1. Fuerst, Mark L.

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The first-in-class histone deacetylase (HDAC) inhibitor gel remetinostat shows promise for the treatment of basal cell carcinoma (BCC). This is the first study to demonstrate a positive clinical effect of topical HDAC inhibitors in BCC in humans.

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"For the last century, the treatment of skin cancers has been largely surgical. However, new therapies may be on the horizon, which target the molecular and genetic pathways involved in BCC growth that may one day enable patients with even early-stage basal cell cancer to avoid the scarring and complications of surgery," said senior author Kavita Sarin, MD, PhD, Associate Professor of Dermatology at Stanford University.


BCC, the most common form of skin cancer, is typically treated with surgical excision. "While BCC is not associated with high mortality, surgical excision can be a costly and burdensome treatment, particularly for patients who develop multiple BCC lesions," said Sarin.


A potential alternative strategy is to treat BCC with a topical cream. However, existing topical treatments for BCC are only effective for the superficial subtype of BCC, highlighting the need for more widely applicable topical treatments, she noted.


"We found that two-thirds of BCCs treated with the topical cream remetinostat met clinical efficacy endpoints, and half of the tumors completely resolved. Even nodular BCC subtypes, which are recalcitrant to other topical therapies such as topical fluorouracil and photodynamic therapy, demonstrated a clinical response to treatment with remetinostat."


Sarin and colleagues previously identified HDAC inhibition as a promising therapeutic approach for BCC. In their latest study, the researchers evaluated the safety and efficacy of the HDAC inhibitor remetinostat in 30 adult patients with BCC. They reported their results online on August 6, 2021 in Clinical Cancer Research (2021; doi: 10.1158/1078-0432.CCR-21-0560). Unlike systemic HDAC inhibitors, which can be associated with various toxicities, remetinostat is designed to lose potency once it is absorbed beyond the skin, allowing its activity to be localized to the skin lesion.


Study Details

The open-label, single-arm, single-institution, Phase II clinical trial included patients who had at least one BCC measuring 5 mm or greater in diameter at diagnosis. The vast majority (90%) of patients identified as non-Hispanic White, and almost half had a prior history of skin cancer. Eight patients had multiple eligible tumors, resulting in a total of 49 tumors in the study. The tumors were found in both sun-exposed and non-exposed parts of the body, and the majority had either nodular or superficial histology.


Participants applied 1 percent remetinostat gel to their tumors 3 times per day for 6 weeks. After 8 weeks, any remaining tumor was surgically removed and examined histologically. Of the 33 tumors included in the final analysis, 69.7 percent responded to the topical treatment, with 17 complete responses (CRs) and six partial responses (PRs). On average, tumor diameter decreased by 62.3 percent, and tumor area decreased by 71.5 percent.


Responses were observed across multiple BCC subtypes. All six superficial BCC tumors included in the analysis responded, including five CRs and one PR. More than two-thirds (68.2%) of the 22 nodular BCCs responded (10 CRs, five PRs). Two of the three infiltrative BCCs had CRs. No responses were observed in the two tumors of micronodular subtype.


There were no systemic or serious adverse events reported. The most reported adverse event was an eczema-like skin reaction at the site of remetinostat application. Despite a 3-times-a-day dosing regimen, the compliance rate was high, with 25 patients successfully completing the trial.


The mechanisms by which remetinostat achieves its anti-oncologic effect are not fully known. "They are thought to be due to remetinostat's broad effects on altering histone acetylation, thereby modulating the transcription of genes involved in cancer growth and immunity. In addition, inhibition of HDAC1 can interfere with the hedgehog transcription factor, Gli1, blocking its access to chromatin and subsequently the transcription of hedgehog signaling genes, the major driver of BCC growth," said Sarin.


The best candidates for topical therapy are individuals concerned about scarring, have BCCs where surgery could lead to functional morbidity, or who have a high propensity to develop skin cancers and may suffer from surgical morbidity and exhaustion, she said.


"While further research is needed, our results suggest that remetinostat could be a safe and promising alternative to surgical treatment of BCC due to the high rate of complete responses we observed," said Sarin. "However, if a therapy is to replace surgical treatment, it needs to not only induce a complete response, but also a durable one." Future trials will examine the longevity of the response to remetinostat, she noted. "We would like to optimize drug delivery and dosage and conduct a durability study to see if the tumor recurs after discontinuation of the drug.


"Our study also showed remetinostat's clinical efficacy against nodular BCC, one of the more common BCC subtypes," Sarin added. "An ideal therapeutic for BCC should treat both nodular and superficial BCCs, and ideally the other subtypes as well."


Limitations of the study include the small sample size, its single-arm design, and the lack of durability data.


The clinical efficacy of remetinostat has not yet been compared to other treatment methods. "Oral HDAC inhibitors may similarly be effective for BCC, but this has not been explored, largely due to the systemic toxicities seen with oral delivery. Topical delivery enables the drug to get to the tumor with reduced systemic exposure," said Sarin.


In conclusion, the authors stated: "Given the tolerability and clinical and pathologic response rates demonstrated in this trial across several histological subtypes, HDAC inhibitors could be a realistic new class of topical agents for BCC."


Mark L. Fuerst is a contributing writer.