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Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies

Journal of Thoracic Oncology, Volume 11, Issue 10, October 2016, Pages 1627 - 1643

Commentary by Tom Stinchcombe

Brain metastases are common in patients with NSCLC and some data suggest that patients with EGFR mutant or ALK positive NSCLC may have a higher rate of brain metastases at time of diagnosis. Patients with these oncogenic drivers are treated with targeted therapy and frequently developed progressive disease in the CNS. Tyrosine kinase inhibitors appear to be more effective than chemotherapy in controlling CNS disease. Data suggest that erlotinib CNS penetration exceeds the median inhibitor concentration for EGFR inhibition based on studies evaluating CNS penetration. Small studies revealed gefitinib has a lower rate of CSF penetration. AZD3759 is a novel class of EGFR TKI with better blood brain barrier penetration, but importantly does not have activity against the T790M acquired resistance mutation. Crizotinib has a low penetration of the blood brain barrier, and treatment with crizotinib results in better CNS disease control than chemotherapy. The second-generation alectinib and ceretinib have better CSF penetration than crizotinib. Recently stereotactic radiosurgery (SRS) has been used to treat patients with a limited number of brain metastases (generally 1 to 4), and emerging data suggest SRS is safe in patients with up to 10 brain metastases. Most of the studies investigating the combination of targeted therapies with radiation were performed in unselected patients or are retrospective. The optimal timing and sequence and of targeted therapies and radiation and radiation treatment strategy are undefined. This review on behalf on the IASLC advanced radiation committee provides a valuable update of the ongoing clinical trials and previous trials.

Abstract

Brain metastases (BMs) will develop in a large proportion of patients with NSCLC throughout the course of their disease. Among patients with NSCLC with oncogenic drivers, mainly EGFR activating mutations and anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements, the presence of BM is a common secondary localization of disease both at the time of diagnosis and at relapse. Because of the limited penetration of a wide range of drugs across the blood-brain barrier, radiotherapy is considered the cornerstone of treatment of BMs. However, evidence of dramatic intracranial response rates has been reported in recent years with targeted therapies such as tyrosine kinase inhibitors and has been supported by new insights into pharmacokinetics to increase rates of tyrosine kinase inhibitors' penetration of the cerebrospinal fluid (CSF). In this context, the combination of brain radiotherapy and targeted therapies seems relevant, and there is a strong radiobiological rationale to harness the radiosentizing effect of the drugs. Nevertheless, to date, there is a paucity of high-level clinical evidence supporting the combination of brain radiotherapy and targeted therapies in patients with NSCLC and BMs, and there are often methodological biases in reported studies, such as the lack of stratification by mutation status. Moreover, among asymptomatic patients not suitable for ablative treatment, this strategy is challenged by the promising results associated with the administration of targeted therapies alone. Herein, we review the biological rationale to combine targeted therapies and brain radiotherapy for patients with NSCLC and BMs, report the clinical data available to date, and discuss future directions to improve outcome in this group of patients.

Keywords: NSCLC, Brain metastases, Radiotherapy, Targeted therapies, EGFR, Anaplastic lymphoma kinase.

Introduction

NSCLC accounts for approximately 85% of lung cancers. Most patients present with advanced disease, and despite recent advances in standard treatment, NSCLC still has a poor prognosis, with an estimated 5-year overall survival (OS) rate of 15% to 21%.1 and 2 NSCLC is characterized by a high incidence of central nervous system (CNS) metastases. Brain metastases (BMs) will develop in approximately 25% to 50% of patients with NSCLCs within the course of their disease,3 and 4 with 10% to 20% of them having BMs when the disease is first diagnosed.5 and 6EGFR activating mutations are present in approximately 10% to 20% of white patients with NSCLC (in whom mutations in exons 19 and 21 account for more than 90% of mutations)7 and 8 and anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements (ALK-positive) are present in 3% to 7% of patients with NSCLC.9EGFR mutations are thought to be a positive prognostic factor for outcome,10 whereas the data on ALK rearrangements are more controversial.11 In EGFR-mutated and ALK-positive patients, the incidence of BM at the time of diagnosis is slightly higher than in unselected patients, with an approximate rate of 25%, suggesting that EGFR mutations and ALK rearrangements might be associated with a metastatic tropism to the brain and then with an increased risk for BM.12, 13, 14, 15, and 16 Furthermore, the CNS is a common site of relapse in patients previously treated with tyrosine kinase inhibitors (TKIs) in approximately 30% to 60% of EGFR-mutated17, 18, and 19 and 40% to 70% of ALK-positive NSCLC.20, 21, and 22 This compares with slightly lower overall brain failure rates of 22% to 55% in unselected patients with locally advanced NSCLC treated with definitive therapy.23 There is a paucity of data in the literature on intracranial progression rate for unselected stage IV patients. Interestingly, among patients with NSCLC with EGFR mutation or ALK rearrangement, TKIs seem more effective than chemotherapy to control intracranial disease, suggesting again the role of these pathways in the development of BMs.24 and 25

