Measuring Toxic Effects and Time to Treatment Failure for Nivolumab Plus Ipilimumab in Melanoma

Shoushtari, Alexander N.; Friedman, Claire F.; Navid-Azarbaijani, Pedram; Postow, Michael A.; Callahan, Margaret K.; Momtaz, Parisa; Panageas, Katherine S.; Wolchok, Jedd D.; Chapman, Paul B.

doi:10.1001/jamaoncol.2017.2391

Cited by 139 publications

(124 citation statements)

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“…Finally, the endpoint was TTF, which is slightly more subjective than the more commonly reported PFS or overall response rate (ORR). Indeed, PFS or ORR would be preferred measures of treatment efficacy in the prospective setting, but retrospective assessment of these outcomes is fraught with challenges, especially when Response Evaluation Criteria for Solid Tumors (RECIST)‐defined or Immune‐Related RECIST (irRECIST)‐defined progression are not recorded, as in our institutional database . Other studies have found that the baseline NLR was associated with PFS and/or ORR in patients with melanoma who received treatment with a checkpoint inhibitor, but it remains to be determined whether a change in the NLR during treatment would be similarly associated.…”

Section: Discussionmentioning

confidence: 99%

“…OS was the primary outcome and was calculated from the date of the first dose of PD‐1 inhibitor monotherapy until death or the date of last follow‐up. The time to treatment failure (TTF) was defined as the interval between the date of the first dose of PD‐1 inhibitor and the earliest occurrence of either clinical progression, initiation of new therapy (local or systemic), or death …”

Section: Methodsmentioning

confidence: 99%

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High neutrophil‐to‐lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD‐1 inhibitor monotherapy

Bartlett

Flynn

Panageas

et al. 2019

Cancer

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113

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Background An elevated neutrophil‐to‐lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD‐1 inhibition. Methods Patients undergoing initial treatment with PD‐1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan‐Meier and landmark analyses. Results Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow‐up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3‐2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2‐2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P < .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months). Conclusions Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD‐1 inhibitor monotherapy. Combined, these biomarkers can widely risk‐stratify patients for treatment failure and survival.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

High neutrophil‐to‐lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD‐1 inhibitor monotherapy

Bartlett

Flynn

Panageas

et al. 2019

Cancer

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113

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“…7,8 This is in contrast to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor occupancy, which is believed to last on the order of several weeks. 7,8 This is in contrast to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor occupancy, which is believed to last on the order of several weeks.…”

Section: Introductionmentioning

confidence: 99%

Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1‐based therapy

Saab

Mooradian

Wang

et al. 2018

Cancer

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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 postprogrammed 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. Cancer 2019;125:884-891.

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“…Unfortunately, existing data also indicate a marked increase in the risk of serious treatment-related side effects associated with such drug combination approaches [1-3]. …”

mentioning

confidence: 99%

“…Centers with considerable experience dealing with the side effects associated with the delivery of combination checkpoint inhibitors have noted a high risk of serious toxicity, including required hospitalizations and emergency room visits [3]. However, it can be anticipated that when patients are treated in the real-world setting outside the realm of clinical trials (e.g., older patients, patients with existing clinically relevant comorbidities, etc.)…”

mentioning

confidence: 99%

A Cautionary Note: “Real-World” Toxicity of Checkpoint Inhibitors

Markman

2018

Oncology

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Measuring Toxic Effects and Time to Treatment Failure for Nivolumab Plus Ipilimumab in Melanoma

Cited by 139 publications

References 8 publications

High neutrophil‐to‐lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD‐1 inhibitor monotherapy

High neutrophil‐to‐lymphocyte ratio (NLR) is associated with treatment failure and death in patients who have melanoma treated with PD‐1 inhibitor monotherapy

Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1‐based therapy

A Cautionary Note: “Real-World” Toxicity of Checkpoint Inhibitors

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