Chronic Plasma Exposure to Kinase Inhibitors in Patients with Oncogene-Addicted Non-Small Cell Lung Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Patients and Methods
2.1. Patients
2.2. Assessment of Plasma Exposure
- Optimal: The optimal concentration corresponds to the true residual plasma concentration at a steady state, in the blood collection performed immediately before the next administration.
- Evaluable: The residual plasma concentration is estimated by an extrapolation method from known pharmacokinetic parameters (distribution volume, half-life, clearance) and from data obtained in population pharmacokinetic models [14]. This estimate of standard trough concentration (Cmin, std) is only possible when blood samples were collected at steady state or during the terminal elimination phase of the drug, since in this phase, the elimination rate is linear [14,15].
- -
- C (min, std) = C(t) * 0.5 ^ (Delta (t)/t1/2)
- -
- C (min, std) = C(t) * exp (k(e) x Delta (t))
- 3.
- Not interpretable: Extrapolation is not feasible for samples taken during the plasma peak period.
2.3. Somatic Molecular Analysis
- -
- CHP2 (Ion AmpliSeq Cancer Hotspot Panel v2 (CHP2)) designed to amplify 207 amplicons covering 50 genes (Thermo Fisher Scientific)).
- -
- Oncomine lung (Oncomine Lung ctDNA Assay contains 35 amplicons covering 11 genes (Thermo Fisher Scientific)). A unique molecular identifier is combined with each single DNA molecule. For calling the detected variants, the following parameters were applied: Allele Read count > 10; Fusion read count > 1; Variant type: Single nucleotide variant, insertion-deletion, multi-nucleotide variant, copy number variant, long deletion, fusion; Variant effect: Unknown, missense, none frameshift Insertion, none frameshift Deletion, non-sense, stop loss, frameshift insertion, frameshift deletion.
- -
- MOSC4 (Ion AmpliSeq MOSC4 designed to cover 82 genes, combining two other panels (CHP2 + Safir02)).
- -
- OCAV3 (Ion AmpliSeq Oncomine Comprehensive Assay V3 enables the detection of mutations across 161 genes, gene fusions, and copy number variations (Thermo Fisher Scientific)).
- -
- Sentosa SQ NSCLC (Sentosa SQ Non-Small Cell Lung Cancer panel targets 11 genes with 28 amplicons (Vela Diagnostics)). For calling the detected variants, following parameters were applied: 5000 Exomes Global MAF < 0.01; Allele frequency > 0.02; Allele ratio > 0.02; Allele read counts > 50; Alternate read counts > 30; Fusion read counts > 50; Variant effect: Unknown, missense, none frameshift insertion, none frameshift deletion, stop loss, non-sense, frameshift insertion, frameshift deletion; Variant type: Single nucleotide variant, insertion-deletion, multi-nucleotide variant, copy number variant, long deletion, fusion.
2.4. Statistical Analysis
3. Results
3.1. Suboptimal Concentration and KI Response
3.2. Clinical Relevance of Suboptimal Concentration
3.3. KI Exposure and Resistance Mechanisms
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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N# | Driver Alteration | Other Alteration | Kinase Inhibitor | NGS Panel (Tissue) | NGS Panel (Blood) | EGFR T790M ddPCR Stilla® (Blood) |
---|---|---|---|---|---|---|
1 | EGFR exon 21 p. L858R | No | Gefitinib | - | CHP2 *: Not detected | Not detected |
2 | EGFR exon 21 p. L858R | No | Gefitinib | - | - | T790M detected |
3 | EGFR exon 21 p. L858R | No | Gefitinib | Oncomine® Lung: T790M detected | CHP2 *: Not detected | - |
4 | EGFR exon 21 p. L858R | No | Gefitinib | - | CHP2 *: Not detected | Not detected |
