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.
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.
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.
Wang C, Thudium KB, Han M, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2014;2:846–56.
Poole RM. Pembrolizumab: first global approval. Drugs 2014;74:1973–81.
Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014;32:1020–30.
Patnaik A, Kang SP, Rasco D, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015;21:4286–93.
Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 2017;18:31–41.
Dhomen N, Marais R. BRAF signaling and targeted therapies in melanoma. Hematol Oncol Clin North Am 2009;23:529–45, ix.
Satyamoorthy K, Li G, Gerrero MR, et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 2003;63:756–9.
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54.
Krauthammer M, Kong Y, Ha BH, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 2012;44:1006–14.
Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med 2010;8:67.
Lovly CM, Dahlman KB, Fohn LE, et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS ONE 2012;7:e35309.
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Carvajal RD, Lawrence DP, Weber JS, et al. Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. Clin Cancer Res 2015;21:2289–96.
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Chan MMK, Haydu LE, Menzies AM, et al. The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition. Cancer 2014;120:3142–53.
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Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568–71.
Ayers M, Lunceford J, Nebozhyn M, et al. Relationship between immune gene signatures and clinical response to PD-1 blockade with pembrolizumab (MK-3475) in patients with advanced solid tumors. J Immunotherapy Cancer 2015;3(Suppl 2):P80.

KIT INHIBITION SINGLY AND IN COMBINATION

The KIT receptor protein tyrosine kinase is a transmembrane protein consisting of extracellular and intracellular domains. Activating KIT mutations occur in 2% to 8% of all melanoma patients and may be found in all melanoma subtypes but are commonest in acral melanomas (10%–20%) and mucosal melanomas (15%–20%). Activating KIT mutations primarily occur in exons 11 and 13, which code for the juxtamembrane and kinase domains, respectively.^5,81–83

Imatinib mesylate is a tyrosine kinase inhibitor of the 2-phenyl amino pyrimidine class that occupies the tyrosine kinase active site with resultant blocking of tyrosine kinase activity. Imatinib mesylate is known to block KIT and has been extensively studied in patients with gastrointestinal stromal tumors (GIST), 80% of whom harbor KIT mutations, in both the adjuvant and the metastatic settings. In melanoma, imatinib mesylate was studied in a Chinese open-label, phase 2 study of imatinib mesylate monotherapy in metastatic melanoma harboring KIT mutation or amplification; 25% of the study patients had mucosal disease and the rest had cutaneous disease, with acral involvement in 50% of all patients.⁸⁴ Overall response rate was 23%, while 51% of patients remained alive at 1 year with no differences in response rate and/or survival being noted between patients with either KIT mutations or amplifications. In a separate study of imatinib mesylate at 400 mg daily or 400 mg twice daily in Caucasian patients with KIT-mutated/amplified melanoma, similar response and survival rates were reported, although patients with KIT mutations did nonsignificantly better than those with KIT amplifications.⁸⁵

Other novel studies evaluating KIT inhibitors include KIT inhibition in combination with the VEGF inhibitor bevacizumab and a study of selective BCR-ABL kinase inhibitor nilotinib in imatinib-resistant melanoma. In the former phase 1/2 study, Flaherty and colleagues studied imatinib 800 mg daily and bevacizumab at 10 mg/kg every 2 weeks in 63 patients with advanced tumors, including 23 with metastatic melanoma. Although the combination was relatively nontoxic, no significant efficacy signal was seen and further accrual to the phase 2 portion was halted after the first stage was completed.⁸⁶ Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor intelligently designed based on the structure of the ABL-imatinib complex that is 10 to 30 times more potent than imatinib in inhibiting BCR-ABL1 tyrosine kinase activity. Nilotinib is approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML), with reported efficacy in patients with central nervous system (CNS) involvement.^87,88 Nilotinib has been studied in a single study of KIT-mutated/amplified melanoma that included patients with imatinib-resistance and those with treated CNS disease. Nilotinib appeared to be active in imatinib-resistant melanoma, although no responses were seen in the CNS disease cohort.⁸⁹ Overall, the response rates observed with KIT inhibition in melanoma are much lower than those observed in CML and GIST.

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.
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.
Wang C, Thudium KB, Han M, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2014;2:846–56.
Poole RM. Pembrolizumab: first global approval. Drugs 2014;74:1973–81.
Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014;32:1020–30.
Patnaik A, Kang SP, Rasco D, et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015;21:4286–93.
Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 2017;18:31–41.
Dhomen N, Marais R. BRAF signaling and targeted therapies in melanoma. Hematol Oncol Clin North Am 2009;23:529–45, ix.
Satyamoorthy K, Li G, Gerrero MR, et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 2003;63:756–9.
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54.
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Targeted Therapy and Immunotherapy in the Treatment of Metastatic Cutaneous Melanoma

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KIT INHIBITION SINGLY AND IN COMBINATION

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