Systemic treatments for metastatic cutaneous melanoma

Background

We included 122 RCTs (28,561 participants). Of these, 83 RCTs, encompassing 21 different comparisons, were included in meta-analyses. Included participants were men and women with a mean age of 57.5 years who were recruited from hospital settings. Twenty-nine studies included people whose cancer had spread to their brains. Interventions were categorised into five groups: conventional chemotherapy (including single agent and polychemotherapy), biochemotherapy (combining chemotherapy with cytokines such as interleukin-2 and interferon-alpha), immune checkpoint inhibitors (such as anti-CTLA4 and anti-PD1 monoclonal antibodies), small-molecule targeted drugs used for melanomas with specific gene changes (such as BRAF inhibitors and MEK inhibitors), and other agents (such as anti-angiogenic drugs). Most interventions were compared with chemotherapy. In many cases, trials were sponsored by pharmaceutical companies producing the tested drug: this was especially true for new classes of drugs, such as immune checkpoint inhibitors and small-molecule targeted drugs.When compared to single agent chemotherapy, the combination of multiple chemotherapeutic agents (polychemotherapy) did not translate into significantly better survival (overall survival: HR 0.99, 95% CI 0.85 to 1.16, 6 studies, 594 participants; high-quality evidence; progression-free survival: HR 1.07, 95% CI 0.91 to 1.25, 5 studies, 398 participants; high-quality evidence. Those who received combined treatment are probably burdened by higher toxicity rates (RR 1.97, 95% CI 1.44 to 2.71, 3 studies, 390 participants; moderate-quality evidence). (We defined toxicity as the occurrence of grade 3 (G3) or higher adverse events according to the World Health Organization scale.)Compared to chemotherapy, biochemotherapy (chemotherapy combined with both interferon-alpha and interleukin-2) improved progression-free survival (HR 0.90, 95% CI 0.83 to 0.99, 6 studies, 964 participants; high-quality evidence), but did not significantly improve overall survival (HR 0.94, 95% CI 0.84 to 1.06, 7 studies, 1317 participants; high-quality evidence). Biochemotherapy had higher toxicity rates (RR 1.35, 95% CI 1.14 to 1.61, 2 studies, 631 participants; high-quality evidence).With regard to immune checkpoint inhibitors, anti-CTLA4 monoclonal antibodies plus chemotherapy probably increased the chance of progression-free survival compared to chemotherapy alone (HR 0.76, 95% CI 0.63 to 0.92, 1 study, 502 participants; moderate-quality evidence), but may not significantly improve overall survival (HR 0.81, 95% CI 0.65 to 1.01, 2 studies, 1157 participants; low-quality evidence). Compared to chemotherapy alone, anti-CTLA4 monoclonal antibodies is likely to be associated with higher toxicity rates (RR 1.69, 95% CI 1.19 to 2.42, 2 studies, 1142 participants; moderate-quality evidence).

We found high-quality evidence that many treatments offer better efficacy than chemotherapy, especially recently implemented treatments, such as small-molecule targeted drugs, which are used to treat melanoma with specific gene mutations. Compared with chemotherapy, biochemotherapy (in this case, chemotherapy combined with both interferon-alpha and interleukin-2) and BRAF inhibitors improved progression-free survival; BRAF inhibitors (for BRAF-mutated melanoma) and anti-PD1 monoclonal antibodies improved overall survival. However, there was no difference between polychemotherapy and monochemotherapy in terms of achieving progression-free survival and overall survival. Biochemotherapy did not significantly improve overall survival and has higher toxicity rates compared with chemotherapy.There was some evidence that combined treatments worked better than single treatments: anti-PD1 monoclonal antibodies, alone or with anti-CTLA4, improved progression-free survival compared with anti-CTLA4 monoclonal antibodies alone. Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival, and a combination of BRAF plus MEK inhibitors was associated with better overall survival for BRAF-mutated melanoma, compared to BRAF inhibitors alone.The combination of BRAF plus MEK inhibitors (which can only be administered to people with BRAF-mutated melanoma) appeared to be the most effective treatment (based on results for progression-free survival), whereas anti-PD1 monoclonal antibodies appeared to be the least toxic, and most acceptable, treatment.Evidence quality was reduced due to imprecision, between-study heterogeneity, and substandard reporting of trials. Future research should ensure that those diminishing influences are addressed. Clinical areas of future investigation should include the longer-term effect of new therapeutic agents (i.e. immune checkpoint inhibitors and targeted therapies) on overall survival, as well as the combination of drugs used in melanoma treatment; research should also investigate the potential influence of biomarkers.