BMs from NSCLC are associated with major negative effects on both patient quality of life and survival, with a median OS of 3 to 15 months depending on the prognostic group.3, 26, and 27 A range of therapeutic interventions are available depending on the patients’ characteristics and prognosis. There is a belief that chemotherapy alone has a limited role in the treatment of BM owing to the assumed inability of these drugs to cross the blood-brain barrier (BBB), although response rates as high as 30% to 40% have been reported in the brain with platinum-based chemotherapy, principally in chemonaive patients, which is consistent with the rates observed extracranially.28 and 29 In this context, local treatments have been widely assessed in patients with BMs. In patients with a limited number of BMs (1–4 BMs30) and controlled or potentially controllable distant extracranial disease and thoracic disease, several randomized trials have investigated the combination of whole brain radiotherapy (WBRT) with surgery or stereotactic radiosurgery (SRS) performed with “radical” intent. The studies demonstrated that surgery or SRS associated with WBRT improved local control compared with WBRT alone. There was also an impact on OS with the addition of surgery or SRS to WBRT, but only in patients with a single BM.31, 32, 33, 34, and 35 Conversely, the addition of WBRT to surgery or SRS compared with surgery or SRS alone has been proved to increase local control within the brain, but it does not improve survival.36, 37, 38, 39, 40, and 41 Historically, in patients not suitable for local treatments such as SRS and neurosurgery, WBRT has been considered the standard of care despite the lack of level 1 evidence supporting the utility of WBRT compared with supportive care. However, this concept has recently been challenged by the data from the QUARTZ trial comparing optimal supportive care, including dexamethasone plus WBRT (20 Gy in five daily fractions) or optimal supportive care alone in patients with NSCLC, with BM deemed unsuitable for surgery or SRS. Notably, most patients enrolled had a poor overall prognosis according to the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) classification26: 50% had an RPA of 3 and 92% had an RPA of 2 to 3.42 The results presented in abstract form at the 2015 American Society of Clinical Oncology meeting showed no evidence of a difference in OS (hazard ratio [HR] = 1.06, 95% confidence interval: 0.90 – 1.26), overall quality of life, or steroid use between the two groups.43

Nevertheless, it should be noted that most of these strategies have been developed in heterogeneous populations of patients with BMs from a range of solid tumors, whereas evidence of dramatic intracranial response rates have been reported in recent years with TKIs in EGFR-mutated patients with NSCLC,44, 45, and 46ALK-positive patients,47, 48, and 49 and also in unselected patients.50 and 51

In recent years, molecular screening has become the standard of care in stage IV NSCLC, and targeted therapies have been evaluated in patients with NSCLC and BMs in the hope of improving the poor outcomes of this group of patients. This review will focus on the role of targeted therapies combined with brain radiotherapy (RT) in patients with NSCLC and BMs. We aim to provide a biological rationale for combination treatment and report clinical data available to date and to then raise several issues in clinical practice relating to this strategy.

Searches for original and review articles in the PubMed and Google Scholar databases and at the ClinicalTrials.gov website were conducted to identify relevant clinical trials registered in this field. General search terms included the following: NSCLC, brain metastases, whole brain radiotherapy, stereotactic radiosurgery, stereotactic radiotherapy, combination, targeted therapies, blood brain barrier, radiosensitization, EGFR, ALK, erlotinib, and crizotinib, as well as the other main targeted therapies described for NSCLC. Individual bibliographies were reviewed for additional relevant references.

Biological Rationale to Combine Brain RT and Targeted Therapies for BMs

BBB and BMs

The BBB is a selective barrier between the systemic circulation and CSF, which is formed by endothelial cells that line cerebral microvessels, together with the end feet of perivascular astrocytes. Because of complex tight junctions between adjacent endothelial cells, it can regulate most molecular traffic, thus acting as a physical barrier. Large hydrophilic molecules, including most chemotherapeutic and molecular-targeted drugs are generally excluded from the CNS unless they can be transferred by specific receptor-mediated transcytosis.52 and 53

Furthermore, many therapeutic agents are substrates for drug efflux pumps highly expressed on the BBB, such as the P-glycoprotein (PgP), members of the multidrug resistance protein family, or ABCG2 transporter (initially named the breast cancer–resistant protein [BCRP]), which can further reduce intracellular drug levels in the brain.54

BM growth will rapidly compromise the structural and functional properties of the BBB by altering vessel permeability and reducing the expression of drug efflux transporters. However, the disruption of the BBB might not be homogeneous within the BM. Moreover, it has been reported that micrometastatic deposits around the macroscopic tumor keep the BBB intact. Therefore, passage of drugs through the BBB remains an important issue in treatment of BMs.52, 54, 55, 56, and 57

CNS Penetration of Targeted Therapies for Treatment of BMs

TKIs are low-molecular-weight organic compounds (<500 Da generally),58 with low to moderate CSF penetration rates within the brain.59 Erlotinib (and its active metabolite OSI-420) has been found to have a CSF penetration rate between 2.8% and 5.1% of total plasma concentration (5.8% for OSI-420).60, 61, and 62 A report from a patient in whom glioblastoma had been diagnosed showed a CSF penetration rate up to 7% (and 9% for OSI-420).63 Although erlotinib CNS penetration is restricted by drug efflux transporters (PgP and BCRP),64 and 65 these data suggest that erlotinib concentration in the CSF exceeds its median inhibitory concentration value for EGFR inhibition.66 A limited number of small cohort studies have shown that as compared with erlotinib, other first-generation TKIs have low (gefitinib62 and 67) or very low (crizotinib68 and 69) CSF penetration rates. Interestingly, AZD3759 belongs to a novel class of EGFR TKIs, with activity similar to that of first-generation TKIs (no T790M activity) but designed to penetrate the BBB. As AZD3759 is not a substrate of PgP and BCRP efflux transporters, early preclinical data showed that it has significantly better penetration across the BBB than do other approved EGFR TKIs.70 Similarly, the second-generation ALK inhibitors, mainly ceritinib and alectinib, which are selective for ALK at very low concentrations in vitro,71 and 72 might not be transported by efflux proteins73 and therefore may provide far higher CSF penetration rates.74 and 75 These data could partly explain the better intracranial response rates obtained with the next-generation ALK inhibitors as compared with crizotinib.49 Potential future directions to increase TKIs CSF penetration rates, and therefore intracranial control, include development of intra-CSF formulation, inhibition of efflux transporters,76 and pulsatile high-dose administration.77 and 78

With regard to monoclonal antibodies (mAbs) such as bevacizumab, as long as the BBB is fully intact, such drugs are theoretically unable to penetrate the CSF because of their high molecular weight. However, there is a paucity of quantitative data available on the CSF penetration of mAbs.79

