Melanoma: intense competition to be the next milestone treatment
pharmafile | February 9, 2011 | Feature | Research and Development | BRAF V600 mutation, Cancer, Tasigna, cancer research, melanoma, tremelimumab
A flurry of new data has emerged in the recent months from an industry-wide pipeline of cancer drugs which could eventually create a major advance in the treatment of melanoma.
The cancer most commonly occurs in the skin, but can also occur in the bowel or the eye, and when it becomes advanced, it is currently one of the hardest tumours to treat. There are an estimated 40,000 deaths worldwide from the disease, with the number of cases in developed countries predicted to double, from 138,000 a year to 227,000 by 2019.
Roche recently published data from its candidate RG7204. The phase III trial data showed it helped previously untreated patients with advanced skin cancer to live longer without their disease getting worse.
“For the first time, a personalised investigational medicine, RG7204, has shown a significant survival benefit in metastatic melanoma,” says Hal Barron, Roche’s chief medical officer.
“This is an important advance for people with the BRAF V600 mutation-positive form of the disease who have had extremely limited treatment options,” he added.
Co-developed by Roche and Plexxikon, the investigational, oral, small molecule is designed to selectively inhibit a cancer-causing mutated form of the BRAF protein.
This is found in about half of all cases of metastatic melanoma, which is the most aggressive form of skin cancer, with life expectancy following diagnosis usually measured in months. RG7204 had already impressed in phases I and II, and in the phase III study BRIM3, it increased overall survival and progression-free survival compared to participants who received current standard of care dacarbazine.
Full data will be presented at a medical meeting later this year but analyst Jefferies International, which has predicted peak sales of $1 billion for RG7204, called the headline results ‘very encouraging’.
Patients on the control arm of Roche’s BRIM3 will now have the option to receive RG7204 and the company says it is ‘working closely’ with global health authorities to expand the RG7204 early access programme.
GSK
GlaxoSmithKline has begun late-stage trials of two new drugs for advanced or metastatic melanoma patients.
As with Roche’s drug, GSK2118436 and GSK1120212 are being studied to see if they stop or slow the progression of skin cancer in patients with the BRAF V600 mutation. The mutation is believed to occur in 50-60% of all melanoma patients and would require a companion diagnostic tool to make the drug effective.
The BRF113683 phase III study will compare GSK’436, a BRAF inhibitor, to chemotherapy drug dacarbazine (DTIC) in previously untreated patients with BRAF V600 mutated advanced or metastatic melanoma.
The second study, METRIC, will compare MEK inhibitor GSK’212 to chemotherapy (DTIC or paclitaxel) in advanced or metastatic melanoma patients with a BRAF V600 mutation.
Paolo Paoletti, president of GSK oncology, said: “By focusing our research programme on patients with the V600 mutation, we are striving to understand how our investigational MEK and BRAF inhibitors can best be used to treat patients with metastatic melanoma.
“In addition to our ongoing research in metastatic melanoma, we are also studying GSK’212 and GSK’436, both alone and in combination with other agents, in other difficult to treat forms of cancers including pancreatic cancer, refractory or relapsed leukaemias and other solid tumours.”
BMS
Bristol-Myers Squibb is behind the most advanced of the new competitors in the field, Yervoy (ipilimumab), but the drug has had its crucial FDA decision delayed.
The drug was accepted for a fast-track review in 2010, with an initial date of late December suggested, but this has now been moved to 26 March 2011.
BMS’ cytotoxic T-lymphocyte antigen 4 (CTLA-4) drug is an immune therapy directed against T-cells, and has shown improved overall survival in patients with unresectable stage III/IV melanoma for whom previous treatment had failed. In response to an FDA request, BMS submitted further analysis of data pertaining to the current application for pre-treated advanced melanoma, and the agency considers this to be a major amendment to the drug’s BLA.
BMS says it remains encouraged by its interactions with the FDA and is confident in the overall development for ipilimumab. Ipilimumab is also currently under review with the European Medicines Agency and other health authorities worldwide for pre-treated advanced melanoma.
Also in BMS’ pipeline is IL-21 protein, a cytokine currently in phase II trials as a potential immunotherapy for metastatic melanoma.
Lilly, Pfizer
Lilly was forced to halt phase III trials of its own melanoma candidate tasisulam in December due to serious safety concerns, after 12 people died during the study.
Pfizer is to co-develop its monoclonal antibody treatment for advanced melanoma with Swiss company Debiopharm.
The companies will conduct phase III trials of Pfizer’s investigational compound tremelimumab (CP-675, 206) in unresectable, stage IV melanoma and use a biomarker to select patients most likely to respond to treatment.
President and general manager of Pfizer’s Oncology Business Unit Garry Nicholson said: “The continuation of the clinical development of tremelimumab with our partner, Debiopharm, is a demonstration of our commitment to personalised medicine for cancer patients.
“Debiopharm is a successful company which has achieved impressive results on a global scale. This co-development partnership is an opportunity to leverage the combined expertise of both companies in this innovative endeavour.” Under the terms of the agreement, Debiopharm will assume responsibility for conducting the phase III trial of tremelimumab, and Pfizer will retain responsibility for worldwide commercialisation of the compound.
In April 2008 Pfizer discontinued a phase III trial of tremelimumab for patients with advanced melanoma, after a safety review of interim data showed that the trial would not demonstrate superiority to standard chemotherapy. Analysis of the data from this trial identified the biomarker that will be used in patient selection for the upcoming trial.
Novartis
Novartis’ Tasigna is also being studied as a potential treatment for particularly hard to treat sub-types of melanoma.
Tasigna (nilotnib) works by blocking the c-kit protein, which plays a role in numerous cancers.
Dr. Howard Kaufman, director of the Rush University Cancer Center in Chicago and lead investigator of the study at Rush, said that this kind of ‘targeted’ therapy holds out hope of transforming cancer from a lethal disease into a chronic, but manageable disease.
“For advanced melanoma, there are currently few satisfactory treatments,” Kaufman said. “But new targeted therapies, including vaccines, antibodies and small molecules like nilotnib are in clinical trials now, adding to an arsenal of treatments that appear to be promising. This trial is especially significant since the c-kit mutation is found more commonly in melanoma arising from the mucosa and foot, which are historically very difficult types of melanoma to treat.”
Amgen
Amgen has bought BioVex for $1 billlion, and the prize asset of the biotech company being its novel cancer vaccine OncoVEXGM-CSF.
OncoVEXGM-CSF is a first-in-class oncolytic vaccine candidate designed to treat melanoma and other solid tumours as well as treating genital warts.
A phase II trial has been conducted in 50 patients with metastatic melanoma who had failed to respond to conventional treatment.
Response rates for those therapies are at best about 15%, while OncoVEX showed a response rate of 26 per cent. Eight of the 50 patients were free of disease by the end of the trial period, which consisted of vaccination every two weeks, for a total of up to 24 injections or until disease disappeared. Four more patients were rendered disease-free after surgery or further vaccination of new lesions. Overall survival was 58% at one year, and 52% at two years. The results were reported last December in the Journal of Clinical Oncology.
Dr Howard Kaufman, of Rush University Cancer Center in Chicago is also working on OncoVEXGM-CSF. Last April he commented:
“What really surprised, and encouraged us was that the vaccine worked not just on the cells we injected, but on lesions in other parts of the body that we couldn’t reach.” He added: “In other words, the vaccine prompted an immune response that was circulated through the bloodstream to distant sites.
“These are the best results to date for any vaccine developed for melanoma, but they need to be confirmed in a larger population.”
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