The Past, Present, and Future of Melanoma Therapy

Malignant melanoma is known to be one of the most difficult metastatic cancers to cure. Melanoma is generally less sensitive to cytotoxic chemotherapeutic agents and radiation than are other types of tumors, and the clinical efficacy of chemotherapeutic drugs is modest when the drugs are administered as single agents. Accordingly, the 5-year overall survival rate in patients with metastatic melanoma is frequently quoted as 5% to 10%.

Dacarbazine was approved by the US Food and Drug Administration (FDA) for the treatment of advanced melanoma in 1975. However, survival rates of patients treated with dacarbazine were never compared with those of patients treated with the best supportive care in a randomized phase III setting, and it is highly unlikely that dacarbazine would be approved by the FDA using today’s standards. High-dose bolus interleukin 2 (IL-2) was approved by the FDA in 1998 despite severe toxicity because IL-2 induces long-term tumor control and survival in a small subset of patients (usually < 10%). Unfortunately, no known clinical, histologic, molecular, or immunologic factors can predict which patients will benefit from this intense treatment. Because clinical investigations failed to show a meaningful clinical benefit of numerous other cytotoxic and immunologic agents, dacarbazine and IL-2 remained the only approved treatments for advanced melanoma until recently.

Advances in our knowledge of the genetics of melanoma and of immune checkpoint molecules have resulted in the development of vemurafenib (Zelboraf) and ipilimumab (Yervoy), which received FDA approval for the treatment of advanced melanoma in 2011. However, with a response rate of approximately 10% for ipilimumab and a median progression-free survival duration of approximately 6 to 7 months for patients treated with vemurafenib (or other selective BRAF inhibitors, such as dabrafenib), most patients receiving these treatments will face disease progression within a year.[1,2] More effective therapeutic agents and better methods of selecting appropriate treatments for each patient are urgently needed.

In their article in this issue of ONCOLOGY, Yushak and colleagues provide a comprehensive review of recent therapeutic advances and promising investigational treatments for melanoma. As described in the article, anti–cytotoxic T-lymphocyte antigen 4 (anti–CTLA-4) antibodies, anti–programmed death 1 (anti–PD-1) or anti–PD-1 ligand (anti–PD-L1) antibodies, and adoptive cell therapy are the most notable immunotherapeutic approaches at this time. Experience with anti–PD-1 (or PD-L1) antibody therapy remains relatively limited, and we are not certain whether the durability of the clinical response is superior to that of high-dose IL-2 therapy. Only time will tell whether this therapy will help more patients live with good disease control for 5 to 10 years or longer. Adoptive cell therapy has shown high response rates of approximately 50%, with a substantial percentage of patients achieving a durable response at a few centers specializing in this therapy.[3,4] However, the current method of preparing adoptive T cells for treatment is labor intensive and is not ready for large-scale clinical trials. Improvement in cell expansion techniques is needed to make a large phase III study of adoptive cell therapy possible.

For patients with BRAF V600E–mutant melanoma, the addition of trametinib (a selective MEK inhibitor) to treatment with dabrafenib resulted in superior clinical efficacy while attenuating the development of cutaneous squamous cell carcinoma and keratoacanthoma, which are rather unique side effects of selective BRAF inhibitors.[5] If the results of the currently ongoing phase III studies comparing treatment with the combination of a BRAF inhibitor and a MEK inhibitor with treatment with a single-agent BRAF inhibitor are positive, these combinations will be the new standards for treatment of advanced BRAF V600E–mutant melanoma. However, despite the potential clinical improvement with combined regimens, most clinicians speculate that resistance will ultimately develop, leaving patients to look for other treatment options.

The authors of this review have raised challenging issues regarding the optimal treatment sequence of effective targeted drugs and immunotherapeutic agents, and the most effective concurrent combinations of these drugs. Opinions differ among experts as to whether to start treatment with immune checkpoint inhibitors or BRAF inhibitors in patients with BRAF V600E–mutant melanoma. In addition, it is unclear whether concurrent treatment with a combination of a BRAF inhibitor and ipilimumab or sequential treatment is best for these patients. A recent report on a phase I study showed an unexpectedly high incidence of hepatic toxic effects in patients treated with the combination of vemurafenib and ipilimumab.[6] This result demonstrates the tremendous challenges ahead in designing and determining the best combinatorial regimens.

