A Prospective Cohort Study Assessing the Relationship between Plasma Levels of Osimertinib and Treatment Efficacy and Safety
Abstract
:1. Introduction
2. Methods
2.1. Study Design
2.2. Patients
2.3. Procedures
2.4. Measuring of Plasma and CSF Concentration
2.5. Outcomes
2.6. Case Number Setting and Statistical Analysis
3. Results
3.1. Patients Characteristics and Clinical Results
3.2. Osimertinib and AZ5104 Concentration
3.3. P1 Trough Level and Adverse Events
3.4. P1 Trough Level and Treatment Efficacy
3.5. P2 Trough at the Time of Adverse Events
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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N = 41 | n | (%) |
---|---|---|
Median age | 68 | 43–81 (range) |
Sex | ||
Male | 8 | (20) |
Female | 33 | (80) |
ECOG PS | ||
0 | 17 | (41.5) |
1 | 16 | (39.0) |
2 | 6 | (14.6) |
3 | 2 | (4.9) |
Smoking status | ||
Former or current smoker | 11 | (26.8) |
Never smoker | 30 | (73.2) |
Stage of disease before first line treatment (7th) | ||
IV | 32 | (78.0) |
Recurrence | 9 | (22.0) |
Number of previous regimens | ||
1 | 20 | (48.8) |
2 | 6 | (14.6) |
≥3 (range 3–8) | 15 | (36.6) |
CNS metastases | ||
positive | 34 | (82.9) |
negative | 7 | (17.1) |
EGFR mutation subtype | ||
Exon 19 del | 27 | (65.9) |
Exon 21 L858R | 14 | (34.1) |
Exon 20 T790M | 41 | (100) |
Response | N | % |
---|---|---|
CR | 0 | 0% |
PR | 22 | 53.7% |
SD | 15 | 36.6% |
PD | 1 | 2.4% |
NE | 3 | 7.3% |
Response Rate | 53.7% | |
Disease Control Rate | 92.7% |
Case | Plasma Trough (ng/mL) | CSF Level (ng/mL) | Plasma Level of the Same Time as CSF (ng/mL) * | CSF/Plasma |
---|---|---|---|---|
OC-02 | 186 | 10.1 | 238 | 4.2% |
OC-03 | 191 | 8.2 | 248 | 3.3% |
Variables | Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|---|
HR (95%CI) | p-Value | HR (95%CI) | p-Value | ||
Age | <75 y vs. ≥75 y | 1.995 (0.907–4.384) | 0.086 | 2.173 (0.873–5.406) | 0.095 |
Sex | Female vs. Male | 1.170 (0.524–2.611) | 0.701 | 2.710 (0.835–8.794) | 0.097 |
Stage | Postoperative recurrence vs. Stage III, IV; | 2.983 (1.057–8.418) | 0.039 | 2.199 (0.555–8.719) | 0.262 |
Smoking | Never vs. Former/Current | 0.636 (0.283–1.425) | 0.271 | 0.284 (0.089–0.903) | 0.034 * |
previous regimens | 1 vs. >2 | 1.050 (0.520–2.123) | 0.892 | 1.051 (0.391–2.828) | 0.922 |
EGFR mutation | L858R vs. Ex 19 del | 1.106 (0.522–2.347) | 0.792 | 1.159 (0.480–2.800) | 0.743 |
Brain metastasis | No vs. Yes | 1.223 (0.588–2.542) | 0.590 | 1.737 (0.590–5.117) | 0.317 |
Osimertinib | Q2 + Q3 vs. Q1 + Q4 | 2.704 (1.235–5.920) | 0.013 | 4.492 (1.643–12.280) | 0.003 * |
P2 Cases | Cases with Grade 3 or Higher AE | Cases Discontinued due to AE | Cases Discontinued due to PD | |
---|---|---|---|---|
Q1 (n = 10) | 3 (30%) | 6 (60%) | 1 (nausea) (10%) | 7 (CNS 2) (70%) |
Q2 + Q3 (n = 18) | 3 (16.7%) | 2 (11.1%) | 2 (ILD 2) (11.1%) | 2 (CNS 1) (11.1%) |
Q4 (n = 10) | 2 (20%) | 4 (40%) | 3 (nausea *, anorexia **, and ILD) (30%) | 5 (CNS 0) (50%) |
Plasma Concentration | P1 | P2 | p | |||
---|---|---|---|---|---|---|
Osimertinib | ng/mL | 216 | (90.6–564) | 618 | (164–832) | 0.022 * |
AZ5104 | ng/mL | 17.9 | (n.d.–61.9) | 33.4 | (16.6–92) | 0.031 * |
Serum | P1 | P2 | p | |||
white blood cell | ×103/μL | 42 | (29–48) | 44 | (30–61) | 0.553 |
neutrocyte | ×103/μL | 26 | (18–29) | 30 | (22–50) | 0.128 |
hemoglobin | g/dL | 10.5 | (8–13.3) | 10.4 | (7.6–12.6) | 0.059 |
platelet | ×103/μL | 135 | (123–338) | 193 | (123–266) | 0.834 |
aspartate aminotransferase | U/L | 21 | (15–45) | 17 | (12–27) | 0.172 |
alanine aminotransferase | U/L | 14 | (7–34) | 11 | (5–25) | 0.14 |
total bilirubin | mg/dL | 0.32 | (0.15–0.6) | 0.33 | (0.21–0.66) | 0.498 |
serum creatinin | mg/dL | 0.72 | (0.58–1.08) | 0.77 | (0.56–0.99) | 0.352 |
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Fukuhara, T.; Imai, K.; Nakagawa, T.; Igusa, R.; Yokota, H.; Watanabe, K.; Suzuki, A.; Morita, M.; Onodera, R.; Inoue, A.; et al. A Prospective Cohort Study Assessing the Relationship between Plasma Levels of Osimertinib and Treatment Efficacy and Safety. Biomedicines 2023, 11, 2501. https://doi.org/10.3390/biomedicines11092501
Fukuhara T, Imai K, Nakagawa T, Igusa R, Yokota H, Watanabe K, Suzuki A, Morita M, Onodera R, Inoue A, et al. A Prospective Cohort Study Assessing the Relationship between Plasma Levels of Osimertinib and Treatment Efficacy and Safety. Biomedicines. 2023; 11(9):2501. https://doi.org/10.3390/biomedicines11092501
Chicago/Turabian StyleFukuhara, Tatsuro, Kazuhiro Imai, Taku Nakagawa, Ryotaro Igusa, Hayato Yokota, Kana Watanabe, Aya Suzuki, Mami Morita, Ren Onodera, Akira Inoue, and et al. 2023. "A Prospective Cohort Study Assessing the Relationship between Plasma Levels of Osimertinib and Treatment Efficacy and Safety" Biomedicines 11, no. 9: 2501. https://doi.org/10.3390/biomedicines11092501