Pembrolizumab in advanced acral lentiginous melanoma: final results of a single-centre, open-label, phase II trial in an East Asian population

Background

Acral lentiginous melanoma (ALM) is the predominant melanoma subtype in East Asian populations, accounting for roughly 50–58% of cases, compared with 2–3% in populations of European ancestry. ALM is genomically and biologically distinct from sun-exposed cutaneous melanoma, and East Asian and acral patients were markedly under-represented in the pivotal anti–PD-1 registration trials. At the time this study was designed, no prospective trial had evaluated a checkpoint inhibitor specifically in ALM. We conducted a phase II trial to estimate the activity of pembrolizumab in this population.

Methods

In this single-centre, single-arm, open-label phase II trial, adults with metastatic or locoregionally advanced inoperable ALM who were naïve to anti–PD-1/PD-L1 therapy received pembrolizumab 200 mg intravenously every 3 weeks until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints included duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety (CTCAE v4.0). A Simon minimax two-stage design (P0=0.10, P1=0.30, α=0.05, power=80%) planned enrolment of up to 28 patients.

Results

Between February 2017 and June 2019, 9 patients were enrolled before recruitment was halted for slow accrual, the interval availability of reimbursed pembrolizumab, and a low observed response signal. Median age was 72 years (range 48–78); 6 (67%) were male; all had ECOG performance status 0 and metastatic disease; 7 (78%) had received prior therapy. One patient achieved a partial response (ORR 11.1%, 95% CI 0.0–31.6%), with a DoR of 19 months; 3 had stable disease and 4 progressed. CBR (response or stable disease ≥12 weeks) was 44.4% (95% CI 12.0–76.9). At a median follow-up of 7.6 months, median PFS was 3.4 months (95% CI 1.4–21.3) and median OS was 7.6 months (95% CI 2.0– 34.3). Two grade 3 adverse events occurred, both assessed as unrelated to study drug; no treatment-related grade ≥3 events were recorded. In an exploratory analysis, an LDH-to–upper-limit-of-normal ratio >1.5 was associated with worse OS (median 4.3 vs 26.5 months; HR 4.58, 95% CI 0.82–25.7; log-rank p=0.06).

Conclusions

Recruitment was constrained by disease rarity and a shifting reimbursement landscape, and the trial closed before completing stage I. Within these limitations, single-agent pembrolizumab showed only modest activity in advanced ALM, consistent with the limited efficacy subsequently reported in larger contemporary acral melanoma cohorts. The exploratory association between elevated LDH ratio and poorer survival warrants prospective evaluation.

What is already known / what this study adds

• ALM is the commonest melanoma subtype in East Asia but was almost absent from the trials that established PD-1 blockade; no prospective checkpoint-inhibitor trial in pure ALM existed when this study was designed.

• In this prospective phase II trial, single-agent pembrolizumab produced an ORR of 11.1% with modest survival, consistent with limited activity later reported in larger acral cohorts.

• An exploratory signal linking elevated LDH ratio to poorer survival supports its prognostic relevance and the need for collaborative, biomarker-driven trials dedicated to ALM.