Impact of Brain RT on BBB Permeability

As described previously, endothelial cells play a fundamental role in the functioning of the BBB. In the context of brain RT, studies have shown that the development of damage to the BBB can be explained by complex interactions involving endothelial cell death, altered gene expression, and microenvironmental changes.80

DNA damage–induced mitotic cell death is known to be the established radiation-induced death pathway for eukaryotic cells, but other cell death pathways after irradiation have been described.81 Indeed, the cell membrane also represents a major target in radiation-induced apoptosis through activation of the acid sphyngomyelinase enzyme, which in turn leads to sphyngomyelin hydrolysis to ceramide, subsequently inducing apoptotic signal transduction.82 and 83 This ceramide-induced apoptosis pathway is crucial in radiation-induced endothelial cell death, particularly in the context of high single-dose radiation (>10 Gy).84 and 85 However, data have also shown that endothelial cells actually undergo two waves of radiation-induced cell death after exposure to radiation: an early ceramide-mediated apoptosis as described (in <24 hours) and also a delayed DNA damage–induced mitotic death (at ≥72 hours)86 that has been reported to occur up to 1 month after RT.87

Overall, these data provide a radiobiological rationale to explain how RT to the brain can lead to early and delayed focal disruption of the BBB, from 1 week after the initiation of RT to 1 month after the completion of treatment, as reported previously.88 and 89 Brain irradiation has been described to affect the blood-tumor barrier as well as the healthy irradiated BBB, but to a lesser extent.89 and 90 These effects were observed for both focal RT to the tumor and WBRT starting with radiation doses in the range of 20 to 30 Gy with a fraction size of 2 Gy.88, 89, 90, and 91 As for SRS, no robust clinical data have been reported to date, although a fraction size larger than 10 Gy has been suggested to disrupt the BBB in a preclinical study.85

Finally, this BBB disruption after focal RT or WBRT is presumed to lead to an increase in drug permeability,90, 91, 92, 93, and 94 although contradictory clinical data have been reported after WBRT in patients with BMs from NSCLC.95

Radiosensitizing Effects of Targeted Therapies

The rationale to combine brain RT and targeted therapies in patients with BM is also based on the radiosensitizing effects of such drugs, thus enabling better intracranial control.

An inverse relationship between wild-type EGFR overexpression and tumor cell response to radiation in vitro and in vivo has been found.96 and 97 This could be explained by the fact that the EGFR pathway has been described as a classic radioresistance pathway through several mechanisms. First, radiation-induced activation of the EGFR pathway without ligand98 leads to accelerated repopulation via the Ras/MAP kinase pathway.99 and 100 Secondly, there is increased cell survival by means of the phosphoinositide 3-kinase (PI3K)/AKT pathway,101 as well as EGFR ligand synthesis (transforming growth factor-α and amphiregulin), which in turn activates the PI3K/AKT pathway in an autocrine loop.102 Third, radiation-induced nuclear translocation of wild-type EGFR in turn activates the nonhomologous end-joining DNA double-strand break repair pathway.103 and 104 EGFR inhibition may silence these EGFR radioresistance pathways and could enhance the antitumor activity of ionizing radiation through several mechanisms, including cell cycle arrest, apoptosis induction, and targeting of accelerated cellular repopulation and DNA damage repair (through inhibition of Rad51).105 and 106

Conversely, NSCLC cell lines with somatic activating mutation have been found to exhibit a highly radiosensitive phenotype compared with wild-type cell lines, partly owing to a defect in radiation-induced translocation to the nucleus.107 and 108 There is a limited understanding of the precise effect of the combination of radiation and TKIs on EGFR-mutated cell lines, but recent data favor an additive rather than a synergistic effect.109 and 110

Overall, the data suggest that TKIs can decrease overexpressed EGFR wild-type cells' radioresistance and increase the radiosensitivity of EGFR-mutated cells.

The echinoderm microtubule associated protein like 4–ALK fusion protein leads to an aberrant activation of the ALK tyrosine kinase involved in several downstream signaling pathways, mainly the mitogen-activated protein kinase and PI3K/AKT pathways.111 ALK-related radiosensitization mechanisms have been less well described, but recent data suggest that in ALK-positive cells only, the combination of crizotinib with radiation results in greater inhibition of tumor growth and microvascular density than does either treatment alone through an increase in antiproliferative and proapoptotic effects.112 and 113

With regard to antiangiogenic agents, their radiosensitizing effects on both the microenvironment and tumor cells have been widely described.114 First, a hypoxic tumor microenvironment stimulates upregulation, through hypoxia-inducible factor-1α, of angiogenic factors such as vascular endothelial growth factor.115 and 116 This prompts angiogenesis, giving rise to anarchic and nonfunctional microvessels, which in turn increases hypoxia. Antiangiogenic agents thus enable the reorganization of microvessels, resulting in a “tumor vasculature normalization window”117 and a radiosensitizing effect through tumor reoxygenation. Second, it has been demonstrated that when delivered before single-dose RT, antiangiogenic agents can enhance radiation-induced acid sphingomyelinase activation, leading to a synergistic increase of endothelial apoptosis.118 Third, data have suggested that antiangiogenic/radiation-induced damage to endothelial cells can result in increased rates of tumor cell apoptosis, through both inhibition of tumor cell-expressed autocrine growth factors and receptors and loss of endothelial-derived paracrine factors needed for tumor growth.119, 120, and 121

Lastly, given that prospective trials using poly–adenosine diphosphate ribose polymerase (PARP) inhibitors in association with brain RT for BM are currently recruiting patients (Table 1), the radiosensitization mechanisms deserve to be briefly mentioned. DNA double-strand break is the critical radiation-induced damage leading to cell death, whereas single-strand breaks, which are much more numerous after irradiation, can easily be repaired by using the PARP enzyme. Inhibition of PARP prevents the irradiated cells from repairing DNA single-strand breaks, leading to an increase in double-strand breaks through the DNA replication machinery.123

