Purpose
To assess (1) the repeatability and (2) the impact of reconstruction methods and delineation on the repeatability of 105 radiomic features in non-small-cell lung cancer (NSCLC) 2-deoxy-2-
18
...Ffluoro-D-glucose (
18
FFDG) positron emission tomorgraphy/computed tomography (PET/CT) studies.
Procedures
Eleven NSCLC patients received two baseline whole-body PET/CT scans. Each scan was reconstructed twice, once using the point spread function (PSF) and once complying with the European Association for Nuclear Medicine (EANM) guidelines for tumor PET imaging. Volumes of interest (
n
= 19) were delineated twice, once on PET and once on CT images.
Results
Sixty-three features showed an intraclass correlation coefficient ≥ 0.90 independent of delineation or reconstruction. More features were sensitive to a change in delineation than to a change in reconstruction (25 and 3 features, respectively).
Conclusions
The majority of features in NSCLC
18
FFDG-PET/CT studies show a high level of repeatability that is similar or better compared to simple standardized uptake value measures.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
We defined “ultracentral” lung tumors as centrally located non–small cell lung cancers with planning target volumes overlapping the trachea or main bronchi. Increased toxicity has been reported after ...both conventional and stereotactic radiotherapy for such lesions. We studied outcomes after 12 fractions of 5 Gy (BED10 = 90 Gy, heterogeneous dose distribution) to ultracentral tumors in patients unfit for surgery or conventional chemoradiotherapy.
Clinical outcomes and dosimetric details were analyzed in 47 consecutive patients with single primary or recurrent ultracentral non–small cell lung cancer treated between 2010 and 2015. Those irradiated previously or with metastasis to sites other than the brain and adrenal glands were excluded. Treatments were delivered using volumetric modulated arc therapy.
The median age was 77.5 years, 49% of patients had a World Health Organization performance score of 2 or higher, and the median planning target volume was 104.5cm3 (range 17.7–508.5). At a median follow-up of 29.3 months, median overall survival was 15.9 months, and 3-year survival was 20.1%. No isolated local recurrences were observed. Grade 3 or higher toxicity was recorded in 38% of patients, with 21% scored as having a “possible” (n = 2) or “likely” (n = 8) treatment-related death between 5.2 and 18.2 months after treatment. Fatal pulmonary hemorrhage was observed in 15% of patients.
Unfit patients with ultracentral tumors who were treated using this scheme had a high local control and a median survival of 15.9 months. Despite manifestation of rates of a fatal lung bleeding comparable to those seen with conventional radiotherapy for endobronchial tumors, the overall rate of G5 toxicity is of potential concern. Additional work is needed to identify tumor and treatment factors related to hemorrhage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
...after the results of the KEYNOTE-024 study involving patients with a TPS greater than 50% became public,3 whether pembrolizumab monotherapy improves progression-free survival and overall survival ...in patients with a PD-L1 TPS less than 50% became the clinical question of interest. Progression-free survival and response were not reported for this subgroup, but, on the basis of historical data, would be expected to be lower than those for platinum-doublet chemotherapy. ...this population might initially derive more benefit from chemotherapy and an as-yet unidentified group of patients with PD-L1 TPS of 1–49% could derive long-term benefits from pembrolizumab. In a post-hoc analysis, PD-L1 was not the only denominator of benefit from PD-1 blockade because patients with high tumour mutation burden derived significant benefit from treatment with nivolumab, irrespective of PD-L1 status. ...the conclusion of Mok and colleagues that pembrolizumab is an appropriate treatment option for patients based only on a PD-L1 TPS lower than 50% should be regarded with caution.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). ...Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure–response relationships of osimertinib in a real-life setting.
Methods
A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C
min,pred
) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship.
Results
A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 – 19.1) months and 9.3 (95% CI: 7.2 – 11.1) months for patients with C
min,pred
< 166 µg/L and C
min,pred
≥ 166 µg/L, respectively (
p
= 0.03). In the multivariate analysis, a C
min,pred
< 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 – 2.01;
p
= 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 – 7.08;
p
= 0.02). No relationship between exposure and toxicity was observed (
p
= 0.91).
Conclusion
In our real-life cohort, no exposure–response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•PD-L1 IHC is biomarker for treatment with PD-1 checkpoint immunotherapy in NSCLC.•Each PD-(L)1 checkpoint inhibitor has been validated with a different PD-L1 IHC assay.•Preferably one affordable, ...clinically validated PD-L1 IHC test is needed.•Selection of critical samples is crucial for validation of PD-L1 IHC assay.
In summary, the PD-L1 biomarker discussed here highlights the importance of understanding the practice of IHC. This can be used to the patients advantage, with appropriate usage. The currently available literature on PD-L1 IHC from a methodologic point of view has not shown that different assays are comparable. The route of laboratory developed test and commercial test validation is the same: challenging and complex. Executing this process along proper methodologic lines is needed to ensure that patients receive the most accurate and representative test outcomes.
