Have We Won the Race in the Treatment of Advanced Melanoma-Or Are We Just Learning to Walk?

February 15, 2015

The unprecedented improvements in melanoma therapeutics over a short period of time have been nothing short of extraordinary. It may be that we are now on a road to cure, but surely the destination is not yet in sight.

Dr. Bhatia and colleagues present a comprehensive review of systemic treatment options for metastatic melanoma.[1] As they discuss, the clinical management of patients has changed dramatically over a short period of time. Since 2011, six drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of advanced melanoma. These include ipilimumab, the fully human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), the BRAF V600 serine-threonine kinase inhibitors vemurafenib and dabrafenib, the MEK1/2 kinase inhibitor trametinib, and the anti–programmed cell death 1 antibodies pembrolizumab and nivolumab. Five of these drugs have been shown to improve the overall survival (OS) of patients with melanoma in phase III clinical trials,[2-7] and data for pembrolizumab are maturing.[8]

Other treatment approaches are maturing as well. The combination of ipilimumab and nivolumab has demonstrated an impressive response rate and yielded 2-year survival,[9,10] while the MEK1/2 inhibitor cobimetinib is under consideration for FDA approval after being shown to confer an OS benefit when administered in combination with vemurafenib for melanoma with the BRAF V600 mutation.[11] Other relevant drugs include imatinib for KIT-mutant melanoma[12] as well as several drugs that are on the horizon of clinical practice, having entered or completed phase III clinical trials; these agents include the injectable oncolytic herpesvirus talimogene laherparepvec (TVEC),[13] the MEK1/2 inhibitor binimetinib in NRAS-mutant melanoma, and the combination of binimetinib with the BRAF V600 inhibitor encorafenib for BRAF V600–mutant melanoma.

In considering the treatment options for an individual patient, it would seem at first pass that melanoma has entered a golden age of therapeutics and that any choice may be a good one. When comparing these options to those available 10 years prior (chemotherapy or interleukin-2 for fit patients), that is certainty the case. It is sobering, however, to point out that for each of these treatments, or even for combination approaches, the median reported progression-free survival time is approximately 3 to 10 months, and overall survival remains on the order of 2 years in randomized clinical trials. In this context, instead of describing the current standing of research as being “on a road to cure,” one might more appropriately describe it as having taken the first steps past the starting line for the race.

Targeted and immunotherapeutic treatments are important in the management of melanoma, but each approach has attributes and drawbacks that must be considered. The rates of response to treatment with BRAF inhibitors and MEK kinase inhibitors are high; however, response duration is modest in most patients. Ipilimumab benefits a small number of patients and has unusual treatment kinetics. However, it has been associated with overall survival of approximately 20% at 3 years and the potential for longer-term disease control.[14] Anti–PD-1 antibodies can achieve substantial response rates with relatively rapid onset and durability of responses, while the combination of anti–PD-1 with anti–CTLA-4 antibodies may be even more robust. How, then, should a practitioner make a decision about which therapy is best for an individual patient?

At the current time, this question is without a definitive answer and subject to debate within the melanoma community. Broadly speaking, most clinicians believe that in the absence of mitigating circumstances (rapidly progressive disease, brain metastases, autoimmunity, etc), consideration should be given to upfront use of immunotherapy. This is predominately due to the retrospective data for interleukin-2 and ipilimumab, suggesting that up to 10% and 20% of patients, respectively, may be long-term survivors after these treatments, and that if an effective anti-tumor immune response is induced, no further therapy may be necessary. Additionally, small data sets have been published suggesting that patients treated with BRAF inhibitors first may have poorer outcomes than patients treated initially with immunotherapy.[14] It is important to point out, however, that few long-term data on kinase inhibitors exist, and there may be a population of patients that has long-term survival after these treatments as well.

Many questions remain about the individual agents described above. What are the best doses, schedule, and duration for immune checkpoint–blocking antibodies? Are there biomarkers for selection of patients who will benefit the most from immunotherapy or kinase inhibitor treatment? Should kinase inhibitors be used before or after immunotherapy? Should these treatments be combined?

