Marked Differences in CNS Activity among EGFR Inhibitors: Case Report and Mini-Review
2016; Elsevier BV; Volume: 11; Issue: 11 Linguagem: Inglês
10.1016/j.jtho.2016.07.010
ISSN1556-1380
AutoresVipul Pareek, Mary Welch, Elizabeth Ravera, Richard Zampolin, Lecia V. Sequist, Balázs Halmos,
Tópico(s)Cancer therapeutics and mechanisms
ResumoOver the past decade we have gained significant insights into oncogenic driver pathways involved in NSCLC, leading to the molecular subclassification of NSCLC. Tyrosine kinase inhibitors (TKIs) such as erlotinib, afatinib and gefitinib are highly effective for the upfront treatment of EGFR mutant NSCLC. The central nervous system (CNS) is a frequent site of metastases in lung cancer. Approximately 9% of patients with NSCLC initially present with brain metastasis (BM),1Waqar SN, Waqar SH, Trinkaus K, et al. Brain metastases at presentation in patients with non-small cell lung cancer [e-pub ahead of print]. Am J Clin Oncol. http://dx.doi.org/10.1097/COC.0000000000000230, accessed August 12, 2016.Google Scholar with the incidence of BM in patients with EGFR and anaplastic lymphoma receptor tyrosine kinase gene (ALK)-driven advanced NSCLC possibly even higher—approximately 25% at diagnosis and increasing up to 50% by year 3.2Rangachari D. Yamaguchi N. VanderLaan P.A. et al.Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers.Lung Cancer. 2015; 88: 108-111Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar Although first-line EGFR TKIs such as erlotinib, gefitinib, and afatinib have good CNS activity,3Schuler M. Wu Y.L. Hirsh V. et al.First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases.J Thorac Oncol. 2016; 3: 380-390Abstract Full Text Full Text PDF Scopus (252) Google Scholar, 4Togashi Y. Masago K. Masuda S. et al.Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.Cancer Chemother Pharmacol. 2012; 70: 399-405Crossref PubMed Scopus (232) Google Scholar, 5Lee E. Keam B. Kim D.W. et al.Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer.J Thorac Oncol. 2013; 8: 1069-1074Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar less is known about the cerebrospinal fluid (CSF) efficacy of newer EGFR-targeting drugs such as osimertinib and rociletinib.6Janne P.A. Yang J.C. Kim D.W. et al.AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699Crossref PubMed Scopus (1627) Google Scholar, 7Sequist L.V. Rolfe L. Allen A.R. Rociletinib in EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2015; 373: 578-579Crossref PubMed Scopus (41) Google Scholar Herein, we present the case of a patient who had rapid CNS progression while receiving rociletinib followed by a dramatic remission with osimertinib, highlighting marked differences in CNS activity of these two novel agents. The patient is a 49-year-old white female with a limited smoking history and a personal history of early-stage breast cancer in whom metastatic lung adenocarcinoma harboring an EGFR exon 19 deletion mutation was diagnosed in November 2014 after she presented with dyspnea. Staging examinations demonstrated extensive bilateral miliary lung metastases and no CNS metastases according to a magnetic resonance imaging (MRI) brain scan. She began receiving afatinib, 40 mg/d, and had an excellent response until August 2015, when restaging scans showed progression of disease in her lungs, liver, and bones (Fig. 1A). She underwent a computed tomography–guided biopsy of a lung nodule, and molecular testing confirmed the presence of an EGFR T790M mutation in addition to the baseline exon 19 deletion mutation. She therefore consented to participation in a phase 2 study with rociletinib. During the study screening, an MRI brain scan was performed; it showed no evidence of metastatic disease (Fig. 2A). The patient stopped taking afatinib on September 11, 2015, and started taking rociletinib, 500 mg orally twice daily, on September 18, 2015, as the trial required a 7-day washout from afatinib. Three weeks into the treatment course, the patient presented with new left-sided chest pains and