Most Cost-effective to Use Immunotherapy First in Melanoma

Up-front immunotherapy is the most cost-effective option for treating newly diagnosed unresectable stage III or IV melanoma with unknown BRAF mutation status, concludes a modeling analysis. Investigators evaluated eight up-front options and found that nivolumab monotherapy was the most cost-effective, followed by pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab.

Using targeted therapy (with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib) in the first line was not cost-effective when mutation status was unknown, which is often the case with melanoma. BRAF testing to guide first-line treatment was also not cost-effective.

Targeted therapies are best used in the second line for patients with confirmed pathogenic BRAF mutations, the authors comment.

The investigators also found that the survival benefit is best by several years when the first treatment is nivolumab plus ipilimumab, although it was not the least expensive option.

"Nivolumab plus ipilimumab could be recommended up front across the commonly used treatment strategies, especially when the mutation status is not clear for newly diagnosed patients," investigators Bin Wu, PhD, of Shanghai Jiaotong University, Shanghai, China, and Lizheng Shi, PhD, interim chair of the Department of Health Policy at Tulane University, New Orleans, Louisiana, said.

The study was published in JAMA Dermatology.

Approached for comment, melanoma expert Jeffrey Weber, MD, PhD, a professor of medicine at New York University, New York City, said he wasn't surprised by the findings, given the longer duration of use and shorter median overall survival with targeted therapy.

Checkpoint inhibitors are currently the first-line treatment option for newly diagnosed advanced melanoma, he emphasized.

As for BRAF testing, Weber said he and his colleagues always test BRAF early on to guide second-line treatment in case immunotherapy fails and because "some frontline patients need rapid regression, so if they're mutated, we do use frontline BRAF plus MEK inhibitors" first line, he said.

Cost-effectiveness Analysis

In the study, Wu and Shi were looking for the biggest bang for the buck among newer first-line treatments for advanced melanoma. Checkpoint inhibitors and BRAF and MEK inhibitors have dramatically improved outcomes in recent years, but they are expensive, and it hasn't been clear which options best balance medical benefit and cost in newly diagnosed patients.

The analysis assessed the following eight first-line regimens:

Ipilimumab
Nivolumab
Nivolumab plus ipilimumab
Pembrolizumab every 3 weeks
BRAF testing followed by nivolumab for BRAF wild-type tumor and nivolumab plus ipilimumab for confirmed BRAF pathogenic variant
BRAF testing followed by pembrolizumab every 3 weeks for BRAF wild-type tumor and dabrafenib plus trametinib for confirmed BRAF pathogenic variant
BRAF testing followed by nivolumab for BRAF wild-type tumor and dabrafenib plus trametinib for confirmed BRAF pathogenic variant
BRAF testing followed by pembrolizumab every 3 weeks for BRAF wild-type tumor and nivolumab plus ipilimumab for confirmed BRAF pathogenic variant

Clinical information, including the latest survival data, came primarily from four advanced melanoma trials: CheckMate 067 (nivolumab and ipilimumab); KEYNOTE-006 (pembrolizumab vs ipilimumab); COMBI-d (dabrafenib plus trametinib); and COMBI-v (dabrafenib plus trametinib vs vemurafenib).

Costs were in US dollars and included drug prices and the expense of additional treatments as well as management of anticipated adverse events and other complications.

The mean cost of up-front nivolumab monotherapy was $231,082 for 5.3 quality-adjusted life-years (QALYs); for pembrolizumab monotherapy, the mean cost was $236,111 for 7.4 QALYs; and for nivolumab plus ipilimumab, which offered the greatest medical benefit, the mean cost was $402,221 for 10 QALYs.

The three options "formed the cost-effective frontier," the investigators say.

Pembrolizumab had an incremental cost-utility ratio (ICUR) ― a measure of cost/benefit ― of $8593 per additional QALY over nivolumab. For nivolumab plus ipilimumab, the ICUR was $125,593/QALY over pembrolizumab.

At a willing-to pay-threshold of $150,000/QALY, a common metric in US healthcare analysis, first-line nivolumab plus ipilimumab produced the greatest incremental net health benefit and net monetary benefit.

Up-front BRAF testing followed by corresponding regimens for BRAF-negative and BRAF-positive mutations were more costly but less effective.

This study "makes an important contribution in identifying strategies that have the most patient benefit and lowest cost," commented Joseph Skitzki, MD, surgical oncologist and chair of the Melanoma/Sarcoma Disease Site Research Group at Roswell Park Comprehensive Cancer Center, in Buffalo, New York.

"Current treatments for metastatic melanoma are effective but incredibly expensive, and strategies to safely optimize care and reduce cost are warranted, but maybe incredibly complex," he added. More information is needed on dosing schedules and BRAF plus MEK with checkpoint inhibitors in the first line, something the investigators didn't model.

The findings of the current study are consistent with a 2017 economic analysis that pegged nivolumab monotherapy as the most cost-effective first-line choice, with nivolumab monotherapy and nivolumab plus ipilimumab both more cost-effective than ipilimumab monotherapy.

No source of funding for the analysis was reported. The authors have disclosed no relevant financial relationships. Weber is a video commentator for Medscape Oncology, has relationships with many pharmaceutical companies, and has been named on patents for biomarkers for ipilimumab and nivolumab.

JAMA Dermatol. Published online July 22, 2020. Abstract

M. Alexander Otto is a physician assistant with a master's degree in medical science. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape, including McClatchy and Bloomberg. He is an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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