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Older Age Correlates With Better Response to Anti-PD-1 Therapy in Melanoma

Jason Harris
Published Online:3:03 PM, Wed July 18, 2018

Ashani Weeraratna, PhD

Patients aged ≥62 years with melanoma were more likely to respond to treatment with pembrolizumab (Keytruda) than younger patients, according to results published in Clinical Cancer Research. Investigators at The Wistar Institute in Philadelphia concluded that the risk for progression following anti-PD–1 therapy declined by 13% with each decade of life.

“Our study shows that age is an important factor to consider when administering immunotherapy to melanoma patients,” corresponding author Ashani Weeraratna, PhD, the Ira Brind associate professor and co-program leader of the Immunology, Microenvironment, and Metastasis Program at Wistar, said in a release. “A combination approach to deplete immune suppressive cells in combination with checkpoint blockade therapy might benefit younger patients, although further studies will be required to evaluate more broadly the potential immune toxicities of this approach.”

Investigators collected samples from 538 patients, 300 aged ≥62 years and 238 aged <62 years, who were treated with pembrolizumab for primary or metastatic melanoma at 7 medical centers in the United States. Among the younger patients, 48% derived no benefit from treatment compared with 37% of the older cohort.1

Overall, the complete response (CR) rate was 15% in older patients. Forty-eight percent had stable disease and 37% had progression. In patients <62 years, the CR rate was 13%, with a stable disease rate of 38% and a progressive disease rate of 48%.

Prior treatment with MAPK inhibitors did not affect the association between age and treatment response even though the use of such agents was more common in younger patients. The median age for MAPK use was 59 years, while the median age for patients who were MAPK-naïve was 64 years. However, among patients who received MAPK inhibitors, patients younger than 64 years had a much lower rate of CR (4% vs 15%).

Investigators then conducted a similar experiment on BSC9AJ2 tumors in female mice aged 2 months and those aged 10 months to see if the age-related difference could be replicated.

Compared with mice treated with the IgG2AK control, younger mice treated with anti–PD-1 therapy did not see a significant reduction in tumor growth. Older mice “had a modest but significant reduction in tumor growth” after receiving the same dose of anti–PD-1 therapy.

The results were reproduced in male mice, and investigators added that the results were not dependent on tumor burden—young and old mice received genetically identical tumors.

Previous study results have showed that treatment combinations that include immune checkpoint inhibitors can cause lethal inflammation in elderly mice. However, investigators conducting this study did not record any significant distress or weight loss in the study animals.

Investigators concluded that a decrease in CD4-positive and FOXP3-positive regulatory T cells (Tregs), an immunosuppressive subpopulation of T cells, in tumors in the older animals was the major difference in the immune microenvironment between young and old mice. “It is important to note that these ratios are not reflected in other organs such as the spleen, where in fact, Tregs are elevated, consistent with data from other aging studies,” they wrote.

Weeraratna and her team then analyzed an independent cohort of 268 samples for FOXP3 immunohistochemistry (IHC) positivity and 84 samples for CD4/CD8 IHC positivity. They found that presence of intratumoral FOXP3+ cells declines after age 50 years. They also found that younger patients were more likely to have immune infiltrate containing >20% killer CD8+ cells, and noted that patients who progress on PD1 therapy have been observed to have lower numbers of CD8+ T cells. As expected, patients younger than 66 years had a significantly lower percent of CD8+ T cells.

Based on these observations, investigators used an antibody against CD25 to deplete Treg cells and improve the ratio of CD8+ to Treg in the young mice. Anti-CD25 delayed tumor growth, but the combination of anti-CD25 and anti-PD–1 therapies induced response rates comparable to what was observed in older mice. Furthermore, the combination was tolerable and did not induce distress or weight loss.

“Our results suggest that reconditioning the tumor microenvironment in younger patients by depleting Tregs could make them respond to anti-PD1 immunotherapies better,” Weeraratna said.

“Our studies suggest that in designing therapies for melanoma, age should be considered as a factor in both preclinical and clinical models,” she added. “A combination approach to deplete immune suppressive cells in combination with checkpoint blockade therapy might benefit younger patients, although further studies will be required to evaluate more broadly the potential immune toxicities of this approach.”

This report from Weeraratna et al is not the first report published this year suggesting that older patients derive greater benefit from immunotherapy. French investigators found that patients aged ≥65 years had better overall survival (OS) and progression-free survival (PFS) than younger patients following treatment with pembrolizumab, ipilimumab (Yervoy), or nivolumab (Opdivo).2

First author Marie Perier-Muzet, MD, and colleagues conducted a retrospective analysis of 92 patients treated for metastatic melanoma at the Centre Hospitalier Lyon Sud from January 2007 to February 2016. Fifty-four patients were aged ≤65 years and 38 were aged >65 years.

