In the Journals

Skin toxicity from anti-PD-1 therapy associated with better melanoma outcomes

Photo of Douglas B. Johnson 2018
Douglas B. Johnson

Patients with advanced melanoma who experienced cutaneous toxic effects during treatment with anti-PD-1 therapy appeared to have better clinical outcomes than patients who did not experience these effects, according to a research letter published in JAMA Oncology.

Specifically, cutaneous toxic effects that developed after 3 months of immunotherapy treatment appeared associated with the best outcomes.

“We do see a correlation between skin toxicity and response [to the therapy], but patients without skin toxicity can still respond,” Douglas B. Johnson, MD, MSCI, assistant professor of medicine, clinical director of the melanoma research program at Vanderbilt University Medical Center, told HemOnc Today. “It is not clear if there is cross reactivity between the tumor and the skin, or if the skin toxicity just indicates a more activated and responsive immune system.”

Checkpoint inhibitors produce antitumor responses and autoimmune toxic effects because they block mediators of immune tolerance. However, it is unknown whether off-target toxic effects indicate that antitumor activity is occurring.

Johnson and colleagues retrospectively studied possible associations between cutaneous toxic effects and clinical responses among patients with advanced melanoma treated with immune checkpoint inhibitors.

Researchers analyzed 318 patients (median age, 63 years; range, 22-89; 63% men) from a single center who received anti-PD-1 therapy with or without ipilimumab (Yervoy, Bristol-Myers Squibb).

Patients with cutaneous toxic effects (n = 120) appeared more likely to have been treated with ipilimumab plus nivolumab (Opdivo, Bristol-Myers Squibb) and previous systemic therapies.

Results showed that these patients, compared with those who did not experience cutaneous toxic effects (n = 198), had better response rates (60% vs. 28.6%; 2 P < .001) and longer median PFS (797 days vs. 112 days; P < .001) and OS (1,691days vs. 526 days; P < .001).

A multivariable regression analysis controlled for age, combination therapy, prior therapy, lactate dehydrogenase levels and sex confirmed the independent association of cutaneous toxic effects and better response rates (OR = 3.58; 95% CI, 2.17-5.9).

Additionally, Johnson and colleagues observed higher response rates in patients with vitiligo or rash compared with patients who had pruritus (75% vs. 64.9% vs. 25%; P = .009).

Patients with vitiligo or rash vs. pruritus also had longer median PFS (974 days vs. 820 days vs. 137 days; P < .001) and OS (not reached vs. 1,691 days vs. 728 days; P = .01).

Results of a multivariate analysis confirmed higher response rates for patients with vitiligo (OR = 7.05; 95% CI, 1.69-29.42) and rash (OR = 4.37; 95% CI, 2.51-7.6), but not pruritus (OR = 0.75; 95% CI, 0.23-2.45) compared with patients without cutaneous toxic effects.

Patients who experienced cutaneous toxic effects after 3 months of anti-PD-1 therapy initiation (n = 41) had better response rates (68.3% vs. 55.7% vs. 28.6%; P < .001), longer PFS (median not reached vs. 383 days vs. 112 days; P < .001) and longer OS (median not reached vs. 1,065 days vs. 526 days; P < .001) than patients with early or no cutaneous toxic effects.

A multivariable analysis confirmed a higher response rate for patients with late toxic events (OR = 5.72; 95% CI, 2.72-12.03) and early toxic effects (OR = 2.75; 95% CI, 1.55-4.89).

Researchers did not observe any significant differences in outcomes among patients with cutaneous toxic effects who received steroids.

“There have been several [melanoma] studies that have suggested that toxicities correlated with a better outcome,” Johnson said. “It is a challenge, though, to untangle the effects of steroid treatment and the effects of [patients who are on therapy longer and have longer exposure/more toxicity].” – by John DeRosier

For more information:

Douglas B. Johnson, MD, MSCI, can be reached at Department of Medicine, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave., Nashville, TN 37232; email: douglas.b.johnson@vumc.org.

Disclosures: Johnson reports advisory roles with Array Biopharma, Bristol-Myers Squibb, Genoptix, Incyte, Merck and Novartis, and research funding from Bristol-Myers Squibb and Incyte. Please see the study for all other authors’ relevant financial disclosures.