Full text
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutations in patients with non–small cell lung cancer (NSCLC) and are ...associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). There is evidence of activity of combining EGFR TKIs with monoclonal antibodies. This study reports on the efficacy and safety of afatinib in combination with cetuximab.
Methods
In this single‐arm phase 2 trial, patients with advanced NSCLC harboring an EGFR ex20ins mutation were treated with afatinib 40 mg once daily in combination with cetuximab 500 mg/m2 every 2 weeks. The primary end point was disease control rate (DCR) at 18 weeks of treatment.
Results
Thirty‐seven patients started treatment, with a median age of 65 years (range, 40–80 years), 78% female, and 95% White. The study achieved its primary end point with a DCR of 54% at 18 weeks, an overall response rate (ORR) of 43%, and a 32% confirmed ORR. Best responses were partial (n = 16), stable (n = 16), progressive disease (n = 2), or not evaluable (n = 3). Median progression‐free survival was 5.5 months (95% CI, 3.7–8.3 months) and median overall survival was 16.8 months (95% CI, 10.7–25.8 months). The most common treatment‐related adverse events (TRAEs) were diarrhea (70%), rash (65%), dry skin (59%), paronychia (54%), and erythema (43%). Grade 3 TRAEs were reported in 54% of all patients.
Conclusions
Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 54% at 18 weeks and a 32% confirmed ORR. Toxicity was significant, although manageable, after dose reduction.
Combination treatment with afatinib and cetuximab in patients with non–small cell lung cancer harboring an EGFR exon 20 insertion mutation demonstrated antitumor activity with a disease control rate of 54% at 18 weeks of treatment and a 32% confirmed overall response rate.
Full text
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The pathological and molecular classification of lung cancer has become substantially more complex over the past decade. For diagnostic purposes on small samples, additional stains are frequently ...required to distinguish between squamous cell carcinoma and adenocarcinoma. Subsequently, for advanced nonsquamous cell nonsmall cell lung carcinoma (NSCLC) patients, predictive analyses on epidermal growth factor receptor, anaplastic lymphoma kinase and ROS1 are required. In NSCLCs negative for these biomarkers, programmed death ligand-1 immunohistochemistry is performed. Small samples (biopsy and cytology) require “tissue” management, which is best achieved by the interaction of all physicians involved.
the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of ...toxicity in non-small-cell lung cancer patients.
In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups.
A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a C min,ss ≥490, ≥870, ≥405, ≥150, and ≥25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group ( P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups.
For alectinib, high C min,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib.
Better biomarkers are needed to predict treatment outcome in non-small cell lung cancer (NSCLC) patients treated with anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint ...inhibitors. PD-L1 immunohistochemistry has limited predictive value, possibly because of tumor heterogeneity of PD-L1 expression. Noninvasive PD-L1 imaging using
Zr-durvalumab might better reflect tumor PD-L1 expression.
NSCLC patients eligible for second-line immunotherapy were enrolled. Patients received 2 injections of
Zr-durvalumab: one without a preceding dose of unlabeled durvalumab (tracer dose only) and one with a preceding dose of 750 mg of durvalumab, directly before tracer injection. Up to 4 PET/CT scans were obtained after tracer injection. After imaging acquisition, patients were treated with 750 mg of durvalumab every 2 wk. Tracer biodistribution and tumor uptake were visually assessed and quantified as SUV, and both imaging acquisitions were compared. Tumor tracer uptake was correlated with PD-L1 expression and clinical outcome, defined as response to durvalumab treatment.
Thirteen patients were included, and 10 completed all scheduled PET scans. No tracer-related adverse events were observed, and all patients started durvalumab treatment. Biodistribution analysis showed
Zr-durvalumab accumulation in the blood pool, liver, and spleen. Serial imaging showed that image acquisition 120 h after injection delivered the best tumor-to-blood pool ratio. Most tumor lesions were visualized with the tracer dose only versus the coinjection imaging acquisition (25% vs. 13.5% of all lesions). Uptake heterogeneity was observed within (SUV
range, 0.2-15.1) and between patients. Tumor uptake was higher in patients with treatment response or stable disease than in patients with disease progression according to RECIST 1.1. However, this difference was not statistically significant (median SUV
, 4.9 vs. 2.4;
= 0.06). SUV
correlated better with the combined tumor and immune cell PD-L1 score than with PD-L1 expression on tumor cells, although neither was statistically significant (
= 0.06 and
= 0.93, respectively).
Zr-durvalumab was safe, without any tracer-related adverse events, and more tumor lesions were visualized using the tracer dose-only imaging acquisition.
Zr-durvalumab tumor uptake was higher in patients with a response to durvalumab treatment but did not correlate with tumor PD-L1 immunohistochemistry.
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