With recent expansion of oral small molecule inhibitors, the drug development studies need to provide insight into optimal dose selection for these agents with vastly different mechanism and pharmacokinetic considerations compared to our traditional chemotherapy agents. Currently there is one published meta-analysis that examines intermittent and alternative dosing of oral small molecule inhibitors and it is unclear what guidance is available for treatment personalization beyond package insert labeling for patients undergoing toxicities from treatment.
Methods
A systematic review of oral small molecule inhibitors with intermittent dosing was conducted in the National Library of Medicine PubMed database. Studies were selected based on predefined inclusion/exclusion criteria. Data was extracted to summarize findings on available guidance for intermittent or alternative dosing of oral small molecule inhibitors. Studies were categorized based on food and drug administration (FDA) approved or non-FDA approved agents, and further characterized by comparison of different dosing schemas.
Results
Fifty-five trials were included in the final review and data analysis. Thirty-three trials were phase 1 trials, 26 trials for FDA approved agents and 29 non-FDA approved agents. Most trials reported on agents used in solid tumors, particularly renal cell carcinoma, with most trials examining sunitinib. Of the 55 trials, 28 compared different dosing strategies with 26 of the 28 trials examining efficacy outcomes with 27 of the 28 trials examining safety outcomes.
Conclusions
This systematic review found limited guidance for clinicians in optimizing dosing for intermittently dosed oral small molecule inhibitors.
MakiRGStinchcombeTESchwartzGK, et al.Combining response and toxicity data to implement project optimus. J Clin Oncol2024; 42: 4123–4125.
2.
TurnerNCOliveiraMHowellSJ, et al.Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med2023; 388: 2058–2070.
3.
Truqap [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP, 2023.
4.
BanerjiUDeanEJPerez-FidalgoJA, et al.A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers. Clin Cancer Res2018; 24: 2050–2059.
5.
DjebbariFStonerNLavenderVT. A systematic review of non-standard dosing of oral anticancer therapies. BMC Cancer2018; 18. DOI: https://doi.org/10.1186/s12885-018-5066-2.
6.
PageMJMcKenzieJEBossuytPM, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ2021; 372: n71.
ChienAJIlliJAKoAH, et al.A phase I study of a 2-day lapatinib chemosensitization pulse preceding nanoparticle albumin-bound paclitaxel for advanced solid malignancies. Clin Cancer Res2009; 15: 5569–5575.
9.
ChuQSSanghaRHotteSJ, et al.A phase I, dose-escalation trial of continuous- and pulsed-dose Afatinib combined with pemetrexed in patients with advanced solid tumors. Invest New Drugs2014; 32: 1226–1235.
10.
DasMPaddaSKFrymoyerA, et al.A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies. Cancer Chemother Pharmacol2018; 82: 541–550.
11.
LorussoPM. Phase I studies of ZD1839 in patients with common solid tumors. Semin Oncol2003; 30: 21–29.
12.
SarkerDMolifeREvansTR, et al.A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res2008; 14: 2075–2081.
13.
PietanzaMCGadgeelSMDowlatiA, et al.Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer. J Thorac Oncol2012; 7: 856–865.
14.
WongALSooRATanDS, et al.Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies. Ann Oncol2015; 26: 998–1005.
15.
NishinaTTakahashiSIwasawaR, et al.Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Invest New Drugs2018; 36: 424–434.
16.
CalvoETolcherAWHammondLA, et al.Administration of CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: a phase I pharmacokinetic and food effect study. Clin Cancer Res2004; 10: 7112–7120.
17.
ChienAJMunsterPNMeliskoME, et al.Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer. J Clin Oncol2014; 32: 1472–1479.
18.
MillerVAJohnsonDHKrugLM, et al.Pilot trial of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib plus carboplatin and paclitaxel in patients with stage IIIB or IV non-small-cell lung cancer. J Clin Oncol2003; 21: 2094–2100.
19.
van GeelRMJMvan BrummelenEMJEskensFALM, et al.Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer. Br J Cancer2020; 122: 1166–1174.