Table 1

Ongoing and/or Unpublished Clinical Trials Combining Radiation and Novel Targeted Agents for NSCLC BMs

source: Data from ClinicalTrials.gov.122

 

Study Trial Phase Estimated Enrollment Estimated Primary Completion Date Selected Mutation Group Primary Site Arms Primary End Point(s) Secondary End Point(s)
EGFR inhibitors
 Erlotinib
NCT02556593 2 116 August 2019 EGFR wild type NSCLC WBRT (45 Gy in 15 fx) + errlotinib (150 mg/d) 2-y CNS PFS
NCT01518621 2 150 December 2017 Unselected NSCLC WBRT (30 Gy in 10 fx) + erlotinib (150 mg/d) vs. WBRT alone Median OS Toxicity, LC, TNP
NCT01887795 3 224 August 2016 EGFR mutant NSCLC WBRT (40 Gy in 20 fx) + erlotinib (150 mg/d) vs. WBRT alone TNP OS, tumor response, QOL
NCT00268684 3 381 Unselected NSCLC WBRT + SRS + TMZ vs. WBRT + SRS + erlotinib vs. WBRT+SRS alone OS
 Gefitinib
NCT02338011 2/3 210 November 2017 EGFR mutant NSCLC WBRT (30 Gy in 10 fx) + gefitinib (250 mg/d) vs. gefitinib alone PFS OS, QOL, MMSE
NCT01363557a 2 1 August 2012 EGFR mutant Lung NOS WBRT (30 Gy in 10 fx) + gefitinib (250 mg/d) vs. gefitinib alone Tumor response Toxicity, PFS, OS
 Icotinib
NCT01926171 4 80 September 2016 Unselected NSCLC WBRT (40 Gy in 20 fx) + icotinib Tumor response DC, PFS, toxicity
 Vandetanib
NCT00807170a 1 5 August 2010 Unselected NSCLC WBRT (30 Gy in 10 fx) + vandetanib (100 mg/d, 200 mg/d, 300 mg/d) MTD Clinical and radiographic PFS
 Lapatinib
NCT01218529b 2 82 August 2014 Unselected Lung NOS, breast WBRT (30 Gy in 10 fx) + lapatinib (1250 mg/d) Tumor response DC, PFS, toxicity
 Nimotuzumab
NCT00872482a 2 21 July 2011 Unselected NSCLC WBRT (30 Gy in 10 fx) + nimotuzumab (200 mg/wk) vs. WBRT alone Tumor response OS, TNP, PFS, OS
ALK inhibitors
 TKI (NOS)
NCT02314364 2 30 November 2021 EGFR mutant, ALK+ or ROS1 mutant NSCLC SRS + TKI 12-mo DF Toxicity, PFS, OS, patterns of failure
Antiangiogenic agents
 Cediranib
NCT00937482b 1 18 March 2011 Unselected NSCLC WBRT + cediranib MTD Neurologic PFS, OS
 Sunitinib
NCT00981890b 1 22 July 2014 Unselected Any cancer SRS + sunitinib MTD, toxicity Toxicity, PFS
 Sorafenib
NCT01276210 1 23 January 2018 Unselected Any cancer, excluding SCLC and lymphoma SRS + sorafenib MTD PFS, OS
NCT00639262b 1 35 September 2012 Unselected Any cancer RT + sorafenib (200 mg twice daily) MTD Tumor response, PFS, toxicity
 Endostar
NCT01410370 2 80 Unknown Unselected Any cancer WBRT (30 Gy in 10 fx) + endostar (7.5 mg/m2/d) vs. WBRT alone ORR OS, VEGF levels, toxicity
 Cilengitide
NCT00884598 1 21 Unknown Unselected Lung (SCLC or NSCLC) WBRT + cilengitide MTD, toxicity ORR, OS, PFS, toxicity
PARP inhibitors
 Veliparib (ABT-888)
NCT01657799b 2 307 January 2015 Unselected NSCLC WBRT (30 Gy in 10 fx) + veliparib (low and high dose) vs. WBRT + placebo OS Tumor response, PFS
 Iniparib (BSI-201)
NCT01551680a 1 3 February 2014 Unselected Any cancer WBRT (37.5 Gy in 15 fx) + iniparib (2.8, 4, 5.6, 8, or 11.2 mg/kg) MTD Toxicity, QOL, ORR, PFS
mTOR inhibitors
 Everolimus
NCT00892801a 1 5 February 2011 Unselected NSCLC WBRT (30 Gy in 10 fx) + everolimus (5 or 10 mg/d) MTD, median OS Tumor response, toxicity, TNP, PFS
ATR inhibitors
 VX-970
NCT02589522 1 46 June 2017 Unselected NSCLC WBRT + VX-970 MTD, toxicity QOL, toxicity, PFS, OS

a Study terminated.

b Study completed.

BM, brain metastasis; WBRT, whole brain radiation therapy; fx, fraction; CNS, central nervous system; PFS, progression-free survival; OS, overall survival; LC, local control; TNP, time to neurological progression; QOL, quality of life; SRS, stereotactic radiosurgery; TMZ, temozolomide; MMSE, Mini Mental Status Examination; NOS, not otherwise specified; DC, distant control; MTD, maximum tolerated dose; TKI, tyrosine kinase inhibitor; DF, distant failure; RT, radiation therapy; ORR, objective response rate; VEGF, vascular endothelial growth factor; PARP, Poly(adenosine diphosphate ribose) polymerase; mTOR, mammalian target of rapamycin; ATR, ataxia telangiectasia receptor.