The optimal sequence or combination of the available treatment agents is not clear. BRAF inhibitors and MEK inhibitors have substantial anti-tumor activity in BRAF-mutant melanoma and may be particularly attractive to combine with immunotherapy. It has been hypothesized that antigen release through BRAF inhibitor–induced tumor cell death may lead to increased antigen presentation or cross-presentation to tumor-specific T cells.[16] At high doses, however, MEK inhibition has been shown to decrease proliferation and viability of T lymphocytes.[17] Also, while early clinical trials have begun to combine targeted and immunotherapeutic approaches, the results have been punctuated by toxicity. The combinations of vemurafenib with ipilimumab-as well as dabrafenib, trametinib, and ipilimumab-were discontinued due to adverse events, predominately hepatitis and colitis.[18,19]

These open questions regarding optimal agent selection and combination or sequencing strategies highlights the need for continued robust accrual to clinical trials for melanoma. Many studies evaluating concomitant or sequential administration of kinase inhibitors and immune-checkpoint blockade are ongoing or in development. Examples include a study of BRAF-MEK inhibition with an anti–PD-1 antibody (dabrafenib, trametinib, and pembrolizumab) in BRAF-mutant melanoma (ClinicalTrials.gov Identifier: NCT02130466); a study of the MEK inhibitor cobimetinib with the anti–PD-L1 antibody MPDL3280a in NRAS-mutant melanoma (NCT01988896); and sequential approaches using a BRAF-plus-MEK inhibitor combination (dabrafenib-trametinib), followed by an anti–CTLA-4 plus anti–PD-1 combination (ipilimumab-nivolumab) or vice versa (NCT02224781).

Drug development for melanoma has set a new bar in cancer drug development and significantly expanded the array of tools available to the practicing physician. At the same time, there is an urgent need to determine the best approach for combining or sequencing targeted treatments and immunotherapies. Biomarker selection of patients seems likely to be an important component of any clinical practice algorithm that may be developed, and therefore collection of blood and tissue specimens is essential in all research protocols. Finally, continued support from pharmaceutical and governmental sponsors must be prioritized, and robust accrual to clinical trials by patients and their physicians must be maintained.

The unprecedented improvements in melanoma therapeutics over a short period of time have been nothing short of extraordinary. It may be that we are now on a road to cure, but surely the destination is not yet in sight. More likely, the groundwork has now been laid for future clinical research in the setting of melanoma, and we have only taken the first exciting steps toward success for every patient.

Financial Disclosure: Dr. Luke has received payment for consulting or advisory board services for Amgen, Bayer, and Genentech.

Acknowledgement:Dr. Luke receives funding support from the Paul Calabresi Career Development in Clinical Oncology Award (5K12CA139160-05).


1. Bhatia S, Tykodi SS, Lee SM, Thompson JA. Systemic therapy of melanoma: on the road to cure. Oncology (Williston Park). 2015;29:126-35.

2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-16.

3. 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.

4. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-14.

5. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.

6. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015:372:30-9.

7. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2014 Nov 16. [Epub ahead of print]

8. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-44.

9. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.

10. Sznol M, Kluger H, Callahan M, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32(suppl 5s):abstr LBA9003.

11. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867-76.

12. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327-34.

13. Kaufman H, Andtbacka R, Collichio F, et al. Primary overall survival (OS) from OPTiM, a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol. 2014;32(suppl 5s):abstr 9008a.

14. Schadendorf D, Hodi F, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. European Cancer Congress. 2013. Abstract LBA24.

15. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120:1695-701.

16. Hong DS, Vence L, Falchook G, et al. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res. 2012;18:2326-35.

17. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213-9.

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

19. Puzanov I, Callahan M, Linette G, et al. Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM). J Clin Oncol. 2014;32(suppl 5s):abstr 2511.