20.
TaberneroJBahledaRDienstmannR, et al.Phase I dose-escalation study of JNJ-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol2015; 33: 3401–3408.
21.
MacaulayVMMiddletonMREckhardtSG, et al.Phase I dose-escalation study of linsitinib (OSI-906) and erlotinib in patients with advanced solid tumors. Clin Cancer Res2016; 22: 2897–2907.
22.
MinamiSKijimaTHamaguchiM, et al.Phase II study of pemetrexed plus intermittent erlotinib combination therapy for pretreated advanced non-squamous non-small cell lung cancer with documentation of epidermal growth factor receptor mutation status. Lung Cancer2013; 82: 271–275.
23.
HamiltonEPWangJSOzaAM, et al.First-in-human study of AZD5153, a small-molecule inhibitor of bromodomain protein 4, in patients with relapsed/refractory malignant solid tumors and lymphoma. Mol Cancer Ther2023; 22: 1154–1165.
24.
WilsonWHO'ConnorOACzuczmanMS, et al.Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol2010; 11: 1149–1159.
25.
HongDSBowlesDWFalchookGS, et al.A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res2012; 18: 4173–4182.
26.
AmorimSStathisAGleesonM, et al.Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol2016; 3: e196–e204.
27.
RodonJCarducciMASepulveda-SánchezJM, et al.First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res2015; 21: 553–560.
28.
YounesABerdejaJGPatelMR, et al.Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol2016; 17: 622–631.
29.
NessDBPoolerDBAdesS, et al.A phase II study of alternating sunitinib and temsirolimus therapy in patients with metastatic renal cell carcinoma. Cancer Med2023; 12: 13100–13110.
30.
CoplandMSladeDMcIlroyG, et al.Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial. Lancet Haematol2022; 9: e121–e132.
31.
AlexanderWDavisSRamakrishnaR, et al.Outcomes of reduced frequency dosing of ibrutinib in chronic lymphocytic leukemia patients following complete or partial remission: a pilot study. J Hematol2020; 9: 55–61.
32.
RovithiMGerritseSLHoneywellRJ, et al.Phase I dose-escalation study of once weekly or once every two weeks administration of high-dose sunitinib in patients with refractory solid tumors. J Clin Oncol2019; 37: 411–418.
33.
ReardonDAVredenburghJJCoanA, et al.Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma. J Neurooncol2011; 105: 621–627.
34.
JamiesonDGriffinMJSluddenJ, et al.A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours. Eur J Cancer2016; 68: 1–10.
35.
BrittenCDKabbinavarFHechtJR, et al.A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period. Cancer Chemother Pharmacol2008; 61: 515–524.
36.
GerritseSLLabotsMTer HeineR, et al.High-dose intermittent treatment with the multikinase inhibitor sunitinib leads to high intra-tumor drug exposure in patients with advanced solid tumors. Cancers (Basel)2022; 14: 6061. Published 2022 Dec 9.
37.
SafraTAndreopoulouELevinsonB, et al.Weekly paclitaxel with intermittent imatinib mesylate (Gleevec): tolerance and activity in recurrent epithelial ovarian cancer. Anticancer Res2010; 30: 3243–3247.
38.
BiagiJJOzaAMChalchalHI, et al.A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Ann Oncol2011; 22: 335–340.
39.
NowakAKMillwardMJCreaneyJ, et al.A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma. J Thorac Oncol2012; 7: 1449–1456.
40.
NanniniMNigroMCVincenziB, et al.Personalization of regorafenib treatment in metastatic gastrointestinal stromal tumours in real-life clinical practice. Ther Adv Med Oncol2017; 9: 731–739.
41.
BoucheOMaindrault-GoebelFDucreuxM, et al.Phase II trial of weekly alternating sequential BIBF 1120 and Afatinib for advanced colorectal cancer. Anticancer Res2011; 31: 2271–2281.
42.
DialloHMhamdiHAElouarzaziS, et al.Assessment of sunitinib alternative prescription schedules in metastatic kidney cancer: a study of 10 cases. Gulf J Oncolog2018; 1: 33–36.