Combination of RT and Targeted Therapies: Clinical Data

EGFR Inhibitors

The role of EGFR inhibitors combined with RT in patients with BMs has been evaluated in multiple studies: the published studies, summarized in Table 2, included both EGFR-mutant and wild-type patients. One of the most studied EGFR TKIs is erlotinib. Lind et al. conducted a dose escalation phase I trial of erlotinib delivered concurrently with WBRT in patients with NSCLC and BMs and demonstrated no treatment-related neurotoxicity with doses of 100 and 150 mg daily.124 Subsequently, Welsh et al. conducted a phase II trial of erlotinib delivered concurrently with WBRT in patients with NSCLC and BMs, regardless of EGFR status.125 The median OS was 11.8 months for the 40 patients included in the study. In patients with known EGFR status (n = 17), the median survival was 9.3 months for wild-type EGFR (n = 8) compared with 19.1 months for those with EGFR mutations (n = 9). As all patients were treated with WBRT plus erlotinib, it is not possible to conclude whether the EGFR status is a prognostic or predictive factor of survival. Two phase III studies have compared brain RT alone with brain RT plus erlotinib. The Radiation Therapy Oncology Group 0320 study evaluated whether temozolomide or erlotinib combined with WBRT plus SRS in molecularly unselected metastatic patients with NSCLC, irrespective of EGFR status, could improve OS compared with WBRT plus SRS alone.126 They reported a worse survival in the erlotinib and temozolomide combination arms compared with in the arm with WBRT plus SRS alone. Furthermore, grade 3+ toxicity was significantly increased in the combination arms. Limitations of the study included the lack of power (closed early on account of slow accrual) and the absence of stratification by EGFR status.

Table 2

Published Prospective Trials Combining Radiation and Novel Targeted Agents for NSCLC BMs

 

Study Trial Phase No. of Patients Mutation Status Arms Outcomes
EGFR inhibitors
 Erlotinib
 Lind et al.124 1 11 EGFR status not reported Erlotinib (100 mg/d or 150 mg/d) + WBRT (30 Gy in 10 fx) mOS: 4.4 mo Intracranial PFS: 90.9% 1 G3 rash and 1 G3 fatigue (150 mg/d)
 Sperduto et al. (RTOG 0320)126 3 126 EGFR status not reported WBRT (37.5 Gy in 15 fx) and SRS alone vs. TMZ (75 mg/m2/d × 21 d) + WBRT + SRS vs. ETN (150 mg/d) + WBRT + SRS mOS: 13.4, 6.3, 6.1 mo (NS) Grade ≥3 toxicity: 11%, 41%, 49% (SS)
 Welsh et al.125 2 40 EGFR mut (n = 17) EGFR wt (n = 9) Erlotinib (150 mg/d) + WBRT (35 Gy in 14 fx) mOS: 11.8 mo mOS (EGFR positive vs. negative): 19.1 vs. 9.3 mo (NS)
 Lee et al.127 2 80 EGFR mut (n = 1) EGFR wt (n = 34) Erlotinib (100 mg/d) + WBRT (20 Gy in 5 fx) vs. Placebo + WBRT (20 Gy in 5 fx) mOS: 3.4 vs. 2.9 mo (NS) nPFS: 1.6 vs. 1.6 mo (NS)
 Zhuang et al.128 2 54 EGFR mut (n = 11) EGFR wt (n = 12) WBRT alone (30 Gy in 10 fx) vs. Erlotinib (150 mg/d) + WBRT (30 Gy in 10 fx) mOS: 8.9 vs. 10.7 mo (SS) ORR: 54.8% vs. 95.7% (SS) Local PFS: 6.8 vs. 10.6 mo (SS)
 Gefitinib
 Pesce et al. (SAKK 70/03)129 2 59 EGFR status not reported Gefitinib (250 mg/d) + WBRT (30 Gy in 10 fx) vs. TMZ (75 mg/m2) + WBRT (30 Gy in 10 fx) mOS: 6.3 vs. 4.9 mo (NR)
 Icotinib
 Zhou et al.131 1 15 EGFR mut only Icotinib (125 mg tid, 250 mg tid, 375 mg tid, 500 mg tid, 625 mg tid) + WBRT (37.5 Gy in 15 fx) 125–375 mg tid well tolerated
 Fan et al.132 2 20 EGFR mut (n = 10) EGFR wt (n = 8) Icotinib (150 mg tid) + WBRT (30 Gy in 10 fx) mOS: 14.6 mo mOS (EGFR positive vs. negative): 22.0 vs. 7.5 mo (SS) mPFS: 7.0 mo
Antiangiogenic agents
 Bevacizumab
 Levy et al.137 1 19 VEGF status not reported Bevacizumab (5, 10, 15 mg/kg every 2 wk) + WBRT (30 Gy in 15 fx) d 15 3-mo ORR: 52.6% Grade 1 and 2 toxicities: 26% and 47% No intracranial bleeds

BM, brain metastasis; WBRT, whole brain radiotherapy; fx, fraction; mOS, median overall survival; PFS, progression-free survival; G3, grade 3; RTOG, Radiation Therapy Oncology Group; SRS, stereotactic radiosurgery; TMZ, temozolomide; ETN, erlotinib; NS, nonsignificant; SS, statistically significant; mut, mutant; wt, wild-type; nPFS, neurologic progression free survival; ORR, objective response rate; SAKK, Swiss Group for Clinical Cancer Research; NR, not reported; tid, three times daily.

