Combining Novel Therapeutics: Strategies Emerge for Employing Both New Options in Melanoma

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

It is difficult to overstate the excitement surrounding the development of two new effective therapeutic strategies in the management of metastatic melanoma.^1-3 For a painfully long, multiple-decade era, the truly minimally biologically active and highly toxic antineoplastic agent dacarbazine was considered to be the standard of care, at least in the eyes of the drug regulatory agencies. Now, we are in a period in which both the novel immunotherapeutic ipilimumab and a molecularly targeted small-molecule agent, vemurafenib, are available for routine care, and the treatment of this most difficult malignancy has been revolutionized.

Many questions, however, remain regarding the optimal use of these two drugs, including the timing of delivery of the individual agents, dosing and scheduling, and the potential for sequencing the strategies in patients who are candidates to receive a BRAF inhibitor due to the documented presence of a BRAF gene mutation.⁴

Of considerable interest, provocative preclinical data provide strong support for the concept that administering the drugs as components of a combined approach may be of unique importance in this clinical setting. As reported in Wilmott et al,5 investigators examined the effect of treatment on the immune microenvironment on tumor biopsy specimens from 15 patients with advanced or metastatic melanoma and a documented BRAF mutation obtained both before and following treatment with a BRAF inhibitor. Ten of the 15 patients had achieved an objective response to BRAF inhibitor therapy. The median follow-up of the patient population was 11 months, with a range of two to 20 months.

The researchers found that, following BRAF inhibitor therapy, there was a rather substantial increase in the infiltration of the tumor by both CD4-positive and CD8-positive lymphocytes (P = .015, compared with the pretreatment baseline). Further, and of even greater clinical relevance, the extent of CD8-positive expression following therapy was correlated with both the degree of tumor necrosis noted in the post-biopsy specimen (P = .004) and evidence of reduction in the size of tumor masses (P = .011).

A most provocative hypothesis for these observations is that one critically relevant effect of the highly active antineoplastic BRAF inhibitor is a reduction in the immunosuppressive properties of the malignant melanoma cell population, permitting the infiltration of the tissue with biologically active host immune cells. It is theoretically possible that the presence of this more “immune-active environment” will permit a far more favorable response to the subsequent delivery of the immunomodulatory agent ipilimumab. Of course, this hypothesis would support the concept of treating appropriately selected patients with a BRAF inhibitor followed by ipilimumab.

Structure of the BRAF protein.

Trials testing this interesting and potentially highly clinically relevant therapeutic concept are under way, and their results are awaited with considerable interest. It should be noted that early reports have documented the development of an intense skin rash associated with the combination of the BRAF inhibitor vemurafenib plus ipilimumab, suggesting the potential for unique interactions between these two classes of antineoplastic drugs.⁶

Finally, it is relevant to acknowledge how the data generated from laboratory-based research as a component of the drug development process has helped to inform the future establishment of additional novel management strategies. The potential clinical significance of this investigative concept–bench to bedside and back to bench–to improve the efficacy and reduce the toxicity of antineoplastic treatments cannot be overstated.

1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma [published online ahead of print June 5, 2010]. N Engl J Med. 2010; 363(8):711-723.
2. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-819.
3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation [published online ahead of print June 5, 2011]. N Engl J Med. 2011; 364(26):2507-2516.
4. Woodman SE, Lazar AJ, Aldape KD, Davies MA. New strategies in melanoma: molecular testing in advanced disease [published online ahead of print January 24, 2012]. Clin Cancer Res. 2012; 18(5):1195-1200.
5. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma [published online ahead of print December 12, 2011]. Clin Cancer Res. 2012;18(5):1386-1394.
6. Harding JJ, Pulitzer M, Chapman PB. Vemurafenib sensitivity skin reaction after ipilimumab [correspondence]. N Engl J Med. 2012; 366(9):866-868.