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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
MA21.09 - Tyrosine Kinase Inhibitors' Plasma Concentration and Oncogene-Addicted Advanced Non-Small Lung Cancer (aNSCLC) Resistance (Now Available) (ID 830)
14:30 - 16:00 | Author(s): CHARLES Naltet
The development of TKIs against driver molecular alteration has changed treatment paradigm in aNSCLC patients (pts). All tumors eventually progress and a resistance mechanism is identified in only a fraction of pts. Plasma concentration of TKI can decrease after chronic exposition but limited data are available. Our hypothesis is that an insufficient plasma exposure could contribute to tumor progression (PD).Method
We assessed the plasma concentration of TKI in pts with aNSCLC harboring ALK rearrangement, EGFR or BRAF V600E mutation. We defined chronic exposure as a treatment administered > 3 months. Patients’ characteristics and co-medications were collected. Residual plasma concentrations were measured using Ultra Performance Liquid Chromatography coupled with tandem mass spectrometry validated methods. We compared results to currently recommended therapeutic targets and correlated exposure levels to treatment benefit.
Between Apr. 2014 and Feb. 2019, 51 samples were prospectively collected (gefitinib n=11, osimertinib n=10, erlotinib n=13, crizotinib n=7, dabrafenib + trametinib n=5) in 41 pts. Median time of exposure was 20.3 months (range 2.18 - 67.813). Low plasma concentration was observed in 31 (61%) samples. Out of 14 samples collected in pts with ongoing benefit, 10 (71%) had low plasma exposure. Smoking status was associated with low plasma TKI concentration (P=0.01) whatever the TKI used. A total of 37 samples were collected at PD, 21 (57%) had low plasma exposure. The median time to treatment failure (TTF) in the ‘low exposure group' (n=31) was 14.9 months (95% CI 12.48 – 33.2) vs. 24.6 months (95% CI 8.65 -not reached (NR) in the ‘normal exposure group’ (P=0.55). No significant impact of protons pump inhibitors on TTF was found (p=0.12), including with gefitinib and erlotinib (p=0.76; n=24). In case of isolated brain PD (n=4), 3 pts (75%) had low plasma exposure. TKI dose was reduced in 14 pts because of toxicity, median TTF was 17.0 months (95% CI 10.4-NR) vs. 20.1 months (95% CI 10.4-59.8, P=0.45 in pts treated with standard dose. In the EGFR mutated aNSCLC population at PD (n=19), T790M resistance mutation was more frequent in the ‘normal exposure group’ (37.5%, n= 3/8,) than in the ‘low exposure group’ (9.1%, n=1/11), OR=0.13 95%CI (0.01-1.29), p=0.08.Conclusion
TKI is underdose in the majority of aNSCLC patients at PD. Low TKI concentration were more frequent in pts without tumor resitance mechanism. Altogether, it suggests that low TKI exposure might contribute to PD.
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P1.10 - Prevention and Tobacco Control (ID 175)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
P1.10-06 - Pathological Characterization of Radon-Induced Lung Cancer in Rats (ID 1616)
09:45 - 18:00 | Author(s): CHARLES Naltet
Radon is a radioactive gas, considered the leading cause of lung cancer in non-smokers. Although the risk of lung cancer is linear, there is no safe level and even low dose can be associated with risk. In humans, no specific pathological subtypes of lung cancer have been clearly associated with radon. In animals, the French Atomic Energy Commission (CEA) exposed to low dose of radon (25 working level month, WLM) a large cohort of rats in a radon-exposure chamber, showing lung cancer induced by low exposure (Chameaud J, Radiation Prot Dosimetry 1984). We aimed to describe pathological features of radon-induced tumors in rats from the CEA’s cohort.Method
Retrospective assessment of archival samples available of the rats exposed to low-dose radon in the Laboratoire de Pathologie Pulmonaire Experimentale, COGEMA (France), between 1989 and 1992. Autopsy reports were also reviewed. The pathological assessment was performed for a thoracic oncology pathologist (JA) in H&E staining slides according to the current WHO histological classification.Result
Samples from 117 rats were collected. Among 104 tumors, to date the analysis has been performed in 94. Forty tumors (43%) were classified as malignant, 28 (30%) as uncertain malignant potential (UMP) and 26 (28%) benign. In 2 rats (2%) synchronous malignant and non-malignant tumors were observed.
Among the malignant tumors, 23 (58%) were epithelial and 17 (42%) non-epithelial. Lung carcinoma was the most common primary epithelial tumor (n=10, 43%), followed by abdominal area tumors (n=5, 22%), and thyroid (n=3, 13%). In the UMP group, 7 (25%) were epithelial and 21 (75%) non-epithelial, with no lung tumors observed. In the benign group, most of them (n=24, 92%) were epithelial, with 4 cases with lung atypical adenomatous hyperplasia-like lesions; 2 synchronous with other malignant tumors (n=1 lymphoma, n=1 cutaneous squamous cell carcinoma).
A total of 26 tumors (27%) had thoracic involvement: 4 (15%) primary lung non-malignant lesions, 11 primary lung malignancies (42%) and 11 with metastases from other tumors (42%). As primary malignant lung tumors, we observed: 7 (64%) adenocarcinoma in situ, one papillary adenocarcinoma, one undifferentiated large cell carcinoma with bilateral metastases, one metastatic squamous carcinoma and one metastatic undifferentiated tumor, compatible with sarcomaConclusion
In this cohort of radon-induced tumors in rats, we observed different tumor types, from non-malignant lesions to aggressive malignancies, with predominance of epithelial tumors. Lung carcinoma was the most common primary tumor and adenocarcinoma the histological subtype more observed, with histological similarities with humans.