Keywordsbrain metastases, non-small cell lung cancer, EGFR sensitizing mutation, tyrosine kinase inhibitors, erlotinib
First-Line Treatment for Advanced NSCLC 170
Development and Management of NSCLC Brain Metastases 171
Do EGFR Mutated NSCLC Patients have a Higher Risk of Developing Brain Metastases? 172
Are Brain Metastases in EGFR- Mutated Patients Radiosensitive? 172
Do EGFR TKIs have Efficacy in Treatment and Prevention of Intracranial Disease from NSCLC? 174
What is the Efficacy and Safety of Combining Erlotinib with Radiotherapy for Brain Metastases? 175
Is there a Role for Rechallenge and Pulsed dose Escalation of Erlotinib? 176
Lung cancer affects approximately 1.6 million persons a year globally. In the West, it accounts for approximately 10–15% of new cancer cases and 20–30% of cancer deaths ( ). Metastasis to the brain is responsible for death in up to half of cancer patients. Lung cancer is the most frequent primary site of origin, making up 40–50% of cases ( ). Metastasis involving the central nervous system (CNS) affects approximately 20–40% of patients with non-small cell lung cancer (NSCLC) at some stage in their illness, and is present in about 10% at diagnosis ( ). It is highly likely that brain metastasis from NSCLC will present an increasing clinical challenge, due to improvements in initial radiological staging and longer survival following successful treatment of primary and systemic disease.
Patients developing brain metastases are not a homogeneous population. Developments in both neuro-oncology and thoracic oncology have brought about a change in perspective in recent years. First, improved clinical data have resulted in meaningful stratification of patients with brain metastasis, allowing treatment to be adapted according to therapy context and anticipated outcome. In particular, the use of magnetic resonance imaging (MRI) means the extent of intracranial lesions can be more accurately defined. Classic prognostic classification systems ( ) have been refined to take into account these data as well as primary site of origin. Second, the technical capabilities of both surgery and radiotherapy have improved including highly focused stereotactic irradiation techniques. Third, within medical thoracic oncology, a new generation of drugs has expanded the treatment options for molecularly-defined NSCLC subsets. We now have the first and second generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, and now afatinib, which have proven activity against brain metastases in case reports, retrospective case series and prospective clinical trials.
This chapter discusses the characteristics and standard clinical management of intracranial disease in patients with NSCLC. We focus on the pharmacologic aspects of erlotinib and preclinical evidence for intracerebral activity. We review the evidence for the activity of erlotinib in patients with brain metastases in various treatment settings. Lastly, we discuss opportunities for further research in improving the efficacy of erlotinib as a treatment for intracranial disease in NSCLC patients.
First-Line Treatment for Advanced NSCLC
Primary chemotherapy for advanced NSCLC has for a long time been centered on platinum agents, with adjunctive roles for the taxanes, gemcitabine, vinorelbine and pemetrexed. However, in the last decade, NSCLC has joined a short list of malignancies that display major vulnerability to targeted inhibition of single aberrant kinases, derived from so-called “driver” mutations. One such target is a receptor tyrosine kinase, EGFR, which activates major survival and proliferation signaling pathways. In an initial large phase III trial, the EGFR-TKI erlotinib improved survival overall in previously treated unselected NSCLC patients ( ). However, it became apparent that a subset of these patients demonstrated significant and prolonged treatment responses. These patients displayed common clinical characteristics: often female, light or never smokers, with adenocarcinoma and a greater frequency in East-Asians. Post-hoc analysis revealed that their tumors contained mutations in the tyrosine kinase domain of the EGFR gene, specifically an exon 19 deletion and a point mutation in exon 21 (L858R). Preclinical evidence confirmed that these are driver mutations, defining a specific subtype of adenocarcinoma, distinct from the more highly mutated cancers that are associated with long-term cigarette smoking ( ).
While erlotinib remains licensed for unselected patients with NSCLC in the second- and third-line setting, its major clinical benefit is in those with sensitizing EGFR mutations. Subsequent trials have addressed the role of tyrosine kinase inhibition as primary therapy in this patient subpopulation and confirmed that erlotinib is effective in the first-line treatment of EGFR -mutated NSCLC with better progression-free survival and quality of life when compared to chemotherapy ( ).
Development and Management of NSCLC Brain Metastases
Development of intracranial metastasis from NSCLC requires multiple pathophysiologic steps. After dissemination from the primary tumor, cancer cells must enter and survive in the bloodstream, arrest in the brain capillary bed, extravasate and proliferate. Stromal cells associated with the primary tumor, as well as co-opted brain microglia and astrocytes, have been shown to assist this process and are likely to be an increasing focus of therapeutic attention ( ). Establishment and propagation of a blood vessel supply has been shown to occur by a variety of mechanisms, probably varying by tumor type and disease progression; growth of brain metastasis from NSCLC is at least partly dependent on neoangiogenesis via vascular endothelial growth factor.
