward in this disease, it is not a cure. Researchers still believe real progress will come from combinations of therapies and the diverse late-stage melanoma pipeline is set to throw up some interesting results in the next couple of years (see tables below).
Rare but deadly
Melanoma is one of the rarest forms of skin cancer but it is the deadliest. Caught early, surgery to remove the tumours remains the best chance of beating the disease but for many this does not happen.
Melanoma tumour cells have a huge propensity to spread to other parts of the body and the original site of the tumour does not have to be very big before this can happen. A melanoma measuring only 1mm already has a significant risk of invading and spreading, helping to explain why many are not caught early enough. Making treatment even harder, when the cancer is caught the cells are very resistant to traditional chemotherapy and radiation.
Most of the therapies detailed below are aimed at patients whose disease has spread widely and can no longer be removed by surgery, called stage IV or metastatic melanoma. Life expectancy at this stage is normally between 6 and 12 months and many doctors consider the best treatment choice to be enrolment on a clinical trial, testing an experimental agent.
The other option is dacarbazine, a chemotherapy agent with such severe side effects many patients elect not to take anything.
This sets the scene for excitement around the PLX4032 results. In a study of 32 metastatic melanoma patients, the agent generated an 81% overall response rate, including two complete responses, where no evidence of disease is seen, and 24 partial responses, where patients experience tumour shrinkage of at least 30%. This activity has rarely been seen, if ever, in melanoma.
Other BRAF inhibitors have been investigated but this agent’s high selectivity is thought to be responsible for these outstanding results. PLX4032 targets the oncogene BRAF that is specifically mutated in 50-70% of melanomas. The drug targets this specific mutation, which is thought to be the engine that drives the growth of these tumours.
“This particular drug is thought to have about a 30-fold greater activity against this specific form of mutant BRAF, which occurs in over 90% of patients when it is mutated,” says David Fisher, director of the Melanoma Program at Massachusetts General Hospital. “Fortunately BRAF doesn’t have a large collection of mutations, it is usually the same. I think this is a very big deal and helps to explain why we have seen this kind of efficacy.”
Unfortunately, the patients on this trial were not cured, and their disease eventually returned. This highlights the challenge in melanoma, where complete response can still be followed by relapse and death.
“Unfortunately we can see while the efficacy is significant and can be transformative to patients, it is not permanent,” Dr Fisher says. “We need to find how to improve the efficacy through combining it with other drugs, or finding other more potent drugs, to convert these temporary responses into something more durable and hopefully eventually permanent.”
The other drug making headlines in the melanoma world is Bristol-Myers Squibb’s immunotherapy approach, ipilimumab. The agent works by essentially taking the brakes off the immune system, and although this approach has many sceptics hopes have been growing since a well-received presentation at Asco this year (Asco - Pivotal data points to revival for BMS' ipilimumab, June 7, 2010).
So far the company has only presented results in pre-treated patients, data from a second trial in a first-line setting are due in the next couple of months.
However the drug has already been filed with the FDA with a decision due before the end of the year - approval would be a significant event not only for melanoma but also for the immunotherapy space more widely.
Combining an immunotherapy like ipilimumab with targeted agents like PLX4032 are regarded by many doctors as the way to go in this disease, and Dr Fisher says trials are now being planned to do this, using agents both sequentially and at the same time, following the encouraging data.
“One of the major approaches people are looking at now, is how can we take this initial signal, and this is a very very exciting signal for the melanoma research community and patients, and transform it into something that has a more durable impact,” he says.
