Clinical validation of a prognostic 7-marker IHC assay (7-IHC) in 382 patients (pts) with stage IB/IIA cutaneous melanoma (CM; MELARISK-001).
Authors: Amaral Teresa , Forchhammer Stephan , Chatziioannou Eftychia , Johansson Iva , Nagore Eduardo , Manrique-Silva Esperanza , Través-Zapata Víctor , Van Leeuwen Barbara , Jansen Marnix R. , Bañuls José , Jara Noelia , Niveiro de Jaime María , Bohne Ann-Sophie , Teras Jyri , Ross Merrick I. , van Akkooi Alexander Christopher Jonathan , Weber Jeffrey S. , Schadendorf Dirk , Olofsson Bagge Roger , Hauschild Axel 
Published: July 2024

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Background: For pts with resected CM, adjuvant anti-PD1 is approved for AJCC v8 stage IIB–IV and BRAFi/MEKi for stage III–IV disease. Nonetheless, there remains a subgroup of pts within stages IB/IIA, which is at high risk of relapse and death, accounts for a considerable share of overall CM mortality (1), and lacks access to such therapy. Thus, adjuvant clinical trials in this “early”-stage setting may be merited. However, this subgroup is not detectable via AJCC staging alone. A prognostic 7-IHC assay that was developed (2), and analytically (3) and prospectively clinically validated (4) to identify stage IB/IIA pts at high risk of relapse and death, may be useful in selecting pts for adjuvant trials (2,4). Here, we report results from the MELARISK-001 multicenter study of that assay. Methods: MELARISK-001 enrolled consecutive pts diagnosed with stage IB/IIA CM from 2000–16, with available formalin-fixed paraffin-embedded primary melanoma. Specimens were analyzed by 7-IHC and pts classified as either high-risk or low-risk. Kaplan-Meier survival analysis and multivariate Cox regression analysis (MVA) against Breslow thickness, ulceration, age, and sex were performed. Results: MELARISK-001 included 382 pts; 247 (65%) pts in stage IB, 135 (35%) in stage IIA, all sentinel node-negative. Median Breslow thickness was 1.6 mm, median age 60Y. 212 pts (55%) were classified as 7-IHC high-risk, 170 pts (45%) as 7-IHC low-risk. Median follow-up for recurrence-free survival (RFS) was 90 mos, for melanoma-specific survival (MSS) 98 mos. Comparing 7-IHC high-risk vs low-risk pts, 5Y RFS was 79% vs 100%, 10Y RFS, 72% vs 99%, 5Y MSS, 92% vs 100%, and 10Y MSS 82% vs 100% (Table; logrank p<0.001). In MVA, 7-IHC risk class (hazard ratio [HR] 22.3; 95% CI 7.0–70.9), Breslow thickness (1.5; 1.1–1.9), and age (1.61; 1.0–2.5) were significant independent prognosticators of RFS. 7-IHC HR for MSS could not be computed due to 7-IHC's 100% sensitivity. Prognostic performance variables (95% CI) for RFS were: sensitivity 98% (91%–100%), positive predictive value 26% (20%–33%), negative predictive value 99% (97%–100%). Conclusions: 7-IHC risk categorization identified 98% of relapses and 100% of CM-related deaths in stage IB/IIA pts. In MVA, 7-IHC risk class was the strongest independent prognosticator of survival endpoints. 7-IHC high-risk pts have a relapse rate comparable to that of later-stage pts for whom adjuvant therapy is approved. MELARISK-001 provides further evidence supporting use of 7-IHC to identify early-stage pts at high risk of relapse and death who may benefit from adjuvant therapy trials. 1. Whiteman et al J Invest Dermatol 2015. 2. Meyer et al PloS ONE 2012. 3. Ziemer et al Diagnostics2023. 4. Meyer et al Eur J Cancer 2023. [Table: see text]