43.
MolifeLRYanLVitfell-RasmussenJ, et al.Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J Hematol Oncol2014; 7: 1. Published 2014 Jan 3.
44.
MooreMHirteHWSiuL, et al.Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol2005; 16: 1688–1694.
45.
EskensFAde JongeMJBhargavaP, et al.Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin Cancer Res2011; 17: 7156–7163.
46.
AdvaniRHBuggyJJSharmanJP, et al.Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol2013; 31: 88–94.
47.
KawaiANakaNShimomuraA, et al.Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study. Invest New Drugs2021; 39: 1559–1567.
48.
BaumannKHdu BoisAMeierW, et al.A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy. Ann Oncol2012; 23: 2265–2271.
49.
MolinaAMFeldmanDRVossMH, et al.Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer2012; 118: 1868–1876.
50.
EscudierBGrünwaldVRavaudA, et al.Phase II results of dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res2014; 20: 3012–3022.
51.
MotzerRJPortaCVogelzangNJ, et al.Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol2014; 15: 286–296.
52.
AngevinELopez-MartinJALinCC, et al.Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin Cancer Res2013; 19: 1257–1268.
53.
MilowskyMIDittrichCDuránI, et al.Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. Eur J Cancer2014; 50: 3145–3152.
54.
YamadaKYamamotoNYamadaY, et al.Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res2011; 17: 2528–2537.
55.
LaiJSBeaumontJLDiazJ, et al.Validation of a short questionnaire to measure symptoms and functional limitations associated with hand-foot syndrome and mucositis in patients with metastatic renal cell carcinoma. Cancer2016; 122: 287–295.
56.
DeprimoSEBelloCLSmeragliaJ, et al.Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med2007; 5: 32. Published 2007 Jul 2.
57.
SteensmaDPWermkeMKlimekVM, et al.Phase I first-in-human dose escalation study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia2021; 35: 3542–3550.
58.
MorenoVSepulvedaJMVieitoM, et al.Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma. Ann Oncol2020; 31: 780–788.
59.
KantarjianHMSchusterMWJainN, et al.A phase 1 study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients with acute myeloid leukemia. Am J Hematol2017; 92: 660–667.
60.
Woei-A-JinFJSHWeijlNIBurgmansMC, et al.Neoadjuvant treatment with angiogenesis-inhibitor dovitinib prior to local therapy in hepatocellular carcinoma: a phase II study. Oncologist2021; 26: 854–864.
61.
CorbaciogluSLodeHEllingerS, et al.Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol2024; 25: 922–932.
62.
KhanQBohnenkampCMonsonT, et al.Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer: the X-7/7 trial. J Clin Oncol2023; 41: 1007.
63.
VanoYAElaidiRBennamounM, et al.Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial. Lancet Oncol2022; 23: 612–624.
64.
DengHLiMWuQ, et al.A 2/1 sunitinib dosing schedule provides superior antitumor effectiveness and less toxicity than a 4/2 schedule for metastatic renal cell carcinoma: a systematic review and meta-analysis. Front Oncol2020; 10: 313.
65.
KrishnamurthyJLuoJSureshR, et al.A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis. NPJ Breast Cancer2022; 8: 35.
66.
GebbiaVBellaviaGFerrauF, et al.Adherence, compliance and persistence to oral antineoplastic therapy: a review focused on chemotherapeutic and biologic agents. Expert Opin Drug Saf2012; 11: S49–S59.
67.
PirazzoliVPolitiK. Generation of drug-resistant tumors using intermittent dosing of tyrosine kinase inhibitors in mouse. Cold Spring Harb Protoc2014; 2014: pdb.prot077842.
68.
LeeYChoiYKimK, et al.The impact of intermittent versus continuous exposure to EGFR tyrosine kinase inhibitor on selection of EGFR T790M-mutant drug-resistant clones in a lung cancer cell line carrying activating EGFR mutation. Oncotarget2016; 7: 43315–43323.