Photo of Douglas B. Johnson 2018
Douglas B. Johnson

Patients with advanced melanoma who experienced cutaneous toxic effects during treatment with anti-PD-1 therapy appeared to have better clinical outcomes than patients who did not experience these effects, according to a research letter published in JAMA Oncology.

Specifically, cutaneous toxic effects that developed after 3 months of immunotherapy treatment appeared associated with the best outcomes.

“We do see a correlation between skin toxicity and response [to the therapy], but patients without skin toxicity can still respond,” Douglas B. Johnson, MD, MSCI, assistant professor of medicine, clinical director of the melanoma research program at Vanderbilt University Medical Center, told HemOnc Today. “It is not clear if there is cross reactivity between the tumor and the skin, or if the skin toxicity just indicates a more activated and responsive immune system.”

Checkpoint inhibitors produce antitumor responses and autoimmune toxic effects because they block mediators of immune tolerance. However, it is unknown whether off-target toxic effects indicate that antitumor activity is occurring.

Johnson and colleagues retrospectively studied possible associations between cutaneous toxic effects and clinical responses among patients with advanced melanoma treated with immune checkpoint inhibitors.

Researchers analyzed 318 patients (median age, 63 years; range, 22-89; 63% men) from a single center who received anti-PD-1 therapy with or without ipilimumab (Yervoy, Bristol-Myers Squibb).

Patients with cutaneous toxic effects (n = 120) appeared more likely to have been treated with ipilimumab plus nivolumab (Opdivo, Bristol-Myers Squibb) and previous systemic therapies.

Results showed that these patients, compared with those who did not experience cutaneous toxic effects (n = 198), had better response rates (60% vs. 28.6%; 2 P < .001) and longer median PFS (797 days vs. 112 days; P < .001) and OS (1,691days vs. 526 days; P < .001).

A multivariable regression analysis controlled for age, combination therapy, prior therapy, lactate dehydrogenase levels and sex confirmed the independent association of cutaneous toxic effects and better response rates (OR = 3.58; 95% CI, 2.17-5.9).

Additionally, Johnson and colleagues observed higher response rates in patients with vitiligo or rash compared with patients who had pruritus (75% vs. 64.9% vs. 25%; P = .009).

Patients with vitiligo or rash vs. pruritus also had longer median PFS (974 days vs. 820 days vs. 137 days; P < .001) and OS (not reached vs. 1,691 days vs. 728 days; P = .01).

Results of a multivariate analysis confirmed higher response rates for patients with vitiligo (OR = 7.05; 95% CI, 1.69-29.42) and rash (OR = 4.37; 95% CI, 2.51-7.6), but not pruritus (OR = 0.75; 95% CI, 0.23-2.45) compared with patients without cutaneous toxic effects.

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Patients who experienced cutaneous toxic effects after 3 months of anti-PD-1 therapy initiation (n = 41) had better response rates (68.3% vs. 55.7% vs. 28.6%; P < .001), longer PFS (median not reached vs. 383 days vs. 112 days; P < .001) and longer OS (median not reached vs. 1,065 days vs. 526 days; P < .001) than patients with early or no cutaneous toxic effects.

A multivariable analysis confirmed a higher response rate for patients with late toxic events (OR = 5.72; 95% CI, 2.72-12.03) and early toxic effects (OR = 2.75; 95% CI, 1.55-4.89).

Researchers did not observe any significant differences in outcomes among patients with cutaneous toxic effects who received steroids.

“There have been several [melanoma] studies that have suggested that toxicities correlated with a better outcome,” Johnson said. “It is a challenge, though, to untangle the effects of steroid treatment and the effects of [patients who are on therapy longer and have longer exposure/more toxicity].” – by John DeRosier

For more information:

Douglas B. Johnson, MD, MSCI, can be reached at Department of Medicine, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave., Nashville, TN 37232; email: douglas.b.johnson@vumc.org.

Disclosures: Johnson reports advisory roles with Array Biopharma, Bristol-Myers Squibb, Genoptix, Incyte, Merck and Novartis, and research funding from Bristol-Myers Squibb and Incyte. Please see the study for all other authors’ relevant financial disclosures.

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