Table 1.
CSF Pharmacokinetics of Small Molecule Inhibitors and Immune Checkpoint Inhibitors
| Reference | Study type | Drug | Study population | N | Time of collection | CSF concentrationa | Plasma concentrationa | CSF penetration rateb,c | Clinical outcome |
|---|---|---|---|---|---|---|---|---|---|
| EGFR inhibitors | |||||||||
| Togashi et al., 2012 [44] | Prospective | Erlotinib 150 mg daily | EGFR-mutant NSCLC ± LM | 8 | N/A | 66.9 ± 39.0 nM | N/A | 2.77 ± 0.45% | PR in 4/7, SD in 1/7, PD in 2/7 |
| Gefitinib 250 mg daily | EGFR-mutant NSCLC ± LM | 7 | N/A | 8.2 ± 4.3 nM | N/A | 1.13 ± 0.36% | PR in 1/3, SD in 2/3 | ||
| Jackman et al., 2006 [47] | Single patient dose escalation | Gefitinib 500 mg daily | EGFR-mutant NSCLC LM | 1 | N/A | 6.2–18 nM | N/A | N/A |
Clinical, cytologic, and radiographic improvement in LM at dose of 1000 mg daily. Prolonged high-dose exposure limited by transaminitis and somnolence |
| Gefitinib 750 mg daily | N/A | 32 nM | N/A | N/A | |||||
| Gefitinib 1000 mg daily | N/A | 42 nM | N/A | N/A | |||||
| Gefitinib 1250 mg daily | N/A | 39 nM | 3730 nM | 1.06%c | |||||
| Jackman et al., 2015 [48] | Phase I | Gefitinib alternating 750 mg daily with 500 mg daily q2wk | EGFR-mutant NSCLC LM | 3 | Steady state | 14.7–54.0 nM | 1345.8–4993.0 nM | 1.09%c | Median neurologic PFS = 2.3 mo (range 1.6–4.0). Median OS = 3.5 mo (range 1.6–5.1) |
| Gefitinib alternating 1000 mg daily with 500 mg daily q2wk | EGFR-mutant NSCLC LM | 4 | Steady state | 17.3–143.1 nM | 1552.3–5094.4 nM | 1.11–2.81%c | |||
| Tamiya et al., 2017 [49] | Prospective | Afatinib 40 mg daily | EGFR-mutant NSCLC LM | 11 | 8 d | 3.16 ± 1.95 nM | 233.26 ± 195.40 nM | 2.45 ± 2.91% | ORR 27.3%. Median PFS = 2.0 mo (95% CI: 0.6–5.8). Median OS = 3.8 mo (95% CI: 1.1–13.1) |
| Nanjo et al., 2018 [57] | Prospective | Osimertinib 80 mg daily | EGFR T790M-mutant NSCLC LM | 13 | N/A | 14.4 ± 2.8 nM | 555.3 ± 51.5 nM | 2.5 ± 0.3% |
Median PFS = 7.2 mo (95% CI: 4.0–UD). PFS longer in CSF-T790M+ (7.8–9.6+ mo) vs CSF-T790M- (1.0–4.7+ mo). Median OS = NR |
| Xing et al., 2020 [61] | Prospective | Osimertinib 80 mg daily | EGFR-T790M–mutant NSCLC BM + LM | 12 | 6 wk | 10.8 nM (5.2–30.4 nM) | 47.2 nM (11.9–69.5 nM)d | 31.7% (19.8–57.8%)d | CR 1/3 and PR 1/3 in LM cohort. Intracranial ORR = 68.8% (95% CI: 50.0–83.9) and DCR = 96.9% (95% CI: 83.8–99.9) in total cohort (N = 32) |
| Yang et al., 2020 [59] | Phase I | Osimertinib 160 mg daily | EGFR-mutant NSCLC LM | 35 | 22 d | 5.6 nM (2.2–17.2 nM) | N/A | 16%d | LM ORR = 62% (95% CI: 45–78). LM DoR = 15.2 mo (95% CI: 7.5–17.5). Median OS = 11.0 mo (95% CI: 8.0–18.0) in total cohort (N = 41) |
| MET inhibitors | |||||||||
| Ninomaru et al., 2021 [70] | Case report | Tepotinib 500 mg daily | MET exon 14-mutant NSCLC LM | 1 | 2–8 wk | 49.7–59.3 nM | 2869–4945 nM | 1.19–1.73% | LM disease control for 5+ mo, with clinical and radiographic improvement |
| Tanaka et al., 2021 [71] | Case report | Tepotinib 500 mg daily | MET exon 14-mutant NSCLC LM | 1 | 20 d | 62 nM (30.6 ng/mL) | 1648 ng/mL | 1.83% | LM disease control for 5 mo, with clinical and radiographic improvement |
| ALK inhibitors | |||||||||
| Okimoto et al., 2019 [77] | Case report | Crizotinib 250 mg BID | ALK-rearranged NSCLC BM + LM | 1 | 15 d | 4.32 ng/mL | 158 ng/mL | 2.60% | Clinical, radiographic, and cytologic response lasting 2 mo. Drug withdrawn due to transaminitis |
| Gadgeel et al., 2014 [81] | Phase I/II | Alectinib 600–900 mg BID | ALK-rearranged NSCLC BM + LM | 5 | Steady state | 2.69 nMe | 3.12 nMd,e | 86.2%c,d | PR in 1 patient with LM. CNS ORR 52% in total cohort (N = 21) |
| Bauer et al., 2018 [92] | Phase I/IIf | Lorlatinib 100 mg daily | ALK-rearranged NSCLC BM + LM | 5 | N/A | N/A | N/A | 73 ± 14% | LM response data not provided |
