Summary of recommendations and practice points: Immunotherapy for melanoma

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Clinical practice guidelines for the diagnosis and management of melanoma > 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.

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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


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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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Consensus Statement: Anti-PD-1 based therapies versus combination BRAF inhibitor plus MEK inhibitor have not been compared head to head, see Practice Points 6, 7 and 10.

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Practice point 1 All patients with unresectable stage III/IV metastatic melanoma (especially patients with brain metastases) should be discussed at a multidisciplinary team meeting, and managed by medical oncologists who have expertise using targeted and immune therapies.


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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 3 All patients with unresectable stage III/IV metastatic melanoma should have molecular testing of their melanoma for the V600 BRAF mutation, including V600E, V600K, V600R, V600D and V600M. Methodology should be used to detect appropriate mutations and be performed in an accredited laboratory using appropriate controls.


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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 6 Cross phase III trial comparisons of landmark survival analyses (progression-free and overall survival) suggest that more durable responses and possibly higher long-term landmark survival values may be achieved with anti-PD-1-based therapy compared with combined BRAF inhibitor and MEK inhibitor in the first-line setting.^

^Check PBS guidelines before prescribing any drug.


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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.


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Practice point 9 While not formally compared, there is no suggestion that there is a difference in efficacy between dabrafenib/trametinib, vemurafenib/cobimetinib or encorafenib/binimetinib combinations, but toxicity profiles are distinct.


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Practice point 10 The combination of ipilimumab and nivolumab causes immune-related side effects, inducing grade 3/4 drug-related toxicities in 59% of patients, including asymptomatic laboratory abnormalities. Disease factors that may be considered in the selection of patients for this combination regimen include: rapidly progressive melanoma, baseline serum lactate dehydrogenase (LDH) > upper limit of normal, mucosal melanoma, active brain metastases, BRAF mutation-positive melanoma and low PDL-1 expression on melanoma cells (assay as per CheckMate 067).

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 12 Any patient on immunotherapy can develop an auto-immune toxicity directed of any organ (and this risk must be discussed with the patient), The common toxicities are fatigue, rash, itch, diarrhoea, thyroiditis and hepatitis. Although a rare toxicity, it is important to note hypophysitis (inflammation of the pituitary gland) with subsequent hypopituitarism may occur, especially in regimens containing anti-CTLA-4 (e.g. ipilimumab).


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Practice point 13 Anti-PD-1 monotherapy may be administered in selected patients with auto-immune diseases with careful monitoring and after discussion with the patient and relevant clinicians regarding the risk of a flare of the auto-immune disease, planned treatment of the flare, and risk of death from auto-immune disease or melanoma.


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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).


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Practice point 15 BRAF inhibitor monotherapy is not a recommended alternative to BRAF inhibitor combined with MEK inhibitor. Absolute contraindications to MEK inhibitors are rare, and single agent BRAF inhibitors are inferior to the combination in both efficacy and toxicity.


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Practice point 16 Patients with serum lactate dehydrogenase >2 x upper limit of normal at baseline have shorter progression-free and overall survival for both immune and targeted therapies, thus patients should be appropriately followed up and counselled.


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Practice point 17 Chemotherapy and binimetinib (for NRAS mutant melanoma) can be considered only after progression on immune checkpoint and BRAF inhibitor-based therapy, if appropriate.

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.

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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.

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References

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