⚡Anti-PD-1 win for desmoplastic melanoma

Good morning — it’s Saturday, August 23, and we’re covering desmoplastic melanoma as a top anti-PD-1 responder, a first-in-class anti-KIT antibody in prurigo nodularis, and more.

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Pembrolizumab (Keytruda) showed striking activity in unresectable desmoplastic melanoma, according to a Phase 2 trial published in Nature Medicine.

This uncommon melanoma subtype typically arises in chronically sun-damaged skin, features abundant fibrotic stroma with spindle cells, and commonly carries NF1 mutations.

A high tumor mutational burden and dense immune infiltration may render desmoplastic melanoma particularly responsive to PD-1 blockade, which restores T-cell anti-tumor activity.

In the single-arm trial, 27 patients received pembrolizumab 200 mg every three weeks for up to two years. The cohort reflected the disease’s epidemiology: mostly older men (median age 75) with head and neck primaries.

At a median follow-up of 51 months, the complete response rate was 37%. Overall response rate—defined as ≥30% tumor reduction—was 89%. Responses were frequently deep (complete or near complete), rapid (seen within 2 months), and durable.

Three-year overall and melanoma-specific survival reached 84% and 96%. Of nine deaths, one was from melanoma progression and eight from unrelated causes.

Toxicity limited treatment duration. Eighty-one percent of patients discontinued before two years, including one-third due to adverse events. Older age and comorbidities likely amplified risk. Notably, responses appeared to be durable even after early discontinuation.

The trial was small and lacked a control arm, but the results remain significant. Desmoplastic melanoma joins Hodgkin lymphoma and Merkel cell carcinoma as one of the most responsive cancers to single-agent PD-1 blockade.

The authors recommend anti–PD-1 monotherapy as the frontline option for unresectable disease, rather than combination regimens with CTLA-4 or LAG-3 inhibitors.  

> Barzolvolimab demonstrates efficacy in prurigo nodularis after one dose: In a Phase 1b trial published in JAAD, barzolvolimab showed encouraging efficacy in moderate-to-severe prurigo nodularis. The first-in-class investigational anti-KIT antibody, developed by Celldex, depletes mast cells by blocking stem cell factor–dependent KIT activation, a pathway implicated in disease pathogenesis. Investigators randomized 23 adults to a single IV infusion of placebo or barzolvolimab at 1.5 or 3.0 mg/kg. At Week 8, 57% of patients on 3.0 mg/kg achieved a ≥4-point reduction in itch severity on the WI-NRS (0–10 scale), compared with 30% on 1.5 mg/kg and 25% on placebo. Clear or almost clear skin (IGA 0/1) was achieved by 29% on 3.0 mg/kg versus none with placebo. Tryptase levels were suppressed below assay detection, while plasma stem cell factor rose in parallel. Adverse events, all mild or moderate, occurred in 40% on barzolvolimab versus 63% on placebo. Limitations include the small sample and short follow-up. According to the authors, efficacy was comparable to that reported with approved biologics dupilumab and nemolizumab. Barzolvolimab is also under investigation for chronic urticaria and atopic dermatitis.

> Upadacitinib outperforms dupilumab on optimal atopic dermatitis targets: A post-hoc analysis of three Phase 3 trials (Measure Up 1 & 2 and Heads Up) shows upadacitinib delivers faster, more stringent disease control than placebo or dupilumab in moderate-to-severe atopic dermatitis. Stringent control was defined as achieving EASI 90 (≥90% reduction in disease severity) plus WP-NRS 0/1 (minimal-to-no itch). Both endpoints are recognized individually in the AHEAD consensus as optimal treatment targets. In Measure Up 1 & 2, 40% of patients on upadacitinib 30 mg and 25% on 15 mg achieved this outcome by Week 16, versus only 2% on placebo (P < 0.001). In Heads Up, 36% on upadacitinib 30 mg met this endpoint by Week 24, compared with 20% on dupilumab (P < 0.001). Upadacitinib separated from both placebo and dupilumab as early as Week 2 (P < 0.001). Limitations include the absence of safety reporting and the evaluation of only the 30-mg dose in Heads Up. However, the Level Up trial showed that starting upadacitinib at 15 mg, with escalation as needed, also outperformed dupilumab in achieving stringent endpoints. By aligning with AHEAD-defined targets, upadacitinib demonstrates that optimal control of atopic dermatitis is within reach.

> Neonatal BCG vaccination lowers 5-year incidence of eczema: Five-year data from the MIS BAIR trial, published in Allergy, suggest that neonatal BCG vaccination may reduce the risk of childhood eczema. Between 2013 and 2016, investigators randomized 1,272 Australian newborns to receive BCG or no vaccine within 10 days of birth. At 5 years, cumulative incidence of eczema was 37% in the BCG group versus 45% in controls (adjusted risk difference –8.2%, 95% CI –14.1 to –2.2). The effect size translates to an estimated number needed to treat of 12, meaning one case of eczema could be prevented for every 12 infants vaccinated at birth. The protective effect was present across different definitions of eczema, though not all reached significance. Children with two atopic parents showed a slightly stronger effect (43% vs 54%; adjusted risk difference –11.6). A limitation was incomplete follow-up, with 81% retention at year 1 and full 5-year data available for only 74% of those participants. Additional concerns were unblinding due to visible BCG scarring and reliance on questionnaires. Still, these findings mirror two other randomized trials that reported BCG’s protective effect against eczema at 13–18 months.

Quizzes, cases, and perspectives to sharpen your clinical eye.

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In a pooled Phase 2/3 analysis of 219 patients with truncal acne, Cabtreo gel (clindamycin/adapalene/benzoyl peroxide) showed a favorable safety profile. Adverse events were higher than vehicle (6% vs 1%), but were mostly mild and led to only one discontinuation (More)