Severe Cutaneous and Neurologic Toxicity in Melanoma Patients during Vemurafenib Administration Following Anti-PD-1 Therapy

Abstract

Immune checkpoint inhibitors such as ipilimumab and targeted BRAF inhibitors have dramatically altered the landscape of melanoma therapeutics over the past few years. Agents targeting the programmed cell death-1/ligand (PD-1/PD-L1) axis are now being developed and appear to be highly active clinically with favorable toxicity profiles. We report two patients with BRAF V600E mutant melanoma who were treated with anti-PD-1 agents as first-line therapy without significant toxicity, followed by vemurafenib at disease progression. Both patients developed severe hypersensitivity drug eruptions with multi-organ injury early in their BRAF inhibitor treatment course. One patient subsequently developed acute inflammatory demyelinating polyneuropathy (AIDP) and the other developed anaphylaxis upon low-dose vemurafenib rechallenge. Further investigation of the immune response during combination or sequences of melanoma therapeutics is warranted. Furthermore, clinicians should maintain a high index of suspicion for these toxicities when vemurafenib is administered following an anti-PD-1 agent.

Coinhibitory Pathways in Immunotherapy for Cancer

“…Conversely, patients who received vemurafenib after ipilimumab or PD-1 blockade experienced pronounced drug hypersensitivity reactions (186,187). High rates of renal toxicity were observed when sunitinib was combined with tremelimumab in metastatic renal cell carcinoma (188), whereas combination of nivolumab with sunitinib or pazopanib appeared to be well tolerated in early studies (189).…”

Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors

“…For these experiments, 10 days after infecting test mice with luciferase-expressing KPC tumor cells, we implanted scaffolds containing 7 × 10 6 NKG2D-CAR + T cells directly onto the resulting temic, these treatments also disrupt immune homeostasis and induce dangerous autoimmune side effects (20)(21)(22). With regard to the problem of tumor heterogeneity, ideally, each patient should be treated with T cells that have been tailored to express CARs aligned to the tumor's protein fingerprint, which would protect these T cells from the emergence of antigen-loss variants.…”

Natural Killer Cells Are Essential for the Ability of BRAF Inhibitors to Control BRAFV600E-Mutant Metastatic Melanoma

“…Thus far, the clinical focus has been to try and improve the curative potential of BRAF V600E inhibitors by combination with T-cell checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1. These combination approaches have surprisingly revealed some new toxicities (36). In contrast, therapies that attempt to improve the antimetastatic activities of BRAF V600E inhibitors by promoting NK cell function have not been rationally explored in the clinic.…”