Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

After yesterday's post about the NY Times article on Roche/Plexxikon's PLX4032, a few people wrote and asked about other therapies in development for the treatment of malignant melanoma.

Melanoma is the deadliest form of skin cancer and occurs in about 69,000 patients in the United States each year, resulting in approximately 9,000 deaths.  Sadly, the number of melanoma cases worldwide is increasing faster than any other cancer.

One of the most promising agents in development is Pfizer's tremelimumab (CP-675,206), a humanised IgG2 monoclonal antibody targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), a natural brake on the immune system that has been implicated in melanoma.  The basic idea is that tremelimumab inhibits CTLA4, thereby stimulating or enhancing the body's immune response to tumours and fight the cancer.

Tremulimumab has had a bit of a chequered history though.  Pfizer discontinued a phase III study of the drug in patients with advanced melanoma after an interim review showed tremelimumab would not be superior to standard chemotherapy. 

What's particularly interesting is that last month Pfizer announced another phase III trial of tremelimumab, declaring that analysis of the data from the discontinued study had identified the biomarker that will be used to select patients for the upcoming study completed in conjunction with Debiopharm, although details on what the biomarker actually was were not given.

Meanwhile, earlier this month, a new article appeared in Cancer Clinical Research, describing the data in a phase II study in people with relapsed melanoma, where the drug had already failed to work.

This trial, a single-arm phase II study, showed that 16 of the 241 evaluable patients had partial responses, ranging in duration from 8.9 to 29.8 months.  Median time to response was 7.0 months.  Eleven of the 16 patients (69%) had ongoing responses at their last assessment. 
The clinical benefit rate was 21%, based on 16 partial responses and 35 people with stable disease.

One patient with a response, who had a family history of sudden death, died of an apparent cardiac event 321 days after enrolling in the study.  The other 15 responders were alive when the researchers wrote the paper, with survival ranging from 20 to 34 months.  Median overall survival for the entire cohort was 10.0 months.

The researchers noted that response rates with single-agent chemotherapy usually range from less than 8% to 15%, with limited durability.  Immunotherapy with high-dose interleukin-2 produces similar response rates, with better durability but with more severe toxicities.  The results with tremelimumab are therefore very encouraging and having a biomarker associated with it can only help screen out those patients who are more likely to respond to therapy.

Medarex and BMS are developing a similar anti-CTLA4 agent, ipilimumab (MDX-010), in melanoma and prostate cancer.  This agent has received more attention in prostate cancer of late, but the phase II data in melanoma was presented at ASCO last year. 
The updated survival results from follow-up extensions of three Phase II ipilimumab studies of patients with advanced metastatic melanoma (Stage III or IV) showed that the two-year survival rate ranged from 29.8 to 41.8 percent in patients who received ipilimumab.

Looking at the data in more detail, we can see that the results are based on follow-up of up to 37.5 months (median follow-up ranged from 10.1 to 16.3 months) of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab during induction and maintenance therapy and showed:

  • Two-year survival rate of 32.8 percent in patients who had progressed while on or after receiving standard treatment (Study 008)
  • Two-year survival rate of 29.8 percent in patients who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies (Study 022)
  • Two-year survival rate of 40.6 percent and 41.8 percent in patients receiving ipilimumab plus budesonide or ipilimumab plus placebo, respectively, which included treatment-naïve patients and patients previously treated with therapy other than ipilimumab (Study 007).

Novartis also have a RAF inhibitor similar to Roche's PLX4032, called RAF265, which is currently in phase I development.  It differs in that it also inhibits VEGFR-2, which is associated with angiogenesis. Another TKI in development, TKI258 (formerly CHIR2558), is a fibroblast growth-factor receptor (FGFR) inhibitor, as well as targeting VEGF and PDGFR.

This raises an interesting idea – in some patients, inhibiting several pathways such as RAF, CTLA4 and FGFR or VEGF may be the ultimate answer to prolonging survival, although we don't know if that approach would work yet.  

Coordinating studies across several companies, each with drugs not yet approved, is also fraught with difficulties.  This is where patient advocacy groups such as the Melanoma Research Foundation and ACOR have most power in conjunction with the physicians to compel Pharma companies to: 

a) consider combination trials earlier in collaborative efforts

b) speed up development of new and promising agents

Overall, the results from the anti-CTLA4 antibodies and RAF inhibitors look promising and it will be interesting to see what happens at ASCO this year as well as moving forward in the future.

ResearchBlogging.orgKirkwood, J., Lorigan, P., Hersey, P., Hauschild, A., Robert, C., McDermott, D., Marshall, M., Gomez-Navarro, J., Liang, J., & Bulanhagui, C. (2010). Phase II Trial of Tremelimumab (CP-675,206) in Patients with Advanced Refractory or Relapsed Melanoma Clinical Cancer Research, 16 (3), 1042-1048 DOI: 10.1158/1078-0432.CCR-09-2033


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3 Responses to “Update on malignant melanoma therapies”

  1. gedster

    The key thing about the CTLA-4s is that only a small proportion of patients respond but among those that do the responses can be incredibly durable. The other issue is the immune-related AEs such as gastrointesinal perforations in some patients. It will be interesting to see how or if these agents can fit into the treatment mix in melanoma if PLX4032 is approved. They will most likely be used to treat patients with wild type BRAF tumours.

  2. MaverickNY

    Indeed, but maybe that was Pfizer’s point – if you have a biomarker to id those most likely to respond you increase the overall response rates in a selective pool and reduce the exposure to unwanted side effects in those less likely to respond.
    It may well be that malignant melanoma ends up being segmented into various segments basd on the underlying biology eg BRAF, CTLA4 (or whatever biomarker is used) subtypes etc.

  3. Tim Turnham

    You’re right that coordinating studies across pharma to test combination therapies isn’t easy – tough government regulations, market realities, the need to assure patient safety add up to a challenge. But patients with advanced melanoma are in a much tougher spot with the limited number of treatment options available. These patients need answers today, not 6 months or 6 years from now. At the Melanoma Research Foundation (MRF) we’re coordinating the Melanoma Breakthrough Consortium to accelerate research with our partners and take years of this difficult process. More information is available at http://www.melanoma.org.
    Tim Turnham
    Executive Director
    Melanoma Research Foundation

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