Development of a PD-L1 companion diagnostic assay for treatment with MEDI4736 in NSCLC and SCCHN patients.

Rebelatto, Marlon C.; Mistry, Amita; Sabalos, Costi; Walker, Jill; Midha, Anita; Steele, Keith; Robbins, Paul B.; Li, Xia; Shi, Li; Blake-Haskins, John A.; Ibrahim, Ramy; Richman, Laura K.

doi:10.1200/jco.2015.33.15_suppl.8033

Cited by 28 publications

(29 citation statements)

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“…PD-L1 was analysed using the validated Ventana SP263 immunohistochemistry assay optimised for use on the automated BenchMark ULTRA® platform and samples were considered positive if ≥25% of tumour cells demonstrated membrane staining for PD-L1. 15 This cutoff was clinically validated based on the durvalumab monotherapy study in patients with NSCLC or squamous cell carcinoma of the head and neck (SCCHN). 9 The only PD-L1 staining parameter that correlated with response was PD-L1 expression in the membrane of tumour cells, regardless of staining intensity.…”

Section: Methodsmentioning

confidence: 99%

“…The selected cutoff for PD-L1 positivity was based on statistical analysis, distribution, prevalence, and other criteria. 15 In order to explore the antitumour activity of durvalumab plus tremelimumab in more detail in patients with <25% PD-L1 staining, the findings of this study are presented separately for patients with 0% staining, who would be more likely to be considered PD-L1 − regardless of assay or PD-L1 expression cutoff used. See appendix p19 for additional details.…”

Section: Methodsmentioning

confidence: 99%

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Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study

Antonia

Goldberg

Balmanoukian

et al. 2016

The Lancet Oncology

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Background PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC). Methods We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naïve patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947. Findings Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18.8 weeks (IQR 11–33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9–44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3–60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8–58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12–74] of ten patients). Interpretation Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study

Antonia

Goldberg

Balmanoukian

et al. 2016

The Lancet Oncology

Self Cite

562

434

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“…The use of multiple assays with widely varying frequencies of positivity have complicated the interpretation of these data. [99][100][101] Preliminary evidence also suggests that smoking history and a greater mutational burden may correlate with heightened response to anti-PD-L1 agents, 99 …”

Section: Immunological Profilementioning

confidence: 97%

Clinicopathologic Features of Advanced Squamous NSCLC

Socinski

Obasaju

Gandara

et al. 2016

Journal of Thoracic Oncology

126

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Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.

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“…With consent, tumor samples taken at baseline were analyzed for EGFR mutations, including T790M, L858R, exon 19 insertion/deletion, using cobas® EGFR Mutation Test v2 (Roche Molecular Systems, Inc, South Branchburg, NJ). MET gene amplification and PD-L1 expression status were analyzed using FISH (Vysis 7q31 and CEP7 probes, Abbot Molecular Inc, Des Plaines, IL) and immunohistochemical analyses, 15 respectively. Plasma samples were taken at baseline for next-generation sequencing of cell-free DNA (Guardant360, Guardant Health, Redwood City, CA; see supplementary Patients and methods, available at Annals of Oncology online).…”

Section: Study Assessmentsmentioning

confidence: 99%

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

et al. 2020

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Background: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. Patients and methods: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25e75 mg p.o. twice a day; continuous or intermittent), savolitinib (600e800 mg p.o. once a day), or durvalumab (3e10 mg/kg intravenous every 2 weeks). Results: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n ¼ 36), savolitinib (n ¼ 18), or durvalumab (n ¼ 23). Most common adverse events (any grade), occurring in 20% of patients across dose groups, were: selumetinib armddiarrhea (75%), rash (58%), nausea (47%); savolitinib armdnausea (67%), rash (56%), vomiting (50%); durvalumab armdrash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n ¼ 1), 50 mg (n ¼ 1), and 75 mg (n ¼ 4) continuous-dose groups, savolitinib 600 mg (n ¼ 1) and 800 mg dose groups (n ¼ 2), and durvalumab 10 mg/kg (n ¼ 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. Conclusion: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. Clinical trials number: NCT02143466.

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Development of a PD-L1 companion diagnostic assay for treatment with MEDI4736 in NSCLC and SCCHN patients.

Cited by 28 publications

References 0 publications

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study

Clinicopathologic Features of Advanced Squamous NSCLC

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

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