In the U.K. TACTIC study, 80 molecularly unselected patients with NSCLC with multiple BMs were randomized to either WBRT plus placebo or WBRT plus erlotinib followed by erlotinib maintenance. The study showed no advantage in neurological progression-free survival (PFS) or OS for concurrent erlotinib and WBRT in patients with predominantly EGFR wild-type NSCLC (only 1 of 35 patients with available samples had an EGFR mutation).127

Few studies have reported the outcome of the combination of erlotinib and brain RT in patients with a known EGFR status. A phase II trial from China (n = 54) found the combination WBRT plus erlotinib to have improved local PFS and OS as compared with WBRT alone. Of the 23 patients included in the WBRT plus erlotinib arm, 48% were EGFR mutated, and 52% were EGFR wild type. PFS and OS were similar in both groups. This study should be interpreted with caution, however, because the treatment was not allocated randomly and EGFR status in the WBRT-only cohort was unknown.128

The benefit of combining gefinitib with RT has also been evaluated. The Swiss Group for Clinical Cancer Research 70/03 trial was a phase II trial randomizing unselected patients with NSCLC and BMs to receive WBRT plus gefitinib or WBRT plus temozolomide.129 Although gefinitib appeared to be well tolerated, median OS was poor in both arms (6.3 months and 4.9 months, respectively). A recent pooled analysis of the literature included eight prospective trials (980 participants) evaluating the efficacy and safety of EGFR TKIs (including erlotinib and getitinib) combined with RT in NSCLC and BMs. The analysis demonstrated a significant benefit of the addition of EGFR TKIs in terms of objective response rate (HR = 1.56), prolonged time to intracranial progression (HR = 0.58), and median OS (HR = 0.68). The analysis did not assess outcomes according to EGFR status.130

Icotinib has also demonstrated tolerable side effects and efficacy in association with brain RT NSCLC,131 and 132 and other EGFR TKIs (vandetanib and lapatinib) are being tested.

Additional studies are being conducted with anti-EGFR monoclonal antibodies. Nimotuzumab is one such agent found to have promising activity in multiple cancers, including head and neck, pediatric, and NSCLC. Preclinical data suggest that it may enhance antitumor activity of RT, and the overall side effects appear tolerable.133 Unlike other anti-EGFR mAbs, nimotuzumab is not associated with a severe acneiform rash.134 Preliminary phase II randomized data on nimotuzumab combined with WBRT versus WBRT alone for advanced NSCLC with unresectable BMs was presented at the annual European Organisation for Research and Treatment of Cancer meeting in 2008.135 The primary end point was disease control rate (DCR) and the secondary end points were OS and safety. The study found a higher DCR with combined modality treatment (91.6% versus 44.4%) and an improved median OS when compared with WBRT alone (7.00 versus 2.47 months [p = 0.0039]).

Clinical trials combining EGFR inhibitors with brain RT (WBRT or SRS) and currently recruiting patients are summarized in Table 1.

Anaplastic Lymphoma Kinase Inhibitors

There are currently no published prospective clinical trials evaluating toxicity and outcomes of brain RT delivered concurrently with an ALK inhibitor. However, a recent multi-institutional, retrospective study reported outcomes of 90 patients with NSCLC and BMs and ALK positivity treated with a TKI (crizotinib [n = 84], ceritinib [n = 21], AP-26113 [n = 16], alectinib [n = 2], or X-396 [n = 2]).136 Most patients (84 of 90) were treated with brain RT (WBRT or SRS): 43 received a repeat RT procedure and 21 received three or more procedures. However the timing of RT was not precisely described. Overall, the authors concluded that ALK-positive patients with BMs had a prolonged survival when treated with systemic TKIs and brain RT, as the median OS after diagnosis of BM was 49.5 months. Notably, the study reported improved median OS among patients with no history of TKIs before the development of BM as compared with among those patients who began TKI therapy before the diagnosis of BM (54.8 months versus 28.4 months [p < 0.001]). Median intracranial PFS was 11.9 months. The ongoing phase II trial (NCT02314364) combining SRS with any TKI will provide further information on the safety and efficacy of ALK inhibitors in the treatment of ALK-positive patients with NSCLC and BMs (see Table 1).

Antiangiogenic Agents

The safety and efficacy of combining WBRT with bevacizumab was prospectively evaluated in the REBECA phase I study (see Table 2).137 Patients received three cycles of bevacizumab at escalating doses (5, 10, and 15 mg/kg every 2 weeks) with WBRT (30 Gy in 15 fractions) administered from day 15 of bevacuzimab; 10 of the 19 patients had an intracranial treatment response at 3 months, with grade 1 and 2 toxicities occurring in five and nine patients respectively; no grade 3 or higher toxicity was reported. There are currently no published clinical data regarding the combination of vascular endothelial growth factor inhibitors and SRS in patients with NSCLC.

Ongoing clinical trials combining other antiangiogenic agents, such as multitargeted antiangiogenic TKIs (sunitinib, sorafenib, and cediranib), endostar, or cilengitide, with brain RT are summarized in Table 1. Endostar is a human recombinant of endostatin (an endogenous inhibitor of angiogenesis and tumor growth138); it was approved by the Chinese State Food and Drug Administration in 2005 for use in combination with chemotherapy for the treatment of NSCLC. Lastly, cilengitide is an antagonist of the αvβ3 integrin which has been proved to radiosensitize lung cancer cells in vitro,139 probably through tumor vasculature normalization and tumor hypoxia regulation.140

Other Targeted Therapies in Combination with Brain RT

There are multiple ongoing trials evaluating other targeted therapies combined with WBRT or SRS in the treatment of patients with NSCLC and BM (see Table 1).

PARP has also been demonstrated to be overexpressed in multiple cancers, including NSCLC.141 PARP inhibitors such as veliparib are being actively studied in NSCLC. Results from a phase I trial (NCT00649207) evaluating the maximum tolerated dose and associated toxicity of veliparib plus WBRT found better than predicted survival rates and toxicity comparable to that in the historical data on WBRT alone.142 and 143 The subsequent phase II study (NCT01657799) comparing veliparib and WBRT to placebo and WBRT was presented at the 2015 American Society of Clinical Oncology meeting.144 The trial found no statistically significant difference in OS, intracranial response rate, or time to clinical or radiographic progression between the two study arms.