a computed tomography chest angiogram was obtained; it ruled out pulmonary embolism but incidentally noted an excellent response to rociletinib within multiple lung metastases (Fig. 1B). Three days later, she experienced seizures and altered mental status requiring admission. Brain MRI showed miliary BMs as well as leptomeningeal involvement (Fig. 1C). After the patient's condition was stabilized with antiepileptics and steroids, she was treated with whole brain radiotherapy, which temporarily improved her neurologic symptoms. She continued to receive rociletinib with a sustained systemic response while receiving whole brain radiation therapy. Unfortunately, after 4 weeks, worsening neurologic symptoms, including confusion and loss of bladder control, redeveloped. Brain MRI showed worsening of disease with new parenchymal and leptomeningeal lesions and progression of existing lesions (Fig. 2). The patient then began receiving osimertinib, 80 mg orally every day, just 1 week after it had received U.S. Food and Drug Administration (FDA) approval. The patient experienced very rapid improvement in cognitive function that was noticeable within days and then gradual improvement in functional status over the ensuing weeks, allowing resumption of her usual activities at home. A follow-up brain MRI scan after she had taken osimertinib for 6 weeks showed near-complete resolution of her CNS disease (Fig. 1D). Here we have reported the case of a patient with advanced, EGFR T790M–positive EGFR-mutated lung adenocarcinoma in whom CNS parenchymal and leptomeningeal disease developed rapidly after she was switched from prior afatinib to rociletinib. Her CNS parenchymal and leptomeningeal disease had been refractory to radiation, but she had a near-complete remission while receiving osimertinib. This case illustrates several important aspects of disease management with imminent and significant clinical implications, such as acquired resistance to targeted therapy, tumor flare, the importance of the blood-brain barrier (BBB) in targeted therapy, and the efficacy of osimertinib after failure of rociletinib therapy with clear-cut activity in the CNS compartment. Poor response and outcome of BM in NSCLC is due in part to poor penetration of multiple drugs through the BBB as well as to the function of the P-glycoprotein that is a product of the multidrug resistance 1 gene (MDR1) and acts as a scavenger of erlotinib and gefitinib as well as afatinib.8Zhang J. Yu J. Sun X. Meng X. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of central nerve system metastases from non-small cell lung cancer.Cancer Lett. 2014; 351: 6-12Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 9Wind S. Schmid M. Erhardt J. Goeldner R.G. Stopfer P. Pharmacokinetics of afatinib, a selective irreversible ErbB family blocker, in patients with advanced solid tumours.Clin Pharmacokinet. 2013; 52: 1101-1109Crossref PubMed Scopus (76) Google Scholar, 10Elmeliegy M.A. Carcaboso A.M. Tagen M. Bai F. Stewart C.F. Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.Clin Cancer Res. 2011; 17: 89-99Crossref PubMed Scopus (87) Google Scholar Although measuring CSF concentration of a drug is not an exact predictor of CNS response in patients with BM, first-line EGFR TKIs have been shown to cross the BBB and accumulate in the CSF to some extent,4Togashi Y. Masago K. Masuda S. et al.Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.Cancer Chemother Pharmacol. 2012; 70: 399-405Crossref PubMed Scopus (232) Google Scholar, 11Hoffknecht P. Tufman A. Wehler T. et al.Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease.J Thorac Oncol. 2015; 10: 156-163Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar with erlotinib achieving the CSF concentration that is highest among them but still significantly lower than plasma levels (Table 1).4Togashi Y. Masago K. Masuda S. et al.Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.Cancer Chemother Pharmacol. 2012; 70: 399-405Crossref PubMed Scopus (232) Google Scholar, 5Lee E. Keam B. Kim D.W. et al.Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer.J Thorac Oncol. 2013; 8: 1069-1074Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar To increase penetration of TKIs, unique brain-directed strategies such as "pulsatile" dosing have been attempted with gefitinib and erlotinib with mixed results.12Grommes C. Oxnard G.R. Kris M.G. et al."Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer.Neuro Oncol. 2011; 13: 1364-1369Crossref PubMed Scopus (284) Google Scholar, 13Jackman D.M. Holmes A.J. Lindeman N. et al.Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib.J Clin Oncol. 2006; 24: 4517-4520Crossref PubMed Scopus (222) Google Scholar In their retrospective case series, Grommes et al. showed a 78% clinical benefit (complete response plus partial response plus stable disease) rate and median overall survival of 12 months with the use of 1500 mg of erlotinib weekly.12Grommes C. Oxnard G.R. Kris M.G. et al."Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer.Neuro Oncol. 2011; 13: 1364-1369Crossref PubMed Scopus (284) Google Scholar Afatinib, a second-generation TKI, has also shown efficacy and activity in CSF with a measured CNS concentration of approximately 1 nmol/L.11Hoffknecht P. Tufman A. Wehler T. et al.Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease.J Thorac Oncol. 2015; 10: 156-163Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Moreover, when used as initial therapy, afatinib has shown a response rate (RR) of approximately 80% in EGFR-mutant patients with exon 19 deletion and BM.3Schuler M. Wu Y.L. Hirsh V. et al.First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases.J Thorac Oncol. 2016; 3: 380-390Abstract Full Text Full Text PDF Scopus (252) Google Scholar A summary of clinical studies using EGFR TKIs in selected EGFR-mutant patients with BM is provided in Table 2.Table 1CSF Concentration of EGFR TKIsTKICSF ConcentrationPenetration RateReferenceGefitinib8.2 ± 4.3 nM1.13 ± 0.36%Togashi et al.4Togashi Y. Masago K. Masuda S. et al.Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.Cancer Chemother Pharmacol. 2012; 70: 399-405Crossref PubMed Scopus (232) Google ScholarErlotinib66.9 ± 39.0 nM2.77 ± 0.45%Togashi et al.4Togashi Y. Masago K. Masuda S. et al.Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.Cancer Chemother Pharmacol. 2012; 70: 399-405Crossref PubMed Scopus (232) Google ScholarAfatinib1 nM0.7%Hoffknecht et al.11Hoffknecht P. Tufman A. Wehler T. et al.Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease.J Thorac Oncol. 2015; 10: 156-163Abstract Full Text Full Text PDF PubMed Scopus (212) Google ScholarCSF, cerebrospinal fluid. Open table in a new tab Table 2Selected Published Trials Evaluating Efficacy of EGFR TKI Monotherapy in Patients with EGFR-Mutant NSCLC with CNS MetastasesTKIPatient PopulationnTypeRRPFSOSReferenceErlotinibEGFR-mutated17R82%11.712.9Porta et al14Porta R. Sanchez-Torres J.M. Paz-Ares L. et al.Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.Eur Respir J. Mar 2011; 37: 624-631Crossref PubMed Scopus (280) Google ScholarErlotinib or gefitinibEGFR-mutated28P83%6.615.9Park et al.15Park S.J. Kim H.T. Lee D.H. et al.Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation.Lung Cancer. 2012; 77: 556-560Abstract Full Text Full Text PDF PubMed Scopus (280) Google ScholarGefitinibEGFR-mutated41P87.814.521.9Iuchi et al.16Iuchi T. Shingyoji M. Sakaida T. et al.Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma.Lung Cancer. 2013; 82: 282-287Abstract Full Text Full Text PDF PubMed Scopus (214) Google ScholarAfatinibEGFR-mutated (pretreated)32R35%4NRHoffknecht et al.11Hoffknecht P. Tufman A. Wehler T. et al.Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease.J Thorac Oncol. 2015; 10: 156-163Abstract Full Text Full Text PDF PubMed Scopus (212) Google ScholarErlotinibEGFR-mutated (pulsatile therapy)9R67%2.712Grommes et al.12Grommes C. Oxnard G.R. Kris M.G. et al."Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer.Neuro Oncol. 