|Selected Late Stage Pipeline of Melanoma Products|
|Status||Product||Generic Name||Pharmacological Class||Company||Originator||Melanoma specific sales in 2016 ($m)|
|Filed||PEGIntron||peginterferon alfa-2b||Interferon alpha||Merck & Co||Biogen||-|
|Ipilimumab||ipilimumab||Anti-CTLA4 MAb||Bristol-Myers Squibb||Medarex||961|
|Phase III||RG7204 (PLX4032)||-||B-Raf kinase inhibitor||Roche + Plexxikon||Plexxikon||411|
|Allovectin-7||velimogene aliplasmid||HLA-B7 gene therapy||Vical + AnGes MG||Vical||64|
|LY573636||tasisulam sodium||Mitochondrial enzyme modulator (ASAP)||Eli Lilly||Eli Lilly||-|
|MAGE-A3||astuprotimut-R||Anti-MAGE-A3 vaccine||GlaxoSmithKline||Ludwig Institute for Cancer Research||-|
|Genasense||oblimersen sodium||Bcl-2 antisense||Genta||Genta||-|
|Abraxane||paclitaxel (albumin-bound)||Taxane||Abraxis BioScience||American Bioscience||-|
|Elesclomol||elesclomol||Apoptosis inducer||Synta Pharmaceuticals||Synta Pharmaceuticals||-|
|POL-103A||-||Melanoma vaccine||CK Life Sciences||CK Life Sciences||-|
|Zadaxin||thymalfasin||Immunostimulant||SciClone Pharmaceuticals + Sigma-Tau||Roche||-|
The only other targeted agent in the late-stage pipeline is Eli Lilly’s tasisulam. Encouraging phase II data was presented at Asco this year, in a second-line setting in patients with unresectable or metastatic melanoma. A phase III trial in a second line setting versus paclitaxel is ongoing in 800 patients, with results due in 2012.
The mechanism of action of this agent has not been fully characterised but it appears to work by activating the intrinsic mitochondrial-mediated cell death pathway, Lilly believes.
Other agents in late stage testing can certainly be considered at the risky end of drug development - for example Vical’s gene therapy agent Allovectin-7.
In June a safety review board gave the green light for a pivotal study of the agent to continue. Allovectin-7 is a plasmid/lipid complex containing the DNA sequences encoding for an antigen called MHC-I, which when injected directly into tumours is designed to stimulate an immune response against both local and distant metastases.
The therapy is being trialled as a first-line therapy in 390 patients with advanced recurrent metastatic melanoma, pitted against either darcarbazine or temozolomide. Results are expected later in 2011. In an interesting development, Teva Pharmaceutical Industries has already secured rights to the product in Israel.
Genta deserves a reward for perseverance if nothing else, and has been putting its antisense therapy Genasense through phase III trials in melanoma for more than a decade. Having already been turned down by the FDA back in 2004, the company pushed on with another two pivotal studies in a more tightly defined patient population, the data from which has so far failed to impress.
The company is now waiting for updated survival results from a phase III trial called Agenda next year, following a pooled analysis from two pivotal trials it presented at Asco earlier this year. Hopes are not high for a significant breakthrough.
Meanwhile privately-owned BioVex raised $70m over the course of last year to complete the ongoing phase III study of OncoVEXGM-CSF, a therapeutic virus. It hopes to file in the US in the middle of next year, meaning data should be available soon. This is certainly a candidate to watch; if the results are positive as the phase II data suggest the heavily venture capital-backed company is likely to be promptly put up for sale; indeed potential buyers are already likely to be hovering.
The novel and therefore high risk technology is likely to be the reason a buyer was not found following the phase II study, in which 20% of patients achieved a complete response. The therapy works by carrying an oncolytic virus into the tumour cells, which replicates and kills the cells; an immune response to distant tumours is also thought to occur.
It is not only small players working in the field. GlaxoSmithKline’s therapeutic cancer vaccine approach MAGE-A3 is also being trialled in melanoma; the product is most advanced in lung cancer. The company signed a deal with Abbott earlier this year to work on a molecular diagnostic test to help select patients who may benefit from the therapy. A phase III trial called Derma is ongoing, recruiting only patients whose tumours express the tumour-specific antigen MAGE-A3, and Glaxo wants to develop a reliable way of finding them.
Unlike many of these agents that are being designed for patients for whom surgery is no longer an option, MAGE-A3 is being given to patients after surgery, in an attempt to stop the cancer coming back.
As such this patient group is not as sick, as the cancer has not metastised. The Derma trial is seeking to enrol 1,300 patients and data is not expected until 2014.
Prevention and cure?
The table below, which reveals a marked drop off in active candidates between phase II and III, indicates perhaps just how hard this cancer is to treat. At the moment scientists are struggling to extend life let alone cure, and much work remains.
Meanwhile, Dr Fisher points out prevention of melanoma probably deserves just as much attention as the attempts to cure it.
“Melanoma has the dubious distinction of being on one hand the cancer whose frequency is rising more speedily than any other in the world and yet we probably know more about what causes it almost than any other cancer: sun light or ultraviolet radiation. That is an embarrassing statistic,” he says.
|Count of Products for Melanoma|