Clinical Review

Targeted Therapy and Immunotherapy in the Treatment of Metastatic Cutaneous Melanoma

Hospital Physician: Hematology/Oncology. 2017 July;12(4):26-43

References

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30.
Guy GP, Thomas CC, Thompson T, et al. Vital signs: melanoma incidence and mortality trends and projections - United States, 1982-2030. MMWR Morb Mortal Wkly Rep 2015;64:591–6.
Anderson WF, Pfeiffer RM, Tucker MA, Rosenberg PS. Divergent cancer pathways for early-onset and late-onset cutaneous malignant melanoma. Cancer 2009;115:4176–85.
Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135–47.
Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006;24:4340–6.
Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012;150:251–63.
Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 2015;161:1681–96.
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.
McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014;15:323–32.
Hauschild A, Grob J-J, Demidov LV, et al. DaBRAFenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358–65.
Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877–88.
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.
Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371:1867–76.
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275–80.
Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577–81.
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.
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Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320–30.
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Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521–32.
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Eggermont AMM. Therapeutic vaccines in solid tumours: can they be harmful? Eur J Cancer 2009;45:2087–90.
Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Sci Transl Med 2012;4:127ps8.
Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol 2014;192:5451–8.
Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348:62–8.
Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992;356:607–9.
Greenfield EA, Nguyen KA, Kuchroo VK. CD28/B7 costimulation: a review. Crit Rev Immunol 1998;18:389–418.
Sharpe AH, Abbas AK. T-cell costimulation--biology, therapeutic potential, and challenges. N Engl J Med 2006;355:973–5.
Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 2001;19:565–94.
Collins AV, Brodie DW, Gilbert RJC, et al. The interaction properties of costimulatory molecules revisited. Immunity 2002;17:201–10.
Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995;182:459–65.
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734–6.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677–704.
Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002;169:5538–45.
Youngnak P, Kozono Y, Kozono H, et al. Differential binding properties of B7-H1 and B7-DC to programmed death-1. Biochem Biophys Res Commun 2003;307:672–7.
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 2004;173:945–54.
Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25:9543–53.
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114–25.
Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 2013;1291:1–13.
Weber JS, O’Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 2008;26:5950–6.
Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A 2008;105:3005–10.
Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155–64.
Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015;33:1889–94.
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Vemurafenib and dabrafenib were evaluated in this tiered fashion in phase 1 dose-finding studies comprising unselected patients, followed by phase 2 studies in advanced BRAF V600E–mutated melanoma. Both were subsequently evaluated in randomized phase 3 trials (vemurafenib, BRIM-38; dabrafenib, BREAK-310) that compared them with dacarbazine (1000 mg/m² intravenously every 3 weeks) in the treatment of advanced BRAF V600E–mutated melanoma. Response kinetics for both agents were remarkably similar: single-agent BRAF inhibitors resulted in rapid (time to response 2–3 months), profound (approximately 50% objective responses) reductions in tumor burden that lasted 6 to 7 months. Adverse events common to both agents included rash, fatigue, and arthralgia, although clinically significant photosensitivity was more common with vemurafenib and clinically significant pyrexia was more common with dabrafenib. Class-specific adverse events included the development of cutaneous squamous-cell carcinomas and keratoacanthomas secondary to paradoxical activation of MAPK pathway signaling either through activating mutations in HRAS or mutations or amplifications in receptor tyrosine kinases upstream of BRAF, resulting in elevated levels of RAS–guanosine triphosphate complexes.⁷¹ Results of these studies resulted in regulatory approval of single-agent BRAF inhibitors for the treatment of BRAF V600E (and later V600K)–mutated melanoma (vemurafenib in 2011; dabrafenib in 2013). Details regarding trial populations, study interventions, efficacy, and adverse events are summarized in Table 2.

Responses to BRAF inhibitors are typically profound but temporary. Mechanisms of acquired resistance are diverse and include reactivation of MAPK pathway–dependent signaling (RAS activation or increased RAF expression), and development of MAPK pathway–independent signaling (COT overexpression; increased PI3K or AKT signaling) that permits bypass of inhibited BRAF signaling within the MAPK pathway.^72–76 These findings suggested that upfront inhibition of both MEK and mutant BRAF may produce more durable responses than BRAF inhibition alone. Three pivotal phase 3 studies established the superiority of combination BRAF and MEK inhibition over BRAF inhibition alone: COMBI-d11 (dabrafenib/trametinib versus dabrafenib/placebo), COMBI-v12 (dabrafenib/trametinib versus vemurafenib), and coBRIM13 (vemurafenib/cobimetinib versus vemurafenib/placebo). As expected, compared to BRAF inhibitor monotherapy, combination BRAF and MEK inhibition produced greater responses and improved progression-free and overall survival (Table 2). Interestingly, the rate of cutaneous squamous-cell carcinomas was much lower with combination therapy, reflecting the more profound degree of MAPK pathway inhibition achieved with combination BRAF and MEK inhibition. Based on these results, FDA approval was granted for both dabrafenib/trametinib and vemurafenib/cobimetinib combinations in 2015. Although the dabrafenib/trametinib combination was only approved in 2015, trametinib had independently gained FDA approval in 2013 for the treatment of BRAF V600E/K–mutated melanoma on the basis of the phase 3 METRIC study.⁷⁷