2011; 13: 1364-1369Crossref PubMed Scopus (284) Google ScholarAfatinibEGFR-mutated81P82% (del19)60% (L858R)8.222.4Schuler et al.3Schuler M. Wu Y.L. Hirsh V. et al.First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases.J Thorac Oncol. 2016; 3: 380-390Abstract Full Text Full Text PDF Scopus (252) Google ScholarTKI, tyrosine kinase inhibitor; CNS, central nervous system; RR, response rate; PFS, progression-free survival; OS, overall survival. Open table in a new tab CSF, cerebrospinal fluid. TKI, tyrosine kinase inhibitor; CNS, central nervous system; RR, response rate; PFS, progression-free survival; OS, overall survival. Studies have shown that tumor flare can develop in EGFR-mutant patients when the EGFR TKI is removed, even if they are already progressing radiographically while receiving the drug. Chaft et al.17Chaft J.E. Oxnard G.R. Sima C.S. Kris M.G. Miller V.A. Riely G.J. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design.Clin Cancer Res. 2011; 17: 6298-6303Crossref PubMed Scopus (352) Google Scholar noted that clinically significant disease flare developed in 23% of EGFR-mutated patients during the washout period required by clinical trials evaluating newer-generation TKIs. The incidence of BM in the group of patients who had disease flare during the washout period was 29%. In the same study, the median time for disease flare in the brain was 7.5 days and for all sites overall it was 3 to 21 days. Also, the authors did not find any association between disease flare and presence of T790M at the time of acquired resistance. In our patient's case, it is likely that the disease flare developed while she was not receiving afatinib, resulting in early and extensive progression of her disease in the CNS. The half-life of afatinib is 37 hours; therefore, 168 hours of drug cessation (four to five half-lives) could have been sufficient for such development. Also, the fact that she had systemic progressive disease with a documented T790M mutation while receiving afatinib without CNS metastases and her CNS disease developed rapidly subsequent to her stopping afatinib strongly argues that the CNS tumor clones did not carry EGFR T790M and, until that point, were effectively suppressed by afatinib. Rociletinib and osimertinib are third-generation T790M-targeting EGFR TKIs and have each shown activity in T790M-mutant disease. Osimertinib is more potent in inhibiting EGFR phosphorylation in T790M-mutant cell lines with a concentration that inhibits 50% of less than 15 nmol/L as compared with 28 nmol/L in the case of rociletinib.18Cross D.A. Ashton S.E. Ghiorghiu S. et al.AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.Cancer Discov. 2014; 4: 1046-1061Crossref PubMed Scopus (1439) Google Scholar, 19Hirano T. Yasuda H. Tani T. et al.In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.Oncotarget. 2015; 6: 38789-38803Crossref PubMed Scopus (118) Google Scholar In a preclinical study using 11C positron emission tomogrpahy imaging in monkeys, Ballard et al. demonstrated that osimertinib is much more avidly distributed to the cynomolgus monkey brain than is rociletinib.20Ballard P. Yang Z. Cross D. et al.Preclinical activity of AZD9291 in EGFR-mutant NSCLC brain metastases.J Thorac Oncol. 2015; 10 ([abstract]): S300Google Scholar Osimertinib recently received accelerated approval by the FDA on the basis of the results of the AURA-1 and AURA-2 studies showing a RR higher than 50% and progression-free survival of 8.2 months in patients who had progressed after receiving at least one EGFR TKI.6Janne P.A. Yang J.C. Kim D.W. et al.AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med. 2015; 372: 1689-1699Crossref PubMed Scopus (1627) Google Scholar The side effect profile of this drug is very favorable compared with those of older TKIs thanks to its minimal inhibition of wild-type EGFR, and it appears to have better brain penetration as highlighted by our case as well as by cell line and human data.21Nanjo S. Ebi H. Arai S. et al.High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells.Oncotarget. 