| Sun et al., 2022 [93] | Phase I/II | Lorlatinib 100–150 mg daily | ALK or ROS1+ NSCLC LM | 5 | N/A | 2.64–125 ng/mL | 12.7–4574 ng/mL | 77% (61–96%)4 | CR in 3/5, SD in 1/5, NE in 1/5 in patients with suspected or confirmed LM |
| KRAS inhibitors | |||||||||
| Sabari et al., 2022 [108] | Phase I | Adagrasib 600 mg BID | KRAS-G12C-mutant NSCLC BM | 2 | Steady state | 24.2–34.6 nM | N/A | N/A | PR in 1/2 and SD in 1/2 patients with BM |
| HER2 inhibitors | |||||||||
| Freedman et al., 2019 [117] | Phase II | Neratinib 240 mg daily | HER2+ breast BM + LM | 3 | 7–21 d pre-operatively | <1.50 ng/mL | 34.3–53.8 ng/mL | 0–3.41%c | LM response data not available due to drug discontinuation following toxicity in 1 patient with LM |
| Gori et al., 2014 [120] | Case series | Lapatinib 1250 mg daily | HER2+ breast BM | 2 | 5 h | 1.3–4.5 ng/mL | 1515–3472 ng/mL | 0.9–1.3% | Stable CNS disease for 14 and 19 mo in 2 patients with BM |
| Stringer-Reasor et al., 2021 [130] | Phase IIf | Tucatinib 300 mg BID | HER2+ breast LM | 15 | Cycle 1–2 | 0.57–25 ng/mL | N/A | 83 (19.0–210.0%)d | LM response data not available |
| CDK 4/6 inhibitors | |||||||||
| Tolaney et al., 2020 [166] | Phase II | Abemaciclib 150–200 mg BID | HR+ breast BM + LM | 14 | Cycle 3, or 4–15 d pre-operatively | [Abemaciclib, CSF] exceeded the CDK4 and CDK6 IC50g | N/A | [Abemaciclib, CSF] and [abemaciclib, plasma] were equivalentg | SD in 2/7 (HER2−) and 1/3 (HER2+) patients with LM. 1 patient with HER2− LM achieved SD ≥6 mo |
| Tien et al., 2019 [170] | Phase 0 | Ribociclib 900 mg daily | Glioblastoma | 12 | 5 d | 0.267 μmol/L (0.043–0.838 μmol/L) | 0.184 μmol/L (0.030–0.720 μmol/L)d | 180% (60–440%)d | LM response data not available |
| BRAF/MEK inhibitors | |||||||||
| Sakji-Dupré et al., 2015 [190] | Case series | Vemurafenib 960 mg BID | BRAF-mutant melanoma BM + LM | 6 | N/A | 0.47 ± 0.37 mg/L | 53.4 ± 26.2 mg/L | 0.98 ± 0.84% | LM response data not available |
| NTRK inhibitors | |||||||||
| Mayr et al., 2020 [214] | Case study | Entrectinib 600 mg daily | EML4-NTRK3 fusion gliosarcoma + LM | 1 | 40 d | ~14–25 nMg | N/A | N/A | Clinical improvement and radiographic regression of focally irradiated and non-irradiated LM deposits lasting 5 mo |
| Immune checkpoint inhibitors | |||||||||
| Portnow et al., 2020 [235] | Case series | Pembrolizumab 200 mg q3wk | Glioblastoma | 10 | 24 h | 215 ng/mL (104–436 ng/mL) | 37905 ng/mL (26462–54297 ng/mL) | 0.9% (0.4–1.4%) | LM response data not available |
| Pluim et al., 2019 [236] | Case series | Nivolumab 1–3 mg/kg q2–3wk | Solid tumor BM + LM | 5 | Steady state | 14.5–304 ng/mL | 1831–33454 ng/mL | 0.33–1.91%c | LM response data not available |
ALK anaplastic lymphoma kinase, bid twice daily, BM brain metastases, CDK cyclin dependent kinase, CR complete response, CSF cerebrospinal fluid, DCR disease control rate, DoR duration of response, EGFR epidermal growth factor receptor, HER2 human epidermal growth factor receptor 2, HR hormone receptor, LM leptomeningeal metastases, MET c-met, N number, N/A not applicable, NE not evaluable, NR not reported, NSCLC non-small cell lung cancer, NTRK neurotrophic tropomyosin receptor kinase, ORR objective response rate, OS overall survival, PD progressive disease, PFS progression-free survival, PR partial response, q2–3wk every 2–3 weeks, ROS1 ROS proto-oncogene 1, SD stable disease
aMean, median, range selection, and units of measurement as per authors' definitions
bAuthor-defined CSF-to-plasma ratio or CSF penetrate rate used interchangeably and converted to percentage, when applicable
cIf not defined by authors, CSF penetration rate estimated by formula [CSF,average]/[Plasma,average] × 100%
dMeasurement specifies unbound plasma drug level
eSpecifically the extrapolated CSF trough of alectinib 600 mg BID
fPublished results from a study abstract. Final data not currently published
gExact CSF and plasma values were not provided