Pharma Strategy Blog

Malignant melanoma is not a particularly nice cancer to get and patients with metastatic disease unfortunately do particularly poorly.  I was, therefore, very interested to see new data on PLX4032/R7204 from Plexxikon and Roche in this disease.  Over 50,000 Americans are diagnosed with melanoma every year, so it is not an uncommon cancer.

PLX4032 is a small molecule for the treatment of melanoma and other cancers harboring the V600E mutation of the BRAF kinase gene. This defect appears to occur in approximately 60% of melanomas, and in about 8% of all solid tumours, including melanoma, colorectal, thyroid and other cancers. Preclinical data suggest that Plexxikon's novel anti-cancer compound selectively targets and inhibits tumor cells which contain this cancer-causing mutation.

Dr Keith Flaherty, a melanoma specialist at the University of Pittsburgh, who was the PI for the trial.  The most recent data was presented at ESMO in Berlin last month. 

55 patients have been treated in the dose escalation phase of the study, including 24 mutation-positive melanoma patients and 3 mutation-positive thyroid patients, as well as 28 melanoma, rectal and ovarian cancer patients who did not have the mutation or whose mutation status was not known. 

16 BRAF mutation-positive melanoma patients were treated with PLX4032 doses at or above 240 mg twice daily (BID).  PLX4032 was well tolerated at very high doses, with 960 mg BID under evaluation as the maximum tolerated dose. Partial responses were seen in 9 patients showing greater than 30% tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with 7 confirmed.  Minor responses were seen in 4 patients showing tumor regression greater than 10%, but less than 30%.  Disease control lasting up to 14 months with continuous therapy, with many patients still receiving treatment was observed.

The interim median progression-free survival was at least six months, with many responding patients still receiving treatment.  No treatment response was observed in a small group of patients without the mutation, and progression-free survival was less than 2 months, consistent with historical data. 

Overall, dose-limiting toxicities included rash, fatigue and joint pains, were seen at 1120 mg BID. Some serious adverse events were observed in some patients after chronic treatment, including possibly drug-related cutaneous squamous cell carcinoma.

Interestingly, a companion diagnostic test to identify patients with the BRAF mutation is being co-developed by Plexxikon and Roche.  The test is being used to identify mutation-positive patients for ongoing clinical trials, but also enables the potential identification of mutation-positive cancer patients considered most likely to respond to PLX4032 treatment.  

As we understand more about the science and biology of cancer, so we identify and customise treatments for patients with different disease subsets. This also means that patients unlikely to respond are not exposed to the side effects of treatment that is unlikely to be effective.  In other cancers where the BRAF V600E mutation is less common, for example, colorectal, ovarian and prostate cancers, this approach is very important.  This study highlighted evidence for heterogeneity within clinical tumour specimens, especially in melanoma.

A retrospective study of 600 patients with colorectal cancer was reported at ASCO earlier this year, and tumour tissue was tested for the presence of the BRAF mutation and correlated with outcomes.  The data confirmed that approximately 10% of colorectal cancer patients carry this mutation, which is independent of the KRAS mutation, and those BRAF mutation-positive patients have a much poorer prognosis than patients with wild-type BRAF.

This type of targeted approach to the treatment of cancer has been ongoing for a while now and it's hopefully something we are likely to see more of in other tumour types as more data emerge.