Intracranial metastasis is not only a distinct clinical problem in disseminated NSCLC ( ), but is also a frequent site of initial failure in patients with localized disease who have received treatment with curative intent. A review of 112 NSCLC patients found that brain metastasis was observed in 29% of all recurrences, with a median time to brain recurrence of 9 months ( ). Young age, primary tumor size and lymph node metastasis were associated with a higher risk of intracranial involvement. In one retrospective study, the predicted probabilities of developing brain metastasis from node-negative, primary adenocarcinomas measuring 2 or 6 cm were 0.14 and 0.72, respectively ( ). However, tumor size does not fully explain the development of brain metastasis with cases of small or even occult NSCLC metastasizing early to the brain, while other patients with large tumors, or locoregionally or systemically advanced disease may never establish overt intracranial growth. Prophylactic cranial irradiation (PCI) has been shown to reduce the risk of brain metastasis in high-risk NSCLC, but without disease-free or overall survival benefits ( ).
NSCLC patients with brain metastases may present with severe debility and the least-harm, symptom-based approach to maintain quality of life may be the most appropriate management. However, more commonly some permutation of surgery, whole brain radiotherapy (WBRT) and/or stereotactic radiosurgery is usual. In the presence of multiple brain metastases, the basis of treatment is WBRT, combined with short-course corticosteroid therapy to control peritumoral edema. This is historically associated with a median survival of 3–5 months with 10% of patients alive at 1 year. In the presence of three or fewer brain metastases, addition of a second treatment to WBRT (surgery or stereotactic radiotherapy) confers improved prognosis ( ). Furthermore, radiosurgery has been widely adopted as primary sole treatment for patients with oligometastatic disease to the brain. Subsequent systemic cytotoxic chemotherapy is feasible and may confer benefits in a subset of patients with good functional status and a limited number of brain metastases.
Do EGFR Mutated NSCLC Patients have a Higher Risk of Developing Brain Metastases?
There does appear to be a higher incidence of brain metastasis in patients with EGFR -mutated NSCLC. In a retrospective review of 93 patients who developed brain metastasis, 44% demonstrated an EGFR mutation ( ). Median survival in the presence of brain metastasis was higher in the EGFR mutation group, 14.5 vs 7.6 months, although this did not reach independent statistical significance.
Are Brain Metastases in EGFR-Mutated Patients Radiosensitive?
EGFR overactivation was initially viewed as a cause of radioresistance ( ), yet NSCLC with de novo EGFR activation as a driver mutation displays marked radiosensitivity. In vitro , EGFR -mutant lung cancer cell lines show up to 3-log greater sensitivity to ionizing radiation than wild-type cells ( ). A retrospective clinical study of 63 patients with lung adenocarinoma suggested a higher response rate to WBRT in the presence of EGFR -mutated primaries (54% vs 24% wild-type), although interpretation was confounded by concurrent administration of EGFR-targeted drug therapy ( ). Trials with PCI have demonstrated some benefit in patients with NSCLC but it has not been studied in the subset of patient with EGFR mutations. This may be a population in which the benefits of PCI with regard to risk reduction in development of brain metastases, disease-free and overall survival should be studied in a randomized trial.
Erlotinib (OSI-774) is a quinazoline derivative [6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl-(3-ethynylphenyl)amine] which inhibits EGFR kinase activity. It is structurally similar to gefitinib ( Figure 16.1 ). It binds reversibly to the intracellular kinase domain, competing with adenosine triphosphate, and thereby impairing autophosphorylation and the downstream signal cascade. Fifty percent growth inhibition of cell lines with the L858R EGFR mutation is achieved at 100 nanomolar (nM) ( ).
Clinical pharmacology studies have established a standardized oral dose of erlotinib at a 150 milligrams (mg) daily. Adverse effects are principally diarrhea and skin rash, although interstitial lung disease is a rare and potentially life-threatening association. Metabolism is hepatic, mainly via CYP3A4, to the active metabolite desmethyl-erlotinib (OSI-420). The time after administration when the maximum plasma concentration is reached is 3–4 hours with a half-life of 24–36 hours. Concomitant smoking decreases erlotinib exposure. The drug is 93% bound to albumin and alpha-1 acid glycoprotein ( ), disfavoring CNS uptake. It has a molecular weight of 393.4 Dalton (Da) which approaches the limit of blood–brain barrier diffusibility versus active transport. Notably gefitinib has a molecular weight of 446 Da. Erlotinib has moderately high lipophilicity, underlying both relatively good oral absorption and potential for penetration.