Because of the heterogeneous genetic and immune profiles among patients with melanoma, it is highly unlikely that a certain drug combination regimen will be the best choice for every patient. Even if the combination of a BRAF inhibitor and a MEK inhibitor becomes a new standard treatment for BRAF-mutant metastatic melanoma, it may not be the best targeted therapy regimen for melanoma with PTEN deletion, which can feed the survival signal for melanoma cells through activated phosphatidylinositol-3-kinase (PI3K)-AKT pathways with less dependence on the mitogen-activated protein kinase (MAPK) pathway. Trunzer and colleagues and, separately, Nathanson and colleagues have demonstrated that PTEN loss is a negative predictive marker for a clinical benefit from BRAF inhibitors.[7,8] Deng and colleagues showed that the addition of PI3K–mammalian target of rapamycin (mTOR) inhibitors to a BRAF inhibitor (PLX4720) led to an increase in apoptosis in BRAF-mutant, PTEN-null melanoma cell lines.[9] Therefore, for patients with a concurrent BRAF mutation and PTEN aberration, inhibition of both the BRAF/MAPK and the PI3K/AKT pathways may be necessary. However, it remains unclear which PI3K inhibitor or AKT inhibitor would inhibit the signal pathway most effectively. CDKN2A deletion was also predictive of short duration of tumor control in a phase II study of dabrafenib.[8] Would a CDK4 inhibitor be a better drug to combine with a BRAF inhibitor in patients with advanced melanoma harboring a BRAF mutation and a CDKN2A deletion?

Questions also remain regarding a possible clinical benefit of continuing inhibition of mutant BRAF signal after patients have experienced disease progression following prior treatment with a BRAF inhibitor or BRAF inhibitor–containing regimen. Because the pattern of disease progression is heterogeneous among patients who are treated with BRAF inhibitors, some clones of metastatic melanoma could still be dependent on the mutant BRAF kinase for their proliferation and survival. Patients whose disease progresses in limited organ sites after a prolonged response to a BRAF inhibitor could still benefit from continuation of treatment with a BRAF inhibitor after local treatment of the site of progression (eg, stereotactic radiosurgery or surgical resection of progressing brain lesions, or wedge resection of a new pulmonary metastasis). Furthermore, the resistance of melanoma cells to BRAF inhibitors may not be complete, meaning that BRAF inhibitors could still slow the growth rate of “resistant” melanoma. In the clinic, we frequently face a situation in which lesions grow much more rapidly after a BRAF inhibitor is discontinued because of disease progression. A randomized study to compare the clinical efficacy of subsequent treatment with or without continuation of a BRAF inhibitor in patients whose disease progressed after prior treatment with a BRAF inhibitor can be designed to answer this question.

And of course, we will absolutely need to continue our endeavors to evaluate reliable predictive biomarkers for both targeted drugs and immunotherapeutic agents to achieve a truly personalized melanoma therapy with the maximal clinical benefit. Our efforts to address these important issues will shape the future of successful melanoma therapy.

Financial Disclosure:The author has served on advisory boards for, and has received honoraria from, Genentech and Bristol-Myers Squibb.

References:

References

1. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAF V600E-mutated melanoma. J Clin Oncol. 2012;30(suppl):abstr 8502.

2. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-65.

3. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346-57.

4. Radvanyi LG, Bernatchez C, Zhang M, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2012;18:6758-70.

5. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-703.

6. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365-6.

7. Trunzer K, Pavlick AC, Schuchter L, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013 Apr 8. PMID 23569304.

8. Nathanson KL, Martin A, Letrero R, et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol. 2011;29(suppl):abstr 8501.

9. Deng W, Gopal YN, Scott A, et al. Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res. 2012;25:248-58.