A Closer Look at Immunotherapy for Melanoma

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The management of toxicities and re-initiation of medication should be made on a case by case basis, and must take the patient's entire clinical presentation into account.
The management of toxicities and re-initiation of medication should be made on a case by case basis, and must take the patient's entire clinical presentation into account.

Staging melanoma requires consideration of multiple factors: thickness, ulceration status, the number of involved lymph nodes, and the presence of metastases.1

Patients with stage II or worse disease are more likely to develop metastases in their lifetime. While the primary treatment for melanoma is surgical excision, patients with metastatic disease require additional therapy; immunotherapy is an innovative class of medications accumulating data for use in this patient-group.

In melanoma, the immune response plays a crucial role via CTLA-4 and PD-1. CTLA-4 is a regulator of the body's activated immune system response to cancer cells and down-regulates T cell activation.2 Ipilimumab is an anti-CTLA-4 monoclonal antibody designed to stimulate the immune system's response to melanoma by bolstering T cell activation.

In a similar mechanism, PD-1 binds to programmed death ligand-1 on activated tumor cells and down-regulates the immune system's response. Nivolumab and pembrolizumab are monoclonal antibodies that target PD-1.

There are clinical studies and US Food and Drug Administration (FDA) indications supporting the use of either of these medication classes alone or in combination to treat patients with melanoma.3-6 Nivolumab is delivered via intravenous infusion and has several dosing regimens depending on whether the cancer is resectable and on concurrent ipilimumab use.7 The FDA-approved dose of pembrolizumab is 200 mg every 3 weeks, though several dosing regimens have been used in clinical trials.8

Clinical trials evaluating nivolumab in patients with melanoma have shown a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with older chemotherapy agents, including dacarbazine, paclitaxel, and carboplatin. When combined with ipilimumab, furthermore, the 3-year PFS and OS rates are even better, though there is an increased risk of systemic toxicities.6,9 The most common toxicities associated with these agents includes dermatitis, endocrinopathies, hepatotoxicity, enterocolitis, and pneumonitis; they appear to result from the same immune-stimulating effects aimed at treating the patient's underlying malignancy.

The drug classes are, furthermore, associated with varying toxicity profiles: the overall incidence and severity of colitis in patients receiving PD-1 agents is, for example, less significant compared with ipilimumab.4,6,9 In contrast, PD-1 agents are associated with more thyroid toxicities than ipilimumab is.

CheckMate-067 details the varying risk of toxicities between monotherapy and dual regimens. In this study, close to 40% of patients in the combination arm discontinued compared with only 12% to 16% of patients receiving monotherapy. Most of these patients discontinued therapy during the induction phase.

These patients did not, however, have worse outcomes.10 The median PFS was similar between patients who discontinued therapy secondary to adverse events (8.4 months) compared with those who continued treatment (10.8 months). This finding may support the notion that a more severe reaction to dual therapy may signify a significant immune-mediated response to the underlying melanoma.

The optimal time to resume nivolumab or ipilimumab after significant adverse events following both single and dual therapy is, for now, undetermined. Management, furthermore, depends on the type and grade of toxicity. In general, patients with grade 1 toxicity can continue treatment, while those with grade 2 to 4 events should have their dose withheld. Patients with grade 2 toxicities can potentially be managed with steroids and reinitiate treatment after about 1 month. Patients who develop grade 4 toxicities should have their immunotherapy permanently withheld.

The management of toxicities and re-initiation of medication should, however, be made on a case by case basis, and must take the patient's entire clinical presentation into account.11 Additional studies are needed to develop evidence-based algorithms for managing toxicities associated with these agents.


  1. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-92.
  2. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189-99.
  3. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-30.
  4. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Eng J Med. 2015;372(26):2521-32.
  5. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853-62.
  6. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab with ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-56.
  7. Opdivo prescribing information. Bristol-Myers Squibb website. https://packageinserts.bms.com/pi/pi_opdivo.pdf. Updated January 2018. Accessed January 2018.
  8. Keytruda prescribing information. Merck & Co website. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Updated November 2017. Accessed January 2018.
  9. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34.
  10. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807-14.
  11. Immune mediated adverse reactions management guide. Opdivo website. http://www.opdivohcp.com/servlet/servlet.FileDownload?file=00Pi000000ijs1vEAA. Accessed February 2018.
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