Encorafenib (LGX818) and binimetinib (MEK162, ARRY-162, ARRY-438162) are new BRAF and MEK inhibitors currently being evaluated in clinical trials. Encorafenib/binimetinib combination was first evaluated in a phase 3 study (COLUMBUS) that compared it with vemurafenib monotherapy in BRAF-mutant melanoma.⁷⁸ Unsurprisingly, encorafenib/binimetinib combination produced greater and more durable responses compared to vemurafenib monotherapy. The median progression-free survival of the encorafenib/binimetinib combination (14.9 months) was greater than vemurafenib monotherapy (7.3 months) in this study, and intriguingly greater than that seen with vemurafenib/cobimetinib (coBRIM 9.9 months) and dabrafenib/trametinib (COMBI-d 9.3 months; COMBI-v 11.4 months). Of note, although encorafenib has an IC50 midway between dabrafenib and vemurafenib in cell-free assays (0.8 nM dabrafenib, 4 nM encorafenib, and 31 nM vemurafenib), it has an extremely slower off-rate from BRAF V600E, which results in significantly greater target inhibition in cells following drug wash-out.⁷⁹ This may account for the significantly greater clinical benefit seen with encorafenib/binimetinib in clinical trials. Final study data are eagerly awaited. Regulatory approval has been sought, and is pending at this time.

Binimetinib has been compared to dacarbazine in a phase 3 study (NEMO) of patients with NRAS-mutant melanoma, most of whom had been previously treated with immunotherapy.⁸⁰ Response rates were low in both arms, although slightly greater with binimetinib than dacarbazine (15% versus 9%), commensurate with a modest improvement in progression-free survival. FDA approval has been sought and remains pending at this time.

References

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30.
Guy GP, Thomas CC, Thompson T, et al. Vital signs: melanoma incidence and mortality trends and projections - United States, 1982-2030. MMWR Morb Mortal Wkly Rep 2015;64:591–6.
Anderson WF, Pfeiffer RM, Tucker MA, Rosenberg PS. Divergent cancer pathways for early-onset and late-onset cutaneous malignant melanoma. Cancer 2009;115:4176–85.
Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135–47.
Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006;24:4340–6.
Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012;150:251–63.
Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 2015;161:1681–96.
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.
McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014;15:323–32.
Hauschild A, Grob J-J, Demidov LV, et al. DaBRAFenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358–65.
Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877–88.
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.
Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371:1867–76.
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275–80.
Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577–81.
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.
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517–26.
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–54.
Weber JS, Angelo SP D’, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375–84.
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320–30.
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.
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521–32.
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122–33.
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006–17.
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23–34.
Eggermont AMM. Therapeutic vaccines in solid tumours: can they be harmful? Eur J Cancer 2009;45:2087–90.
Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Sci Transl Med 2012;4:127ps8.
Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol 2014;192:5451–8.
Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348:62–8.
Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992;356:607–9.
Greenfield EA, Nguyen KA, Kuchroo VK. CD28/B7 costimulation: a review. Crit Rev Immunol 1998;18:389–418.
Sharpe AH, Abbas AK. T-cell costimulation--biology, therapeutic potential, and challenges. N Engl J Med 2006;355:973–5.
Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 2001;19:565–94.
Collins AV, Brodie DW, Gilbert RJC, et al. The interaction properties of costimulatory molecules revisited. Immunity 2002;17:201–10.
Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995;182:459–65.
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734–6.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677–704.
Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002;169:5538–45.
Youngnak P, Kozono Y, Kozono H, et al. Differential binding properties of B7-H1 and B7-DC to programmed death-1. Biochem Biophys Res Commun 2003;307:672–7.
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 2004;173:945–54.
Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25:9543–53.
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114–25.
Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 2013;1291:1–13.
Weber JS, O’Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 2008;26:5950–6.
Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A 2008;105:3005–10.
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Targeted Therapy and Immunotherapy in the Treatment of Metastatic Cutaneous Melanoma

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