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After the initial landmark treatment advances in metastatic melanoma with ipilimumab (ipi), nivolumab (nivo), and targeted therapy, there has been a paucity of effective new therapeutic advances. Over the past 6 months, however, data have emerged for several promising front-line treatment options.

Bempegaldesleukin (BEMPEG), a CD122 preferential IL-2 pathway agonist, in combination with nivolumab demonstrated a 34.2% complete response (CR) rate in the front-line setting for metastatic melanoma in the . We await results from the phase III study, but one in three patients achieving a CR is encouraging as a future option. This compares with a 22% CR rate reported with ipi/nivo in CheckMate 067.

Changing the treatment paradigm in the front-line setting will require a treatment to achieve a higher response rate, including a higher CR rate, than ipi/nivo or to achieve sustained efficacy with improved toxicity. Combination therapy with ipi/nivo recently demonstrated a 49% overall survival rate at 6 and a half years, setting a high bar for future first-line therapies.

The front-line debate will soon include relatlimab (a LAG3 inhibitor) with nivo from the RELATIVITY-047 phase III study that demonstrated a progression-free-survival benefit in treatment-naïve patients compared with single-agent nivo. Response rate and overall survival data, however, have not yet been reported, so it is too soon for a full comparison.

There are many questions yet to answer in the front-line setting for new therapies. Will BEMPEG with nivolumab demonstrate benefit in a randomized phase III study? Will toxicity prove to be more manageable than ipi/nivo? Are either BEMPEG or relatlimab in combination with nivo efficacious in patients with brain metastases?

With multiple current front-line approvals in metastatic melanoma and more promising agents potentially headed into the line-up, biomarker analyses will be increasingly important. BRAFV600 patients have significant benefit from combination ipi/nivo compared with single-agent anti PD-1, but this same benefit is not seen in BRAF wild-type patients.

Predictive immune biomarkers remain elusive. PIVOT-02 performed extensive exploratory translational studies and did establish several immune markers consistent with response such as high IFN-γ gene expression profiling and high CD8+ tumor-infiltrating lymphocytes; however, the phase III study will shed more light on the utility of these markers.

A consistent predictive biomarker would aid clinicians and patients in the increasingly complex decision-making process, but until testing is available, decisions will be based on toxicities, disease volume, and comorbidities.

Meredith McKean, MD, MPH, is a clinical investigator in the Melanoma and Skin Cancer Research Program at Sarah Cannon Research Institute, Tennessee Oncology, in Nashville.

Read the study here and an interview about it here.