Optimal design and endpoint of clinical trials using immune checkpoint blocking agents

Keam, Bhumsuk; Jung, Hun; Nam, Byung Ho

doi:10.1080/14737140.2016.1248945

Cited by 4 publications

(5 citation statements)

References 12 publications

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“…Because of this unique feature, the milestone PFS rate at specific late time point (that is, durable control) better reflects the benefit of PD-1 blockade. [4][5][6][7] Although debate exists, 7 cancer cell expression of PD-L1 as measured by immunohistochemistry (IHC) or T-cell infiltration has been suggested as a biomarker predicting response before treatment begins. 22 In our data of real clinical practice, there were only 7 patients that had accessible record of PD-L1 IHC measurement.…”

Section: Discussionmentioning

confidence: 99%

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Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer

Kim

Lee

et al. 2017

OncoImmunology

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Drugs that blockade interaction between programmed cell-death protein 1 (PD-1) and its ligand (PD-L1) are promising. Immune-related adverse events (irAEs) might be associated with favorable clinical outcomes, and thyroid dysfunction is one of the most common irAE. We evaluated the association of thyroid dysfunction during PD-1 blockade with the treatment efficacy in patients with non-small cell lung cancer (NSCLC). A total 58 patients with stage IV NSCLC treated with PD-1 blockade were enrolled. Patients were categorized into thyroid dysfunction and euthyroid groups. Overall survival (OS) and progression-free survival (PFS) of the two groups were compared. Patients, tumor, and medication factors were adjusted using Cox proportional hazard modeling. Objective response rate (RR) and durable control rate were assessed according to the severity of thyroid dysfunction. OS [median 118.0 (73.0-267.0) vs. 71.0 (28.0-160.0) days, log-rank = 0.025] and PFS [118.0 (73.0-267.0) vs. 61.0 (28.0-130.0), log-rank = 0.014] were longer in the thyroid dysfunction group. After adjustment, thyroid dysfunction was an independent predictive factor for favorable outcome [adjusted HR = 0.11 (95% CI) 0.01-0.92 for overall death; 0.38 (0.17-0.85) for disease progression]. The severity of thyroid dysfunction was associated with durable control rate ( for trend = 0.008). Thyroid dysfunction during PD-1 blockade is associated with treatment response and could provide supplementary information for immune monitoring in patients with advanced NSCLC.

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Section: Discussionmentioning

confidence: 99%

“…3 Compared to molecular targeted agents, the response rate to PD-1 blockade is low (15-30%), but also maintained for a long period of time. [4][5][6][7] Programmed cell-death protein ligand 1 (PD-L1) has been known as a biomarker which is associated with favorable clinical response, but the measurement is not widely available.…”

Section: Introductionmentioning

confidence: 99%

Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer

Kim

Lee

et al. 2017

OncoImmunology

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“…The efficacy and safety of ICI differs from cytotoxic chemotherapy or molecular-targeted agents. 5 No correlation has been observed between dose and efficacy in phase I clinical trials with ICIs, and no dose–toxicity relationship has been evident. The maximal tolerated dose (MTD) for nivolumab has not been identified, and a similar safety profile has been demonstrated across tumour types and dose levels (0.1–10 mg/kg).…”

Section: Introductionmentioning

confidence: 99%

Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity

et al. 2018

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ObjectivesNivolumab is used at 3 mg/kg or fixed doses of 240 mg every 2 weeks. There was no dose–response/toxicity relationship of nivolumab. This study evaluated the efficacy of low-dose nivolumab as an alternative to the financial toxicity of standard-dose nivolumab in treatment of non-small cell lung cancer (NSCLC).MethodsOutcomes of patients with NSCLC treated with nivolumab as a routine practice at two tertiary hospitals in Korea were retrospectively analysed. Patients who could not afford standard nivolumab treatment received low-dose nivolumab (20 or 100 mg fixed dose every 3 weeks). Others received standard dose of 3 mg/kg every 2 weeks. Progression-free survival (PFS) and overall survival (OS) were measured and compared between low-dose and standard-dose groups in overall and stratified analyses according to programmed death-ligand 1 (PD-L1) status.ResultsAmong the 47 patients with NSCLC, 18 received low-dose nivolumab. PD-L1 positivity was observed in 13 (27.7%) patients and did not differ between the groups. During 5.2 months of follow-up, the objective response rate was 13.8% in the standard-dose group and 16.7% in the low-dose group (p=0.788). Dosing of nivolumab or PD-L1 expression did not significantly affect PFS or OS.ConclusionLow-dose nivolumab can be effective in NSCLC and is worth considering as an alternative option to reducing financial toxicity. The efficacy of low-dose nivolumab requires study.

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“…ICIs influence Tcells to selectively identify cancer cells and indirectly potentiate their attack on cancer cells. 4 ICIs have shown no correlation between dose and efficacy or dose and toxicity in initial phase I trials. The studies were not able to recognize the maximal tolerated dose (MTD) for nivolumab and at various dose levels ranging from 0.1 to 10 mg/kg, there is no difference in safety profile.…”

Section: Introductionmentioning

confidence: 99%

“…ICIs influence T-cells to selectively identify cancer cells and indirectly potentiate their attack on cancer cells. 4…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Low-Dose Nivolumab in Treatment of Advanced Solid Tumors: A Retrospective Audit from Resource-Constrained Settings

Kumar,

Kapoor,

Noronha

et al. 2024

South Asian J Cancer

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Background Immunotherapy has improved outcomes in many advanced solid tumors. In resource-constrained settings, less than 2% of patients can afford standard dose immunotherapy. A recent phase II study showed the efficacy of low-dose immunotherapy in this setting. We used low-dose immunotherapy on a compassionate basis in patients who had progressed on available standard treatment options and standard dose immunotherapy was not feasible. Patients and Methods We retrospectively collected data from the medical oncology department for consecutive patients who had initially received standard lines of therapy followed by low-dose immunotherapy (nivolumab 40 mg) on a compassionate basis. The demographic details, histology, prior treatment, clinical and radiological response, date of disease progression, date of death, and toxicity data were collected. Results A total of 54 consecutive patients, who received low-dose immunotherapy with nivolumab from January 1, 2018 to February 14, 2020, were included in this analysis; 4 patients were not radiologically evaluable. The median age was 50.4 years (range 35–74 years), male:female ratio was 6:1. The most common comorbidities were hypertension and diabetes seen in 12 (22.2%) and 6 (11.1%) patients, respectively. The majority of the patients (70.4%) were of head and neck cancer. The median follow-up was 4.5 months (range 0.5–11.7). Clinical benefit was observed in 18 (33.3%) patients. Partial response and stable disease were achieved in 9 (16.7%) and 5 (9.3%) patients, respectively. Median survival was not reached for these patients. Six months progression-free survival and overall survival were 100 versus 8.7% (hazard ratio [HR] 0.05, 95% confidence interval [CI]: 0.01–0.36; p = 0.003) and 100 versus 29.7% (HR 0.03, 95% CI: 0.00–0.95; p = 0.047), respectively, for responders and nonresponders. The side effects were manageable. Conclusion In resource-constrained settings, low-dose immunotherapy with nivolumab seems to be an effective treatment option. Further studies are warranted to evaluate this approach.

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Optimal design and endpoint of clinical trials using immune checkpoint blocking agents

Cited by 4 publications

References 12 publications

Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer

Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer

Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity

Efficacy and Safety of Low-Dose Nivolumab in Treatment of Advanced Solid Tumors: A Retrospective Audit from Resource-Constrained Settings

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