2015; 7: 3847-3856Crossref Scopus (56) Google Scholar, 22Sequist L.V. Piotrowska Z. Niederst M.J. et al.Osimertinib responses after disease progression in patients who had been receiving rociletinib.JAMA Oncol. 2015; 2: 1-3Google Scholar In the AURA-1 extension study and in the AURA-2 study, the CSF concentrations were 0.77 and 3.44 nmol/L in two patients, which equaled 0.2% and 1% of the free plasma concentration of osimertinib at steady state.23Ahn M.J. Tsai C.M. Yang J.C.H. AZD 9291 activity in patients with EGFR mutant advanced non- small cell lung cancer and brain metastasis: data from phase II studies.Eur J Cancer. 2015; 51 ([abstract]): 3083Abstract Full Text PDF Google Scholar In the phase 1 BLOOM study, patients with leptomeningeal disease who progressed while receiving any EGFR TKI were enrolled and given a 160–mg daily dose of osimertinib. In 10 patients in whom CSF concentration could be measured, the CNS concentration of osimertinib was approximately 5% of the osimertinib concentration in free plasma. Of note is the fact that the dose in this study was 160 mg per day, which is twice the FDA-approved dosing.24Lee D.H. Kim D.-W. Ahn M.-J. et al.AZD9291 activity in patients with leptomeningeal disease from non-small cell lung cancer: a phase I study.Mol Cancer Ther. 2015; 14 ([abstract]): PR07Crossref Google Scholar In comparison, rociletinib had an RR of 34% in T790M-positive patients (the TIGER-X study).25Sequist L.V. Soria J.C. Camidge D.R. Update to rociletinib data with the RECIST confirmed response rate.N Engl J Med. 2016; 374: 2296-2297Crossref PubMed Scopus (68) Google Scholar, 26Goldman J.W. Soria J.-C. Wakelee H.A. et al.Updated results from TIGER-X, a phase I/II open label study of rociletinib in patients (pts) with advanced, recurrent T790M-positive non-small cell lung cancer (NSCLC).J Clin Oncol. 2016; 34 ([abstract]): 9045Crossref Google Scholar These two drugs have not been compared head to head, but clinical proof of concept for the excellent CNS penetration of osimertinib compared with that of rociletinib was described in an analysis of patients who progressed while receiving rociletinib but showed a clinical benefit on osimertinib.22Sequist L.V. Piotrowska Z. Niederst M.J. et al.Osimertinib responses after disease progression in patients who had been receiving rociletinib.JAMA Oncol. 2015; 2: 1-3Google Scholar In this case series, three of nine patients in whom BM had developed while they were receiving rociletinib showed improvement in CNS lesions after treatment with osimertinib. The authors concluded that the lack of response to rociletinib might possibly be due either to only partial inhibition of EGFR signaling or to poor brain penetration of the drug itself. Our case strongly suggests the latter given the disparate systemic and CNS response to rociletinib and very strongly supports the clinical utility of osimertinib in patients with CNS disease and its superiority in this aspect over rociletinib. Overall, our case is notable for the dramatic, near-complete response seen with osimertinib in the setting of extensive, symptomatic, and radiation-refractory CNS and leptomeningeal disease. We believe that the sequence of events was likely a combination of disease flare due to stopping one drug (afatinib) with CNS activity and failure of disease control by a drug with limited CNS penetration (rociletinib), which were eventually controlled by osimertinib, a drug that appears to have good CNS penetration and activity. On the basis of the aforementioned discussion, patients receiving rociletinib should be monitored closely for the development of CNS disease, and osimertinib may be a significantly more potent third-generation EGFR TKI for established CNS disease compared with rociletinib. Osimertinib is FDA approved for the management of patients whose disease harbors T790M mutation, and given its excellent activity and good tolerance, it will have a major impact in the management of this disease. Consent was obtained from the patient before this article was written.
Referência(s)