Durable Clinical Benefit in Metastatic Renal Cell Carcinoma Patients Who Discontinue PD-1/PD-L1 Therapy for Immune-Related Adverse Events

Abstract

The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti-PD-1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7-46.5) and median TTP was 18.4 months (95% CI, 4.7-54.3) per Kaplan-Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients ( = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% ( = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti-PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti-PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. .

The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced‐stage cancer treated with immunotherapy

“…1,2 In total, 6 IO agents targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (ipilimumab), programmed cell death 1 (PD-1) (nivolumab and pembrolizumab), or programmed cell death ligand 1 (PD-L1) (atezolizumab, avelumab, and durvalumab) gained US Food and Drug Administration approval as of January 2018. 1,2 In total, 6 IO agents targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (ipilimumab), programmed cell death 1 (PD-1) (nivolumab and pembrolizumab), or programmed cell death ligand 1 (PD-L1) (atezolizumab, avelumab, and durvalumab) gained US Food and Drug Administration approval as of January 2018.…”

“…Immunotherapy (IO) has emerged as a treatment option for patients with a variety of malignancies because of the potential for durable clinical benefit and favorable toxicity profile. 1,2 In total, 6 IO agents targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (ipilimumab), programmed cell death 1 (PD-1) (nivolumab and pembrolizumab), or programmed cell death ligand 1 (PD-L1) (atezolizumab, avelumab, and durvalumab) gained US Food and Drug Administration approval as of January 2018. 3 There are several other IO agents currently under development.…”

Cancer outcomes in patients requiring immunosuppression in addition to corticosteroids for immune‐related adverse events after immune checkpoint inhibitor therapy

“…There has been significant interest in the relationship between irAEs and cancer outcomes. Several case series have demonstrated ongoing clinical benefit, and perhaps even a heightened response, from checkpoint inhibitor therapy despite cessation for irAEs . The largest of these, a case series from the Memorial Sloan Kettering Cancer Centre, reported on the outcomes of 103 patients who received corticosteroids or additional immunosuppressive medications to treat irAEs.…”

“…Several case series have demonstrated ongoing clinical benefit, and perhaps even a heightened response, from checkpoint inhibitor therapy despite cessation for irAEs. [7][8][9][10][11][12] The largest of these, a case series from the Memorial Sloan Kettering Cancer Centre, reported on the outcomes of 103 patients who received corticosteroids or additional immunosuppressive medications to treat irAEs. In their series, 31 steroid-refractory patients received TNF inhibitors or mycophenolate for immune-related adverse effects secondary to ipilimumab, without a discernible impact on time to treatment failure (TTF) or overall survival (OS).…”

Novel risk group stratification for metastatic urothelial cancer patients treated with immune checkpoint inhibitors

“…Immune checkpoint inhibitors (ICI) have emerged as promising treatment options for patients with various primary cancer histologies including melanoma, lung cancer, renal cell carcinoma, and urothelial cancer (UC). ICI agents have a tolerable toxicity profile and offer the promise of durable responses . Several ICI agents have been approved over the past 4 years by the FDA for treatment of patients with metastatic UC, including nivolumab, atezolizumab, pembrolizumab, avelumab, and durvalumab …”