BackgroundAnti-PD-1 immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of melanoma by producing durable long-term responses in a subset of patients. ICI-treated patients develop unique toxicities - immune related adverse events (irAEs) – that arise from unrestrained immune activation. The link between irAE development and clinical outcome in melanoma and other cancers is inconsistent; and little data exists on the occurrence of multiple irAEs. We sought to characterize development of single and multiple irAEs, and association of irAE(s) development with clinical variables and impact upon outcomes in advanced melanoma patients treated with anti-PD-1 ICIs.MethodsWe conducted a retrospective study of 190 patients with metastatic melanoma treated with single-agent anti-PD-1 ICI therapy between June 2014 and August 2020 at a large integrated network cancer center identified through retrospective review of pharmacy records. irAEs were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.Results190 patients were evaluated of whom 114 patients (60.0%) experienced ≥1 irAE, including 30 (15.8%) with grade 3/4 irAEs. The occurrence of any irAE was strongly associated with the development of investigator-assessed response to anti-PD-1 therapy (p < 0.0001); whether evaluated by current (p=0.0082) or best (p=0.0001) response. In patients with ≥2 irAEs, distinct patterns were observed. Median progression-free survival (PFS) and overall survival (OS) were greater in those with any irAE compared to those without (PFS, 28 months vs. 5 months, p < 0.0001; OS, not reached vs. 9 months, p < 0.0001). Development of ≥2 irAEs had a trend towards improved PFS and OS compared to those who developed a single irAE, although this did not reach statistical significance (p=0.2555, PFS; p=0.0583, OS). Obesity but not age or gender was distinctly associated with irAE development.ConclusionsIn this study, we demonstrated that irAE occurrence was significantly associated with response to anti-PD-1 therapy and improved PFS/OS. Those who developed multiple irAEs had a trend towards improved PFS and OS compared to those who developed only a single irAE. Increased BMI but neither age nor gender were associated with irAE development. Distinct patterns of irAEs observed suggest shared etiopathogenetic mechanisms.
e21579 Background: The COVID-19 pandemic has impacted cancer care beyond the direct implications of viral infection. Delays in presentation and diagnosis may lead to more advanced disease and worse patient outcomes. We evaluated the impact of the pandemic on patients (pts) with melanoma (mel). Methods: A single-institution, retrospective comparison of pts with newly diagnosed invasive mel or metastatic recurrence prior to (pre-cohort, n = 246) and after (post-cohort, n = 246) declaration of the COVID-19 pandemic on March 11, 2020. 492 pts were evaluated between March 1, 2019 and January 12, 2021. Key variables collected included demographics, pathology, stage at diagnosis, surgical management, receipt of adjuvant or systemic therapy, and follow up. Categorical variables were compared using the two-sided Fisher’s exact test, continuous variables were compared using the two-sided Wilcoxon rank sum test, and survival endpoints were evaluated with the Kaplan-Meier method. This study was exempt from review by the IRB. Results: 200 (81.3%) pts presented with early-stage disease and 46 (18.7%) pts presented with metastatic disease in the post-cohort, compared to 209 (85%) and 37 (15%) pts in the pre-cohort, respectively. In the post-cohort there was a significant decrease in stage I pts (28.5% vs 40.7%, p = 0.006), a significant increase in stage III pts (30.5% vs 21.1%, p = 0.023), and a significant increase in pts with metastatic recurrence (7.7% vs 3.3%, p = 0.046) compared to the pre-cohort. There was also a significant increase in pts with brain metastases (BM) in the post-cohort (6.5% vs 1.6%, p = 0.010). For pts with early-stage disease, there was a significant increase in median Breslow depth (2.0 vs 1.4 mm, p = 0.047) and mitotic rate > 1 (78.1% vs 66%, p = 0.008) in the post-cohort. There were trends toward increased ulceration, lymphovascular/perineural invasion, and microsatellite presence. Pts receiving adjuvant therapy in the post-cohort were significantly more likely to receive oral targeted therapy (37.6% vs 27.5%) compared to IV immunotherapy (62.4% vs 72.5%), p = 0.034, perhaps reflecting an attempt to minimize in-person visits. There was not a significant difference between the 2 groups in the type of systemic therapy administered in the metastatic setting. Median progression-free and overall survival were not reached due to a limited number of events in each arm. Conclusions: There was a significant decrease in pts with stage I mel along with a significant increase in pts with stage III mel, metastatic recurrence, and BMs presenting to our institution during the pandemic. Findings are likely related to delays from both the patient (to avoid interaction with the healthcare system - including primary care, dermatology, and oncology) and from the system itself, with some clinics potentially evaluating pts in a limited capacity. These data reaffirm the importance of early detection and evaluation of melanoma.
The gut microbiome acts as a tumor-extrinsic regulator of responses to immune-checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors. Primary resistance to anti-PD-1 ICI can be reversed via responder-derived fecal microbiota transplant (FMT) in patients with refractory melanoma. Efforts to create stool banks for FMT have proved difficult. Therefore, we aimed to establish a novel donor-screening program to generate responder-derived FMT for use in PD-1 refractory melanoma. Candidate PD-1 responder donors and PD-1 refractory recipients were recruited via clinic-based encounters at the University of Pittsburgh Medical Center hospitals. Eligible donors and recipients underwent physician assessment and screening of serum, stool and nasopharynx for transmissible agents, which included SARS-CoV-2 modification. The cost of donor and recipient screening was calculated. Initially, 29 donors were screened with 14 eligible donors identified after exclusion; of the 14 donors, eight were utilized in clinical trials. The overall efficiency of screening was 48%. Seroprevalence rates for cytomegalovirus, Epstein-Barr virus, HSV-2, HHV-6, HTLV-1, HTLV-2, and syphilis were similar to published statistics from healthy blood donors in the USA. Donor stool studies indicated a 3.6% incidence of E. histolytica and norovirus, 3.7% incidence of giardia and 7.1% incidence of C. difficile. A single donor tested positive for SARS-CoV-2 in stool only. The cost for finding a single eligible donor was $2260.24 (pre-COVID) and $2,460.24 (post-COVID). The observed screening efficiency suggests that a well-resourced screening program can generate sufficient responder-derived donor material for clinical trial purposes. Eliminating testing for low-prevalence organisms may improve cost-effectiveness.
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