Preclinical studies have shown that erlotinib is liable to efflux by components of the blood–brain barrier, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Transgenic mice with double deletions of the genes for P-gp and BCRP demonstrate significantly higher brain accumulation of erlotinib than wild-type animals. P-gp function appears to be the dominant barrier to erlotinib uptake into brain tissue ( ). Empiric evidence for brain penetration by erlotinib derives in part from studies in primary brain tumors. In an early pharmacokinetic study, erlotinib was administered in a pulsed schedule of 450 mg or 900 mg every 72 h, the dose chosen according to concurrent usage of enzyme-inducing antiepileptic drugs (EIAEDs). The use of EIAEDs was associated with increased hepatic metabolism to OSI-420 and increased clearance. Cerebrospinal fluid (CSF) concentrations ranged from 1 to 3% of peak plasma concentrations and the schedule was tolerable ( ). In a pharmacokinetic study in patients undergoing resection for glioblastoma, tumor concentrations of erlotinib and OSI-420 were measured after a week of erlotinib 150 mg daily, 24 h after the last dose. Target site concentrations of erlotinib and OSI-420 were 6–8% and 5–11%, respectively, of concomitant plasma concentrations in evaluable patients ( ).
Gefitinib has demonstrated similar characteristics of low CSF concentrations. The CSF concentrations of gefitinib and erlotinib were directly compared in a series of 15 Japanese patients, the majority receiving either drug and two receiving both drugs sequentially ( ). The mean steady state CSF concentration and penetration rate of gefitinib 250 mg daily were 8.2 nM and 1.13%, respectively. For erlotinib 150 mg daily these figures were 66.9 nM and 2.77%, respectively. Erlotinib therefore had higher CSF penetration than gefitinib in this report.
Radiolabeling of drugs with carbon-11, which decays by positron emission, allows in vivo human biodistribution analyses without tissue sampling. In a case report, [11C]-erlotinib ( ) was administered to a 32-year-old patient with exon 19-mutant NSCLC accompanied by multiple brain metastases and meningeal carcinomatosis ( ). Positron emission tomography (PET)/computed tomography (CT) of the brain was performed during treatment and coregistered with magnetic resonance imaging (MRI). [11C]-erlotinib progressively accumulated in two cerebellar metastases over a 60-minute period, with minimal uptake in the cerebral cortex, giving tumor-to-cortex ratios up to 10:1.
Do EGFR TKIs have Efficacy in Treatment and Prevention of Intracranial Disease from NSCLC?
Early observations with gefitinib showed the potential for treating NSCLC brain metastases with EGFR-TKI. A first report in 2003 of four heavily pretreated patients, three of whom had intracranial progression after WBRT, described three partial responses and one complete response ( ). Several groups have also now reported response in leptomeningeal disease ( ).
Similar cases reports have appeared for erlotinib since 2006 ( ). A recently reported phase II trial in 48 patients from a Chinese population has assessed the efficacy of erlotinib as second-line therapy for NSCLC brain metastases ( ). Inclusion criteria included adenocarcinoma or confirmed activating EGFR mutation and asymptomatic brain metastases without extracranial progressive disease after first-line platinum-based chemotherapy. Erlotinib 150 mg daily was associated with 10.1 month median intracranial progression-free survival, extending to 15.2 months for those with EGFR -mutant disease vs 4.4 months for those without EGFR mutation.
In a case-control study of NSCLC patients with brain metastases treated with erlotinib±WBRT, an EGFR -mutant population was compared to a population with unknown or wild-type EGFR. The objective response rate of the brain metastases was 82% in the mutant population compared to 0% in the control group despite all control group patients additionally receiving WBRT ( ). Interestingly, eight of the patients with mutations did not receive WBRT and erlotinib was their sole treatment. The objective response rate of the brain metastases in these patients was striking at 75%. Interestingly, across all patients receiving erlotinib in this series, more complete responses were attained in brain than at primary lung sites, suggesting at minimum that CNS drug delivery considerations are not an obstacle to efficacy, at least initially in the context of macroscopic intracranial disease. This analysis did not however provide comparative time-to-progression data for those patients receiving erlotinib alone vs WBRT plus erlotinib. In retrospective series, with mixed wild-type and mutated patients, conclusions have not been definitive and have not changed practice, but highlight the need for studies in subgroups with the same biological profile.
There is increasing interest in maintenance drug therapy in the management of advanced NSCLC, with evidence for progression and/or overall survival advantages from docetaxel ( ), pemetrexed ( ) and erlotinib ( ). In unselected treatment populations, erlotinib does not prevent the development of brain metastasis. In the BR21 trial of maintenance erlotinib, some patients were observed to develop brain metastases despite ongoing erlotinib ( ). This was recorded as disease progression but patients continued on-study if there was evidence of extracranial control of disease. Data are unavailable from this study regarding the influence of EGFR- mutation status and the development of brain metastases while taking erlotinib. The most convincing evidence derives from a comparison of upfront EGFR-TKI versus chemotherapy in EGFR- mutant lung cancer in 155 patients. At a median follow up of 25 months, 33% of patients in the EGFR-TKI group and 48% in the chemotherapy group had developed CNS progression, with a hazard ratio of 0.56 ( ).