Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer

Blumenthal, Gideon M.; Gong, Yutao; Kehl, Kenneth L.; Mishra‐Kalyani, Pallavi S.; Goldberg, Kirsten B.; Khozin, Sean; Kluetz, Paul G.; Oxnard, Geoffrey R.; Pazdur, Richard

doi:10.1093/annonc/mdz060

Cited by 110 publications

(121 citation statements)

References 33 publications

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“…Recently, TTF has been found to correlate with progression-free survival in clinical trials. 78 In conclusion, this study supports the use of afatinib for the treatment of tumors harboring several uncommon mutation categories: (1) major uncommon mutations; (2) compound mutations, especially those including a major uncommon mutation; and (3) perhaps certain uncommon mutations in the "other" category and certain exon 20 insertions. These categories require further clinical evaluation to identify specific mutation subtypes that may be sensitive.…”

Section: May 2020supporting

confidence: 69%

Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases

Yang

Schüler

Popat

et al. 2020

Journal of Thoracic Oncology

201

198

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Introduction: Limited clinical data are available regarding the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) in patients with NSCLC harboring uncommon EGFR mutations. This pooled analysis assessed the activity of afatinib in 693 patients with tumors harboring uncommon EGFR mutations treated in randomized clinical trials, compassionate-use and expanded-access programs, phase IIIb trials, noninterventional trials, and case series or studies. Methods: Patients had uncommon EGFR mutations, which were categorized as follows: (1) T790M; (2) exon 20 insertions; (3) "major" uncommon mutations (G719X, L861Q, and S768I, with or without any other mutation except T790M or an exon 20 insertion); (4) compound mutations; and (5) other uncommon mutations. Key end points were overall response rate (ORR), duration of response, and time to treatment failure (TTF). Results: In EGFR TKI-naive patients (n ¼ 315), afatinib demonstrated activity against major uncommon mutations (median TTF ¼ 10.8 mo; 95% confidence interval [CI]: 8.1-16.6; ORR ¼ 60.0%), compound mutations (median TTF ¼ 14.7 mo; 95% CI: 6.8-18.5; ORR ¼ 77.1%), other uncommon mutations (median TTF ¼ 4.5 mo; 95% CI: 2.9-*Corresponding author.

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Section: May 2020supporting

confidence: 69%

Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases

Yang

Schüler

Popat

et al. 2020

Journal of Thoracic Oncology

201

198

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“…Because it was not possible to assess dates of disease progression with the available data, time to treatment discontinuation (TTD) and time from 1L treatment initiation to 2L discontinuation or death were included; these measures were previously shown to be real-world proxies for progression-free survival (PFS) (Blumenthal et al 2019; European Medicines Agency 2017). TTD was defined as the interval between 1L treatment initiation and discontinuation for any reason (including death).…”

Section: Discussionmentioning

confidence: 99%

“…IO-based regimens were associated with longer TTD than chemotherapies and targeted therapies, which might be due to better tolerability of IO therapies. Blumenthal et al (2019) reviewed 18 randomized clinical trials conducted after 2007 in patients with metastatic NSCLC. They found a TTD of 3.5 months with immune checkpoint inhibitors compared with 3.8 months with chemotherapy doublet monotherapy and 2.2 months with chemotherapy monotherapies.…”

mentioning

confidence: 99%

Treatment patterns and clinical outcomes in patients with advanced non-small cell lung cancer initiating first-line treatment in the US community oncology setting: a real-world retrospective observational study

Nadler

Arondekar

Aguilar

et al. 2020

J Cancer Res Clin Oncol

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Purpose Treatments for advanced non-small cell lung cancer (NSCLC) have evolved to include targeted and immuno-oncology therapies, which have demonstrated clinical benefits in clinical trials. However, few real-world studies have evaluated these treatments in the first-line setting. Methods Adult patients with advanced NSCLC who initiated first-line treatment with chemotherapy, targeted therapies (TT), or immuno-oncology–based regimens in the US Oncology Network (USON) between March 1, 2015, and August 1, 2018, were included and followed up through February 1, 2019. Data were sourced from structured fields of USON electronic health records. Patient and treatment characteristics were assessed descriptively, with Kaplan-Meier methods used to evaluate time-to-event outcomes, including time to treatment discontinuation (TTD) and overall survival (OS). Adjusted Cox regression analyses and inverse probability of treatment weighting (IPTW) were performed to control for covariates that may have affected treatment selection and outcomes. Results Of 7746 patients, 75.6% received first-line systemic chemotherapy, 11.7% received immuno-oncology monotherapies, 8.5% received TT, and 4.2% received immuno-oncology combination regimens. Patients who received immuno-oncology monotherapies had the longest median TTD (3.5 months; 95% confidence interval [CI], 2.8–4.2) and OS (19.9 months; 95% CI, 16.6–24.1). On the basis of multivariable Cox regression and IPTW, immuno-oncology monotherapy was associated with reduced risk of death and treatment discontinuation relative to other treatments. Conclusion These results suggest that real-world outcomes in this community oncology setting improved with the introduction of immuno-oncology therapies. However, clinical benefits are limited in certain subgroups and tend to be reduced compared with clinical trial observations.

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“…TTD, defined as the time from treatment start to treatment discontinuation for disease progression or death, was chosen as the primary endpoint because of the variation in timing and modality of restaging imaging in the real-world setting prior to referral for phase I clinical trials. 36 TTD was analysed using the Kaplan-Meier method (JR, KRH). The R software packages ‘survival’ and ‘survminer’ were used for statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies

Hegde

Andreev-Drakhlin²,

Roszik³

et al. 2020

ESMO Open

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PurposeThe receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+).MethodsA retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation.ResultsOf 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16–0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04–0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25–1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation.ConclusionOur study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

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Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer

Cited by 110 publications

References 33 publications

Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases

Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases

Treatment patterns and clinical outcomes in patients with advanced non-small cell lung cancer initiating first-line treatment in the US community oncology setting: a real-world retrospective observational study

Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies

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