Additional pathways are also being studied, including the PI3K-Akt–mammalian target of rapamycin pathway, which is thought to play a role in NSCLC cases with acquired resistance to EGFR inhibition.145 Everolimus is currently being evaluated with WBRT in a phase I trial (NCT00892801).

Gray Areas in Combination of RT and Targeted Therapies in Clinical Routine

Treatment Decisions Based on Mutational Status

The question as to whether targeted therapies should be combined with brain RT only in patients with oncogenic drivers remains unanswered. EGFR status is known to be predictive of intracranial response to TKIs when administered alone,45 and 46 and although the radiosensitizing effect of EGFR TKIs has been established with both EGFR wild-type and EGFR-mutated cells, the clinical data that we have summarized here do not support the use of the combination in wild-type patients.

Furthermore, another consideration when assessing the efficacy of targeted therapies is the presence of potential mutational heterogeneity between the primary tumor and the metastases. Substantial both-way discordance (roughly 30%) has been reported in EGFR and KRAS mutational status between the primary tumors and corresponding metastases in patients with NSCLC.146, 147, and 148 However, it is not practical to perform biopsies of the BMs given the risk for complications in patients eligible only for palliative treatment and possible heterogeneity of the samples.

Optimal Timing for the Combination

The optimal timing of targeted therapies and brain RT is still unclear. On the basis of radiobiological considerations, targeted therapies should be introduced before, or at the latest, on the first day of RT in an attempt to potentiate the effects of ionizing radiation as described earlier. In most prospective studies both systemic targeted therapies and brain RT were started on the same day,125, 126, 127, and 128 whereas Lind et al. initiated erlotinib 1 week before the start of RT.124 Such timing could be relevant to synchronize the cell cycle before radiation but most importantly to reach a steady-state concentration of erlotinib in the serum as well as in the CSF,149 particularly during treatment with SRS. To our knowledge, however, no biological data have been published to support either strategy.

Another unanswered question is the duration of systemic therapy, which is to some extent driven by the extracranial disease. As discussed earlier, brain RT durably alters the BBB, so that potential increased permeability and therefore increased CSF drug concentration is expected to be effective for up to approximately 1 month after the completion of brain RT. Consequently, several scenarios should be considered. In case of upfront brain RT plus TKI treatment in patients with an oncongenic driver, the TKI should be continued until unacceptable toxicity, clinically meaningful systemic disease progression, or death. In the case of intracranial progression as a single site of oligoprogression among patients with an oncogenic driver who are receiving a TKI, whether the drug should be interrupted during WBRT or SRS remains debated. As previously discussed, the combination of erlotinib or gefitinib plus WBRT with or without SRS or SRS alone has been reported to be a safe approach.125, 126, 127, 129, and 150 Furthermore, this “no stop” strategy has been evaluated in patients with NSCLC with isolated oligoprogression within the brain while they are receiving erlotinib or crizotinib.22 Treatment with SRS or WBRT and continuation of the same targeted therapy was associated with additional disease control of more than 7 months and acceptable toxicity.

Can WBRT Be Omitted or Delayed in Patients with Oncogenic Drivers?

Given the potential neurocognitive impairment after WBRT,151 emerging data support TKIs being a reasonable option for asymptomatic BM unsuitable for local ablative treatments, but further investigation is required to determine whether this is the optimal option.152

Chemotherapy alone for newly diagnosed NSCLC with asymptomatic BM results in significant intracranial response rates, with no impact of delayed WBRT on patient outcome.28, 153, and 154

Likewise, the use of targeted therapies in patients with oncogenic drivers shows promising intracranial activity, suggesting that the use of WBRT could be omitted or delayed.

In a recent review, the use of first-generation EGFR TKIs without brain RT was associated with intracranial response rates between 10% and 70% among unselected patients (but clinically “enriched” for patients with a high likelihood of activating EGFR mutations) and between 75% and 90% in patients with activating EGFR mutations.155 Two phase II trials were included in this review.44 and 46 In a Korean study evaluating EGFR TKIs alone in 28 patients with NSCLC and BMs harboring EGFR mutations, 83% of patients showed an intracranial partial response with a DCR of 93%. Median PFS and OS were 6.6 months and 15.9 months, respectively.44 Another Asian phase II study reported the results of erlotinib alone as second-line treatment for asymptomatic BMs in 48 patients with adenocarcinoma, 17% of whom were known to have an EGFR mutation and 52% of whom had an unknown status. The overall response rate was 58.3%, with a median OS of 18.9 months. As expected, patients with EGFR mutation–positive disease had significantly longer median PFS as compared with those with EGFR wild-type disease.46

With regard to second-generation EGFR TKIs, a prespecified subgroup analysis of LUX LUNG 3 and LUX LUNG 6 has been reported recently; it assessed the efficacy of afatinib as first-line treatment in patients with asymptomatic BMs from NSCLC and with common EGFR activating mutations. This combined analysis included 81 patients, approximately 30% of whom had received prior WBRT. PFS was significantly improved with afatinib versus with chemotherapy in patients with BMs (8.2 versus 5.4 months [HR = 0.50, p = 0.0297]), with an increase in overall response rate. The magnitude of PFS benefit with afatinib favored those patients who had received WBRT before the study, but statistical significance was not reached.156 No specific data on patients with BMs treated with dacomitinib are available yet; however, a phase II trial is currently recruiting patients (NCT02047747). To date, there are too few data with third-generation EGFR TKIs, but some reports among patients with BMs seem promising.157, 158, and 159

