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Targeted therapies usher in new era in cancer treatment
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Three new therapies bring us closer to personalized treatments for melanoma, lung cancer and Hodgkin’s disease
The discovery of a mutation in the BRAF proto-oncogene, found in 60% of melanomas that generate a constitutively active protein serine kinase, led to the development of PLX4032 (Plexxikon), a selective inhibitor of this mutant kinase. Remarkably, a response rate of 70% was noted in a phase 2 study. A phase 3 study was initiated, comparing PLX4032 to dacarbazine; not clear is the rationale for a phase 2 study, given the high response rate in this tumor that has previously been refractory to chemotherapy. In general, the PLX4032 drug was well tolerated; adverse events included skin rash, fatigue, arthralgia and, of interest, keratoacanthoma skin tumors in a few patients.
The high response rate is clearly a major step forward in the treatment of this disease, but the median duration of response is 8 to 9 months because of development of resistance. Mechanisms whereby tumor cells escape from this drug are being actively pursued in several laboratories and could lead to further advances in the treatment of metastatic melanoma.
Crizotinib for EML4-ALK translocation
Another kinase inhibitor, crizotinib, was reported at the 2010 ASCO meeting to be an effective novel treatment for patients with the EML4-ALK translocation. Results were published in the Oct. 28 issue of The New England Journal of Medicine by Kwak and colleagues. Although only 82 of 1,500 patients screened had this translocation, the response rate in 82 patients was 57%, with an additional 33% of patients having stable disease.
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The investigators noted that patients with this translocation tended to be younger, nonsmokers and have adenocarcinoma, compared with patients who did not have ALK rearrangements. As in the case of patients treated with PLX4032, resistance to crizotinib has been noted, and in a paper in the same issue of the NEJM, Choi and colleagues, using deep sequencing, found two de novo mutations in the kinase domain of EML4-ALK that conferred resistance. The major adverse effects of this treatment are nausea and vomiting, so the incorporation of this drug combined with other therapies will be of potential importance.
Therapy for CD30+ tumors
The third targeted therapy that has resulted in significant benefit for patients whose tumors are CD30+, including Hodgkin’s disease and anaplastic large cell lymphoma, is the antibody to CD30, conjugated to the anti-tubulin agent monomethyl auristatin E (brentuximab vedotin, SGN-35).
In a study published in the Nov. 4 issue of NEJM, Younes and colleagues reported that 36 of 42 patients had objective responses, including complete remissions in many of the patients. The median duration of the response in these previously treated patients was greater than 9.7 months. As treatment was associated with only grade 1 or 2 adverse effects, this new targeted therapy has great promise as part of treatment regimens for patients with poor prognostic factors or as part of pre-transplant regimens.
It is likely that resistance to this single agent will develop, but these preliminary data would indicate that resistance may occur more slowly with this antibody conjugate than with the small molecule targeted inhibitors described above.
New treatment for prostate cancer
The findings that resistance to castrate-producing drugs may be due to generation of testosterone in prostate cancer cells have led to the development of abiraterone acetate, which works by blocking CYP17 and androgen synthesis. In a large phase 3 trial, led by Johann de Bono of the Institute of Cancer Research in London and Howard Scher at Memorial Sloan-Kettering, and reported at the European Society for Medical Oncology in October, abiraterone with prednisone improved OS by 4 months in patients with metastatic prostate cancer who had progressed after treatment with docetaxel.
Abiraterone, likely to be approved by the FDA, adds to two other newly FDA-approved treatments for metastatic prostate cancer: cabazitaxel (Jevtana, Sanofi-Aventis), for patients after relapse on docetaxel therapy, and sipuleucel-T (Provenge, Dendreon), a vaccine also shown to increase survival in patients with metastatic prostate cancer.
Another androgen receptor inhibitor that is showing promise is MDV1300, now in phase 3 trials. Will abiraterone replace current androgen-castrating therapies as first-line? Adverse effects are manageable and include more fluid retention compared with the control arm and an increased incidence of hypokalemia. Grade 3 and 4 toxicities were uncommon.
Suddenly, several new treatment options are available for patients with metastatic prostate cancer, and it will be important to determine the best sequence or combinations of these agents for maximal patient benefit.
For more information:
- Choi YL. N Engl J Med. 2010;363:1734-1739.
- Kwak EL. N Engl J Med. 2010;363:1693-1703.
- Younes A. N Engl J Med. 2010;363:1812-1821.