5 | EGFR exon 19 deletion | TP53 | Gefitinib | MOSC4: T790M not detected | - | - |
6 | EGFR exon 19 deletion | No | Gefitinib | - | - | Not detected |
7 | EGFR exon 19 deletion | No | Gefitinib | MOSC4: T790M not detected | - | T790M detected |
8 | EGFR exon 21 p.L833F | TP53, CKDN2A | Erlotinib | - | - | ddPCR Not detected |
9 | EGFR exon 19 deletion | No | Erlotinib | - | - | Not detected |
10 | EGFR exon 19 deletion | No | Erlotinib | - | - | Not detected |
11 | EGFR exon 19 deletion | No | Erlotinib | - | - | Not detected |
12 | EGFR exon 19 deletion | No | Erlotinib | MOSC4: T790M detected | - | T790M detected |
13 | EGFR exon 21 p. L858R | No | Erlotinib | Unknown: not detected | - | - |
14 | EGFR exon 19 deletion | No | Erlotinib | MOSC4: T790M not detected | - | Not detected |
15 | EGFR exon 19 deletion | No | Erlotinib | MOSC4: T790M not detected | - | - |
16 | EGFR exon 19 deletion | No | Erlotinib | MOSC4: T790M not detected | CHP2 *: Not detected | - |
17 | EGFR exon 21 p. L858R | No | Erlotinib | OCAV3: T790M not detected | Oncomine® Lung: Not detected | - |
18 | EGFR exon 19 deletion | No | Erlotinib | NSCLC: T790M not detected | - | Not detected |
Characteristics, No. (%) | All Samples (n = 51) | Optimal Concentration (n = 25) | Suboptimal Concentration (n = 26) | p-Value |
---|---|---|---|---|
Molecular alteration:ALK-rearranged, BRAFV600E mutation, EGFR deletion exon 19, EGFR mutation exon 21 (L858R), EGFR mutation exon 21 (L833F), ROS-1 rearranged, MET mutation exon 14, No molecular alteration (ALK, BRAF, EGFR, KRAS, MET, ROS-1) | 3 (7%), 10 (19%), 23 (45%), 9 (17%), 1 (2%), 2 (4%), 2 (4%), 1 (2%) | 0 (0%), 4 (16%), 12 (48%), 6 (24%), 1 (4%), 1 (4%), 1 (4%), 0 | 3 (12%), 6 (22%), 11 (42%), 3 (12%), 0, 1 (4%), 1 (4%), 1 (4%) | p = 0.50 |
Kinase inhibitor: Erlotinib, Gefitinib, Osimertinib, Crizotinib, Dabrafenib, Trametinib | 13 (26%), 11 (21%), 10 (19%), 7 (14%), 5 (10%), 5 (10%) | 7 (28%), 8 (32%), 4 (16%), 2 (8%), 2 (8%), 2 (8%) | 6 (23%), 3 (11.5%), 6 (23%), 5 (19.5%), 3 (11.5%), 3 (11.5%) | p = 0.52 |
Stage at diagnosis: I-II, III, IV | 1 (2%), 2 (4%), 48 (94%) | 0, 2 (8%), 23 (92%) | 1 (4%), 0, 25 (96%) | p = 0.24 |
Lines of previous kinase inhibitors: ≤2, >2 | 44 (86%), 7 (14%) | 20 (80%), 5 (20%) | 24 (92%), 2 (8%) | p = 0.25 |
Current smoker: Yes, No | 5 (10%), 46 (90%) | 1 (4%), 24 (96%) | 4 (15%), 22 (85%) | p = 0.35 |
Concomitant proton pump inhibitor: No, Yes | 35 (69%), 16 (31%) | 15 (60%), 10 (40%) | 20 (77%), 6 (23%) | p = 0.19 |
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Geraud, A.; Mezquita, L.; Auclin, E.; Combarel, D.; Delahousse, J.; Gougis, P.; Massard, C.; Jovelet, C.; Caramella, C.; Adam, J.; et al. Chronic Plasma Exposure to Kinase Inhibitors in Patients with Oncogene-Addicted Non-Small Cell Lung Cancer. Cancers 2020, 12, 3758. https://doi.org/10.3390/cancers12123758
Geraud A, Mezquita L, Auclin E, Combarel D, Delahousse J, Gougis P, Massard C, Jovelet C, Caramella C, Adam J, et al. Chronic Plasma Exposure to Kinase Inhibitors in Patients with Oncogene-Addicted Non-Small Cell Lung Cancer. Cancers. 2020; 12(12):3758. https://doi.org/10.3390/cancers12123758
Chicago/Turabian StyleGeraud, Arthur, Laura Mezquita, Edouard Auclin, David Combarel, Julia Delahousse, Paul Gougis, Christophe Massard, Cécile Jovelet, Caroline Caramella, Julien Adam, and et al. 2020. "Chronic Plasma Exposure to Kinase Inhibitors in Patients with Oncogene-Addicted Non-Small Cell Lung Cancer" Cancers 12, no. 12: 3758. https://doi.org/10.3390/cancers12123758