Summary of recommendations and practice points: Immunotherapy for melanoma
Summary of recommendations and practice points
This section includes all recommendations and practice points from the systemic therapies section of the guidelines.
Evidence-based recommendation![]() |
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Anti-PD-1 based immunotherapy should be considered for the first-line/upfront drug treatment for patients with unresectable stage III/IV melanoma. | B |
Evidence-based recommendation![]() |
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A BRAF inhibitor combined with a MEK inhibitor should be considered as first-line/upfront drug treatment for patients with V600 BRAF mutation positive melanoma. | B |
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Practice point 2 Clinical trials should be considered for all patients with unresectable stage III/IV metastatic melanoma. |
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Practice point 4 Baseline PD-L1 expression on melanoma cells should not be used to select patients for anti-PD-1 therapy due to its low predictive value. |
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Practice point 5 Drug therapy is active in untreated melanoma brain metastases, and can be considered as first-line treatment (as an alternative to local brain therapy) in asymptomatic patients with multidisciplinary support with a radiation oncologist and neurosurgeon. See the Brain metastases section. |
Choice of first-line therapy
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Practice point 7 Anti-PD-1-based therapy should be administered as first-line therapy as opposed to following BRAF inhibitor-based therapy. |
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Practice point 8 While not formally compared, there is no suggestion that there is a difference in efficacy or toxicity between pembrolizumab and nivolumab. |
Special notes
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Practice point 11 Ipilimumab (anti-CTLA-4 immunotherapy), alone or in combination with anti-PD-1 may be administered following progression on anti-PD-1 monotherapy. |
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Practice point 14 Toxicity to one class of checkpoint inhibitor (e.g. anti-CTLA-4, ipilimumab) does not preclude use of a separate class of checkpoint inhibitor (e.g. anti-PD-1). |
Considerations in making these recommendations
The use of adjuvant systemic therapies in the Australian setting
At present, the only TGA approved and PBS-funded adjuvant treatment of resected stage III melanoma (see What is the role of adjuvant systemic therapy in patients with resected melanoma?) in Australia is IFN-α. Adjuvant IFN-α confers a small improvement in absolute OS but also has significant toxicity and as such for many patients the option of routine follow-up is considered favourable to IFN-α. Given the superiority of nivolumab over ipilimumab in the CA209-238 study, and the toxicity of ipilimumab, ipilimumab does not have a current role in the adjuvant treatment of melanoma in Australia, and is unlikely to have one in the future. At present combination dabrafenib/trametinib (Combi-AD study, resected stage III melanoma), pembrolizumab (EORTIC 18071 study, resected stage III melanoma) and nivolumab (CA209-238 study, resected stage III and IV melanoma) are not PBS reimbursed for the adjuvant treatment of resected melanoma. Enrolment in a clinical trial remains an alternative to routine follow-up for many patients. Self-funded adjuvant therapy may be an option for some patients, however should be considered only in the context of a multidisciplinary team involving a medical oncologist experienced in melanoma treatment.
Discussion
Issues requiring more clinical research study
There is no formal evidence comparing BRAF inhibitor-based targeted therapy versus immunotherapy in patients whose melanoma has a V600 BRAF mutation in the first-line/upfront setting.
Studies currently underway
There is a US intergroup study of dabrafenib/trametinib vs ipilimumab/nivolumab[1] and the Italian Sequential Combo Immuno and Target Therapy (SECOMBIT) Study (SECOMBIT).[2]
Future research priorities
Multiple combinations of immunotherapies, as well as immunotherapies combined with targeted therapies are underway in order to 1) look for effective combinations that are less toxic than the combination of ipilimumab and nivolumab and 2) target the 30% of patients with primary resistance to checkpoint inhibitors. One such combination that has completed phase III evaluation is pembrolizumab +/- an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor, which showed no response or survival benefit for the combination over pembrolizumab monotherapy.[3] Other examples include BRAF or MEK-directed targeted therapies combined with anti-PD-1 therapy or intra-lesional immunotherapies (e.g. TVEC) combined with anti-PD-1 therapies.
References
- ↑ National Cancer Institute (NCI). Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma. [homepage on the internet] Clinicaltrials.gov; Available from: https://clinicaltrials.gov/ct2/show/NCT02224781.
- ↑ Fondazione Melanoma Onlus. Sequential Combo Immuno and Target Therapy (SECOMBIT) Study (SECOMBIT). [homepage on the internet] Clinicaltrials.gov; Available from: https://clinicaltrials.gov/ct2/show/NCT02631447.
- ↑ Cohen EEW, Rischin D, Pfister DG, Vermorken JB, Zhao Y, Gowda H, et al. A phase 3, randomized, open-label study of epacadostat plus pembrolizumab, pembrolizumab monotherapy, and the EXTREME regimen as first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M SCCHN): ECHO-304/KEYNOTE-669. J Clin Oncol 2018 Jun 2 [cited 2018 Jun 14];36 (suppl; abstr TPS6090) Available from: http://abstracts.asco.org/214/AbstView_214_210675.html.