The intracranial activity of crizotinib in ALK-positive patients is well documented. Data from the PROFILE 1014 trial in first-line treatment showed an intracranial DCR of 56% at 24 weeks with crizotinib versus 25% with chemotherapy.25 A large retrospective study with pooled data from PROFILE 1005 and PROFILE 1007 examined the efficacy of crizotinib beyond first-line treatment in 275 ALK-positive ALK TKI–naive patients with asymptomatic BM at baseline, 109 of whom had received no prior brain RT and 166 of whom had received prior brain RT.21 The 12-week intracranial DCRs among patients previously untreated and treated with RT were 56% and 62%, respectively; the intracranial overall response rates were 18% and 33%, respectively. Interestingly, systemic DCR was statistically correlated with intracranial DCR. The intracranial times to progression were 7 months and 13.2 months, respectively. Even after CNS disease control has been achieved with crizotinib initially, it does not seem to be durable, as patients frequently demonstrate intracranial progression as the first disease of progression. Prolonged survival with crizotinib has been recently described among patients with BMs, particularly in TKI-naive patients with no extracranial metastases, but it should be noted that most of them had received brain RT.136 Data about next-generation ALK TKIs have been compiled in another recent review: these drugs seem to show more promising results in patients with BM, with intracranial response rates between 35% and 100%.49

Finally, bevacizumab has been evaluated in patients with BMs, and it can be delivered safely in addition to chemotherapy in molecularly unselected patients with NSCLC with good intracranial response rates.160 and 161 In the phase II trial AVF3752g (PASSPORT), the addition of bevacizumab to other chemotherapy agents was shown to be safe with a low incidence of brain hemorrhage (no grade ≥2 hemorrhage).160 In the phase II BRAIN trial that evaluated the safety and efficacy of bevacizumab in chemotherapy-naive or pretreated patients with NSCLC and asymptomatic untreated BM, the investigators found higher than expected intracranial (61.2%) and extracranial (64.2%) response rates compared with the historical data and an encouraging PFS of 6.3 months. One grade 1 intracranial hemorrhage occurred and resolved without specific treatment.161 Finally, retrospective analysis of intracranial outcomes of patients with advanced nonsquamous NSCLC treated in the phase III AVAIL trial of cisplatin-gemcitabine with and without bevacizumab demonstrated statistically significantly fewer recurrences in the brain and a lower risk for BM development over time in the bevacizumab arm.162

Conclusions and Future Perspectives

The optimal management of patients with NSCLC and BMs is an evolving paradigm. Patients with a small number of metastases are treated more aggressively with local therapies such as SRS, especially with oligoprogressive disease. Indeed, emerging data suggest that SRS can be delivered safely in patients with up to 10 BMs.163 In patients not suitable for local treatments, new developments in WBRT techniques with hippocampal sparing may reduce neurocognitive toxicity.164

New systemic therapies and particularly targeted therapies have improved the prognosis of metastatic patients with NSCLC.165 and 166 One of the main limitations with regard to the use of such treatment is the insufficient intracranial penetration; however, new generations of targeted therapies show promising results in patients with BM.

On the basis of a strong biological rationale and emerging clinical data, the combination of brain RT with targeted therapies is probably one of the most promising strategies to tackle intracranial metastatic disease in patients with oncogenic drivers. However, there is a need to clarify the efficacy and timing of both local or systemic strategies in prospective clinical trials. Currently, published data and most ongoing trials (see Tables 1 and 2) combine targeted therapies with WBRT. Another important question is the whether the combination of these therapies with SRS is safe and efficacious. The combination of an increased radiation dose to the metastases and reduced RT exposure to the healthy brain makes SRS an attractive RT technique to be combined with systemic therapies to treat BM, but this needs to be confirmed in prospective trials.

Although immunotherapy alone recently showed promising clinical activity in patients with NSCLC and untreated BMs with a favorable safety profile,167 to date there are no peer-reviewed published prospective studies combining RT with immunotherapy in patients with NSCLC and BMs. Several reports, mostly on melanoma and renal cell carcinoma, have described a phenomenon known as the abscopal effect, in which administration of RT, before or after immunotherapy, caused treatment response at a distant tumor site that was not targeted with RT.168 and 169 Future studies are needed to evaluate whether this phenomenon can be replicated in NSCLC BMs.

Finally, in the precision medicine era, another challenge is to identify subgroups of patients with NSCLC and BMs who might benefit more from such combination of treatment on the basis of molecular profiles and histological and clinical data (including performance status, status of thoracic and distant extracranial disease, and the number of BMs). This would lead to the development of new prognostic and predictive scores and is supported by recent retrospective data having suggested a strong impact of gene mutations on OS (positively for EGFR and ALK and negatively for KRAS) in patients with adenocarcinoma after the development of BM, regardless of the use of targeted therapies.170

Even among well-selected patients, the optimal combination of concurrent RT and targeted therapies is still to be defined, mainly owing to pharmacological uncertainties. Further efforts are therefore needed to develop optimal strategies, and quantify the magnitude of benefit, in every subgroup of patients in the context of innovative randomized clinical trials.

Acknowledgments

Dr. Popat acknowledges National Health Service funding to the National Institute for Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research. The authors also would like to thank Nicola Stones for editorial assistance.

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Footnotes

a Radiotherapy Related Research, The Christie National Health Service Foundation Trust, Manchester, United Kingdom

b Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, Colorado

c Lung Cancer Unit, Royal Marsden Hospital, London, United Kingdom

d Manchester Academic Health Science Centre, Institute of Cancer Sciences, Manchester Cancer Research Centre, The University of Manchester, Manchester, United Kingdom

Corresponding author. Address for correspondence: Jonathan Khalifa, MD, Department of Radiation Oncology, Institut Universitaire du Cancer de Toulouse–Oncopôle 1, Avenue Irène Joliot-Curie, 31000 Toulouse, France.

Drs. Khalifa and Amini contributed equally to this work. Drs. Faivre-Finn and Gaspar jointly supervised this work.

Disclosure: Dr. Popat is a consultant to Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Merck Sharp and Dohme, Novartis, Pfizer, and Roche. The remaining authors declare no conflict of interest.