Lung-cancer incidence has been decreasing in part because of a decrease in smoking. However, the decline in population-based mortality from non–small-cell lung cancer has been greater than can be ...accounted for by cancer screening and a decrease in cancer incidence. Evidence indicates that advances in treatment account for the acceleration in decreased mortality.
Immune checkpoint inhibitor use in oncology is increasing rapidly. We sought to determine the frequency, severity, cause, and predictors of AKI in a real-world population receiving checkpoint ...inhibitors.
We included all patients who received checkpoint inhibitor therapy from May 2011 to December 2016 at Massachusetts General Hospital. Baseline serum creatinine, averaged 6 months before checkpoint inhibitor start date, was compared with all subsequent creatinine values within 12 months of starting therapy. AKI was defined by Kidney Disease: Improving Global Outcomes criteria for fold changes in creatinine from baseline. Sustained AKI events lasted at least 3 days and was our primary outcome. The cause of sustained AKI was determined by chart review. Cumulative incidence and subdistribution hazard models were used to assess the relationship between baseline demographics, comorbidities, and medications, and sustained AKI and potential checkpoint inhibitor-related AKI.
We included 1016 patients in the analysis. Average age was 63 (SD 13) years, 61% were men, and 91% were white. Mean baseline creatinine was 0.9 mg/dl (SD 0.4 mg/dl), and 169 (17%) had CKD (eGFR<60 ml/min per 1.73 m
) at baseline. A total of 169 patients (17%) experienced AKI, defined by an increase in creatinine at least 1.5 times the baseline within 12 months; 82 patients (8%) experienced sustained AKI and 30 patients (3%) had potential checkpoint inhibitor-related AKI. The first episode of sustained AKI occurred, on average, 106 days (SD 85) after checkpoint inhibitor initiation. Sixteen (2%) patients experienced stage 3 sustained AKI and four patients required dialysis. Proton pump inhibitor use at baseline was associated with sustained AKI.
AKI is common in patients receiving checkpoint inhibitor therapy. The causes of sustained AKI in this population are heterogenous and merit thorough evaluation. The role of PPI and other nephritis-inducing drugs in the development of sustained AKI needs to be better defined.
The development of highly effective BRAF‐targeted therapy and immune checkpoint inhibition for patients with advanced metastatic melanoma has transformed the treatment of this disease. More recently, ...these advances have moved into the resected, high‐risk stage II and III settings. For patients with resected, BRAF‐mutant stage III melanoma, there are no head‐to‐head data to support the use of BRAF‐targeted therapy (specifically the combination of dabrafenib and trametinib) with either single‐agent nivolumab or pembrolizumab. Because the relapse‐free and distant metastasis–free survivals are similar in a cross‐trial comparison, it is not clear what the best option for these patients is. In this piece, the authors argue on behalf of and against both approaches.
Plain Language Summary
Two types of therapy exist for patients diagnosed with melanoma who have completed surgery and remain at high risk for tumor recurrence: (1) drugs that target the BRAF mutation (found in ∼50% of patients) and (2) immunotherapy.
There are no data showing that either approach is better than the other, so the choice of which therapy is best for an individual patient can be challenging.
In this article, we make arguments for and against each option.
Highly effective BRAF‐targeted therapy and anti–programmed death receptor 1 therapy are approved in the adjuvant setting to treat resected, high‐risk melanoma. Arguments for and against each approach are made in this Insight From the Experts piece.
Expanding use of immune‐checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune‐related adverse events (irAE‐N). We evaluate the ...real‐world frequency, phenotypes, co‐occurring immune‐related adverse events (irAEs), and long‐term outcomes of severe, grade III to V irAE‐N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE‐N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE‐N reporting are outlined. ANN NEUROL 2020;87:659–669
Purpose of Review
While immune checkpoint inhibitor (ICI) therapy has improved melanoma patient outcomes, it has also resulted in the rise of unique immune-related adverse events (irAEs). Here, we ...review and synthesize irAE management recommendations from several oncological societies into a streamlined format to aid in diagnosis and management. We also include clinical pearls highlighting several recent research studies in this field.
Recent Findings
Knowledge of immunotherapy toxicity has continually evolved, and several major oncologic societies have recently released new or updated guidelines.
Summary
Keeping up with the evolving field of immunotherapy and related toxicities is crucial, because ICI use, in combination with other agents, will only continue to increase and likely result in new and different patterns of irAEs. Providing clear and concise references for clinicians will help ensure proper irAE evaluation and management going forward. We present one such reference here, covering management of common and/or serious irAEs.
Immune checkpoint inhibition has fundamentally altered the treatment paradigm of resectable and unresectable melanoma, resulting in dramatic improvements in patient outcomes. With these advances, the ...five-year overall survival in patients with newly diagnosed unresectable disease has eclipsed 50%. Ongoing research is focused on improving outcomes further, with a considerable emphasis on preventing de novo and acquired resistance and personalizing therapeutic options. Here, we review the ongoing advancements in the treatment of malignant melanoma, focusing on novel combination strategies that aim to build upon the successes of the last decade.
OBJECTIVETo describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs).
METHODSPatients with ICI-related neuropathy (irNeuropathy) were ...identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents.
RESULTSWe identified 19 patients with irNeuropathies. ICIs included anti-programmed death–1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy.
CONCLUSIONNeuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.
Background
Combined BRAF and MEK inhibition (BRAF‐MEK) is a standard therapy for patients with BRAF V600–mutant melanoma, but to the authors’ knowledge, the tolerance, adverse event (AE) profile, and ...efficacy have not been well defined in the post–programmed cell death protein 1 (PD‐1) setting.
Methods
Patients with BRAF V600–mutant melanoma who received combined BRAF‐MEK after prior PD‐1–based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan‐Meier methods from the time of the initiation of BRAF‐MEK therapy.
Results
A total of 78 patients were identified as having received a BRAF‐MEK regimen at a median of 34 days after the last dose of PD‐1–based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty‐five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF‐MEK <90 days after the last dose of PD‐1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE‐related hospitalization. Among 55 BRAF‐naive patients, the median time receiving BRAF‐MEK therapy was 5.8 months and the median OS was 15.6 months.
Conclusions
The majority of patients receiving BRAF‐MEK inhibition after PD‐1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.
The efficacy and tolerance of BRAF‐MEK inhibition in patients with melanoma has been defined in trials conducted prior to the advent of frontline programmed cell death protein 1 (PD‐1) blockade. In the current retrospective analysis of patients who experienced disease progression while receiving PD‐1–based therapy, dose modifications are frequent and efficacy appears to be lower compared with previously published prospective trials.
Purpose of Review
This report highlights several of the recent therapeutic advancements in the treatment of
BRAF
-mutant tumors, discusses the most common adverse events observed with
BRAF
-targeted ...agents, and suggests strategies to manage and mitigate treatment-related toxicities.
Recent findings
BRAF and MEK inhibitors represent a significant advancement in the treatment of
BRAF
-mutated malignancies with data across tumor types demonstrating the anti-tumor efficacy of dual MAPK inhibition. Although these agents have a reasonable toxicity profile, variable side effects across organ systems can develop.
Summary
The discovery of activating BRAF mutations and subsequent development of BRAF and MEK inhibitors has transformed the treatment algorithms of
BRAF
-mutant malignancies. With increased application of these targeted regimens, identification and prompt management of their unique adverse events are crucial.
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