Patients received a total of 120 lines of treatment. Mean follow-up was 12.5 months.

PFS (4.8 vs 3.4 months; P =.04) and OS (not reached vs 10.1 months; P .009) favored older patients treated with ipilimumab and anti–PD-1. Age was independently associated with outcome on multivariate analysis.

“This association between older age and a better prognosis was independent of other prognosis covariates, and was stronger for patients treated with anti–PD-1 compared with patients treated with ipilimumab,” investigators wrote.

Older patients had more comorbidities, but investigators found no difference in the incidence or severity of immune adverse events (AEs) between the 2 groups.

The older group had a longer median time to first AE (7.0 vs 5.5 months), but were more likely to experience diarrhea enterocolitis (17% vs 28%).

“In this real-life, single-institution retrospective study, an age greater than 65 years was not associated with more IAEs in patients treated by immunotherapy for metastatic melanoma, confirming that age should not be a limiting factor for immunotherapy,” wrote Perier-Muzet and colleagues.

A poster presented at the 2018 ASCO-SITC Clinical Immunological Symposium found that patients with melanoma ≥65 years had similar efficacy and safety outcomes as younger patients.3

Investigators at the University of Arkansas Melanoma Oncology Service conduced a retrospective analysis of 60 patients, 29 aged >65 years and 31 aged ≥65 years, treated for stage IV melanoma at that institution from January 2012 to December 2016. All patients received at least 1 dose of pembrolizumab, ipilimumab, or nivolumab, or a combination of ipilimumab and nivolumab.

After adjusting for gender, disease type, and the presence of brain metastasis, investigators found no significant differences in time to progression (HR, 0.79; 95% CI, 0.37-1.70; P = 0.46) or OS (HR, 0.75; 95% CI, 0.31-1.82; P = 0.491) between the 2 age groups. The 2 groups were comparable for overall incidence of immunotherapy-related AEs, 45% in the older patients compared with 62% in the younger patients (P = 0.19).

The median age for the 30 patients who responded to treatment was 66.9 years (range, 54.3-73.3) compared with 62.7 years (range, 54-69.1) for 30 nonresponders. Nonresponders were less likely to have immunotherapy-related AEs (40% vs 66.7%; P = 0.04) and more likely to have BRAF mutations (53.3% vs 27.6%; P = 0.04) irrespective of age.

A team of researchers with the Italian Melanoma Intergroup presented data at ASCO this year showing that, compared with previously reported findings, anti–PD-1 treatment was effective and well tolerated in a late elderly patient population (n = 161). The median patient age was 79 years (range, 75-93).4

Francesco De Rosa, MD, with the Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori in Medola, Italy, and colleagues retrospectively analyzed data on patients who were treated with either nivolumab (n = 88) or pembrolizumab (n = 73) for a variety of advanced melanomas. A total of 110 (68%) patients had multiple comorbidities, including 25 with a history of other cancers.

Fourteen (8.7%) patients had CR and 44 (27.3%) had partial response. The overall disease control rate was 54.6%.

The median OS was 17.18 months. The survival curve plateaued around 20 months, and investigators said that roughly one-third of patients derived a long-term benefit from treatment.

There were no treatment-related deaths in the study. Investigators recorded 3 grade 4 AEs and 2 grade 3 AEs. Twenty-nine patients had grade 1/2 AEs. De Rosa et al said those events did not require the use of additional immunosuppressive agents and were managed with corticosteroids.

De Rosa et al concluded based on these results that elderly patients with advanced melanoma should have access to immunotherapy agents.
 
 
References:
  1. Kugel CH, Douglass SM, Webster MR, et al. Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations [published online July 13, 2018]. doi: 10.1158/1078-0432.CCR-18-1116.
  2. Perier-Muzet M, Gatt E, Péron J, et al. Association of immunotherapy with overall survival in elderly patients with melanoma. JAMA Dermatol. 2018;154(1):82-87. doi:10.1001/jamadermatol.2017.4584.
  3. Joshi KP, Atwal D, Ravilla R, et al. Outcomes of immunotherapy in advanced melanoma in relation to age. J Clin Oncol. 36, 2018 (suppl 5S; abstr 187).
  4. De Rosa F, Ridolfi L, Tanda ET, et al. Anti-PD1 antibodies in late elderly advanced melanoma patients: A retrospective multicentre study. J Clin Oncol. 36, 2018 (suppl; abstr 10038).


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