Skin cancers

Ethnicity influences outcomes of immunotherapy in melanoma


Ethnicity plays a role in both response and toxicity to immunotherapy in patients with advanced melanoma beyond the known discrepancies due to melanoma subtype.

According to a study published in the British Journal of Dermatology, most clinical trial data for anti-PD-1 therapies comes from predominantly white populations.

The study therefore compared the clinical benefit and irAEs with anti-PD-1 monotherapy in a cohort of white versus East Asian, Hispanic and African patients from five melanoma centres across Australia, China and the USA.

The retrospective study of 1,135 patients with advanced melanoma treated between 2009 and 2019 found white patients were more likely to have nonacral and unknown primary melanomas than other patients (87% v 43%).

“Among the entire cohort, white patients had significantly better clinical outcomes than East Asian, Hispanic and African patients,” it said.

White patients had significantly higher objective response rate than the East Asian, Hispanic and African patients across the entire cohort (49% v 17%) and the nonacral and unknown primary subtypes (54% v 20%, P <0.0001].

Progression-free survival was also longer in white versus other patients for the entire cohort (9.2 v 4.1 months) and for the nonacral and unknown primary subtypes (14.2 v 5.4 months, P < 0.0001).

“Specifically, white patients had a higher ORR (odds ratio 4.10, 95% CI 248–681; nominal P < 0001, adjusted P < 0001) and a longer PFS (hazard ratio 0.58, 95% CI 046–074; nominal P < 0001, adjusted P < 0001),” the study said.

No significant difference in ORR or PFS was observed between ethnicities in the acral, mucosal and uveal melanoma subtypes.

The researchers, including Professor Georgina Long and Associate Professor Alexander Menzies from the Melanoma Institute Australia, said different levels of eumelanin expression and the resulting variation in mutational burden between ethnicities might contribute to the ethnic discrepancy observed in the nonacral and unknown primary melanoma subtypes.

“Based on our study, in tumours with low TMB like acral, mucosal and uveal melanomas, ethnicity plays a less prominent role because the mechanisms of response to PD-1 blockade are independent of UV-induced mutational burden,” the study authors said.

Associate Professor Menzies told the limbic that race was just one of many factors taken into account when applying clinical trial level data to the individual patient situation.

“We’ve known for a long time that biologically, mucosal melanoma is really different to cutaneous melanoma. Genetically it’s different and absolutely the chance of responding to our current drugs is very different.”

“Asian patients with cutaneous melanoma are also not responding as well either and we think that is mainly due to…many Caucasians are older and have chronic sun damage, lots of SCCs and BCCs …and when they get a melanoma, it looks more foreign to the immune system and therefore the immunotherapy works better.”

Toxicity

The study found the overall incidence of irAEs was similar between ethnicities (both 55%) but the incidence of some subtypes of irAEs varied.

For example, white patients had a significantly higher incidence of GI (9% v 2%), respiratory (8% v 1%) and grade 3/4 (12% v 7%) irAEs than East Asian, Hispanic and African patients.

However white patients had a lower incidence of endocrine (11% v 23%), liver (4% v 13%) and other rare types of irAEs (8% v 13%).

“The differences in irAEs by ethnicity were not attributable to varying melanoma subtypes,” the study said.

Associate Professor Menzies said some of the variation in apparent toxicity may also be driven by the country and centre where patients were treated, and their level of experience and expertise at managing irAEs.

The study concluded the novel response and survival data for patients with different ethnicities should directly impact the discussion of the risks and benefits of PD-1 blockade for patients.

“Furthermore, the knowledge gained in this report may inform surveillance for toxicity in these distinct patient populations.”

In terms of further research, Associate Professor Menzies said race was part of a broader question about how to personalise therapy better.

“Now that we have a number of immunotherapy options available, how can we not only look at likely responses to treatment but also best choose up-front the right tailored treatment for each patient.”

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