Relevant Prescribing Information

We found high-quality evidence that many treatments offer better efficacy than chemotherapy, especially recently implemented treatments, such as small-molecule targeted drugs, which are used to treat melanoma with specific gene mutations. Compared with chemotherapy, biochemotherapy (in this case, chemotherapy combined with both interferon-alpha and interleukin-2) and BRAF inhibitors improved progression-free survival; BRAF inhibitors (for BRAF-mutated melanoma) and anti-PD1 monoclonal antibodies improved overall survival. However, there was no difference between polychemotherapy and monochemotherapy in terms of achieving progression-free survival and overall survival. Biochemotherapy did not significantly improve overall survival and has higher toxicity rates compared with chemotherapy.There was some evidence that combined treatments worked better than single treatments: anti-PD1 monoclonal antibodies, alone or with anti-CTLA4, improved progression-free survival compared with anti-CTLA4 monoclonal antibodies alone. Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival, and a combination of BRAF plus MEK inhibitors was associated with better overall survival for BRAF-mutated melanoma, compared to BRAF inhibitors alone.The combination of BRAF plus MEK inhibitors (which can only be administered to people with BRAF-mutated melanoma) appeared to be the most effective treatment (based on results for progression-free survival), whereas anti-PD1 monoclonal antibodies appeared to be the least toxic, and most acceptable, treatment.Evidence quality was reduced due to imprecision, between-study heterogeneity, and substandard reporting of trials. Future research should ensure that those diminishing influences are addressed. Clinical areas of future investigation should include the longer-term effect of new therapeutic agents (i.e. immune checkpoint inhibitors and targeted therapies) on overall survival, as well as the combination of drugs used in melanoma treatment; research should also investigate the potential influence of biomarkers.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Systemic treatments for metastatic cutaneous melanoma

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-2 for your response.

Enter title in bold, with all first words capitalized, and without a reference number
Design	Objective terms describing the type of study (randomized, uncontrolled, retrospective, placebo-controlled, cross-over, etc.); N= (total subjects)
Objective	State the objective (purpose) of the study using the author’s language(usually beginning with “To” and without a period, assuming a non-complete sentence)
Study Groups	Only the separate groups and their cohort number (n) should be listed. You can describe more details of the cohorts in the methods section so this section can stay very succinct.
Inclusion Criteria	Include relevant inclusion criteria (not a comprehensive list).
Exclusion Criteria	Include relevant exclusion criteria (not a comprehensive list).
Methods	This is our most important section. Data collection and any other information needed to understand the results is presented. Any loose ends from all other sections are tied up here, as concisely as possible.
Duration	Include the duration of the trial as a whole, as well as the duration of the interventions.
Outcome Measures	If the primary outcome measure isn’t explicit from the study, all outcome measures applicable to the inquiry can be listed in this section. If the primary outcome measure is explicit, then make separate sections for ‘Primary’ and ‘Secondary’ Outcome Measures. All outcome measures listed should correlate directly/exactly with the results presented later.
Baseline Characteristics		A	B
	Age, years
	Female
	White
	---
	Include relevant baseline characteristics that will provide a general (big picture) view of the patients in the study.
Results	Endpoint	A	B	p-Value
	----
	----
	All results listed should correlate directly/exactly with the outcome measures presented previously.Results that do not have to do with the inquiry should not be included; just the stated outcomes need corresponding results. Tables are encouraged to display the most info using the least space/words.
Adverse Events	Common Adverse Events: (or those deemed frequent; if not listed in study, use N/A or “Not disclosed”)
	Serious Adverse Events: (or those deemed high risk; if not listed in study, use N/A or “Not disclosed”)
	Percentage that Discontinued due to Adverse Events: (if not listed in study, use N/A or “Not disclosed”)
Study Author Conclusions	Copy and paste the author’s conclusions on the question at hand, using full sentences. Don’t include any conclusions that don’t correspond to results we list.
InpharmD Researcher Critique	As the expert, add 1-2 sentences on strengths, weaknesses, and takeaways from this study. Focus on insight as “more research is needed” is obvious.

Enter title in bold, with all first words capitalized, and without a reference number
Design	Objective terms describing the type of study (randomized, uncontrolled, retrospective, placebo-controlled, cross-over, etc.); N= (total subjects)
Objective	State the objective (purpose) of the study using the author’s language(usually beginning with “To” and without a period, assuming a non-complete sentence)
Study Groups	Only the separate groups and their cohort number (n) should be listed. You can describe more details of the cohorts in the methods section so this section can stay very succinct.
Inclusion Criteria	Include relevant inclusion criteria (not a comprehensive list).
Exclusion Criteria	Include relevant exclusion criteria (not a comprehensive list).
Methods	This is our most important section. Data collection and any other information needed to understand the results is presented. Any loose ends from all other sections are tied up here, as concisely as possible.
Duration	Include the duration of the trial as a whole, as well as the duration of the interventions.
Outcome Measures	If the primary outcome measure isn’t explicit from the study, all outcome measures applicable to the inquiry can be listed in this section. If the primary outcome measure is explicit, then make separate sections for ‘Primary’ and ‘Secondary’ Outcome Measures. All outcome measures listed should correlate directly/exactly with the results presented later.
Baseline Characteristics		A	B
	Age, years
	Female
	White
	---
	Include relevant baseline characteristics that will provide a general (big picture) view of the patients in the study.
Results	Endpoint	A	B	p-Value
	----
	----
	All results listed should correlate directly/exactly with the outcome measures presented previously.Results that do not have to do with the inquiry should not be included; just the stated outcomes need corresponding results. Tables are encouraged to display the most info using the least space/words.
Adverse Events	Common Adverse Events: (or those deemed frequent; if not listed in study, use N/A or “Not disclosed”)
	Serious Adverse Events: (or those deemed high risk; if not listed in study, use N/A or “Not disclosed”)
	Percentage that Discontinued due to Adverse Events: (if not listed in study, use N/A or “Not disclosed”)
Study Author Conclusions	Copy and paste the author’s conclusions on the question at hand, using full sentences. Don’t include any conclusions that don’t correspond to results we list.
InpharmD Researcher Critique	As the expert, add 1-2 sentences on strengths, weaknesses, and takeaways from this study. Focus on insight as “more research is needed” is obvious.