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

Open ArchivePublished:June 22, 2016DOI:https://doi.org/10.1016/j.jtho.2016.06.002

      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

      Introduction

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      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.
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      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,
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      and also in unselected patients.
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      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.
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      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.
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      CNS Penetration of Targeted Therapies for Treatment of BMs

      TKIs are low-molecular-weight organic compounds (<500 Da generally),
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      with low to moderate CSF penetration rates within the brain.
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      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).
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      A report from a patient in whom glioblastoma had been diagnosed showed a CSF penetration rate up to 7% (and 9% for OSI-420).
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      these data suggest that erlotinib concentration in the CSF exceeds its median inhibitory concentration value for EGFR inhibition.
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      A limited number of small cohort studies have shown that as compared with erlotinib, other first-generation TKIs have low (gefitinib
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      ) or very low (crizotinib
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      ) 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.
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      Similarly, the second-generation ALK inhibitors, mainly ceritinib and alectinib, which are selective for ALK at very low concentrations in vitro,
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      might not be transported by efflux proteins
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      and therefore may provide far higher CSF penetration rates.
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      These data could partly explain the better intracranial response rates obtained with the next-generation ALK inhibitors as compared with crizotinib.
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      Potential future directions to increase TKIs CSF penetration rates, and therefore intracranial control, include development of intra-CSF formulation, inhibition of efflux transporters,
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      and pulsatile high-dose administration.
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      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.
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      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.
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      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.
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      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.
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      This ceramide-induced apoptosis pathway is crucial in radiation-induced endothelial cell death, particularly in the context of high single-dose radiation (>10 Gy).
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      • et al.
      Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice.
      • Garcia-Barros M.
      • Paris F.
      • Cordon-Cardo C.
      • et al.
      Tumor response to radiotherapy regulated by endothelial cell apoptosis.
      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)
      • Bonnaud S.
      • Niaudet C.
      • Pottier G.
      • et al.
      Sphingosine-1-phosphate protects proliferating endothelial cells from ceramide-induced apoptosis but not from DNA damage-induced mitotic death.
      that has been reported to occur up to 1 month after RT.
      • Puck T.T.
      Action of radiation on mammalian cells III. Relationship between reproductive death and induction of chromosome anomalies by X-irradiation of euploid human cells in vitro.
      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.
      • van Vulpen M.
      • Kal H.B.
      • Taphoorn M.J.B.
      • El-Sharouni S.Y.
      Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review).
      • Cao Y.
      • Tsien C.I.
      • Shen Z.
      • et al.
      Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy.
      Brain irradiation has been described to affect the blood-tumor barrier as well as the healthy irradiated BBB, but to a lesser extent.
      • Cao Y.
      • Tsien C.I.
      • Shen Z.
      • et al.
      Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy.
      • Qin D.X.
      • Zheng R.
      • Tang J.
      • Li J.X.
      • Hu Y.H.
      Influence of radiation on the blood-brain barrier and optimum time of chemotherapy.
      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.
      • van Vulpen M.
      • Kal H.B.
      • Taphoorn M.J.B.
      • El-Sharouni S.Y.
      Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review).
      • Cao Y.
      • Tsien C.I.
      • Shen Z.
      • et al.
      Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy.
      • Qin D.X.
      • Zheng R.
      • Tang J.
      • Li J.X.
      • Hu Y.H.
      Influence of radiation on the blood-brain barrier and optimum time of chemotherapy.
      • d’Avella D.
      • Cicciarello R.
      • Albiero F.
      • et al.
      Quantitative study of blood-brain barrier permeability changes after experimental whole-brain radiation.
      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.
      • Garcia-Barros M.
      • Paris F.
      • Cordon-Cardo C.
      • et al.
      Tumor response to radiotherapy regulated by endothelial cell apoptosis.
      Finally, this BBB disruption after focal RT or WBRT is presumed to lead to an increase in drug permeability,
      • Qin D.X.
      • Zheng R.
      • Tang J.
      • Li J.X.
      • Hu Y.H.
      Influence of radiation on the blood-brain barrier and optimum time of chemotherapy.
      • d’Avella D.
      • Cicciarello R.
      • Albiero F.
      • et al.
      Quantitative study of blood-brain barrier permeability changes after experimental whole-brain radiation.
      • Qin D.
      • Ma J.
      • Xiao J.
      • Tang Z.
      Effect of brain irradiation on blood-CSF barrier permeability of chemotherapeutic agents.
      • Khatri A.
      • Gaber M.W.
      • Brundage R.C.
      • et al.
      Effect of radiation on the penetration of irinotecan in rat cerebrospinal fluid.
      • Zeng Y.-D.
      • Liao H.
      • Qin T.
      • et al.
      Blood-brain barrier permeability of gefitinib in patients with brain metastases from non–small-cell lung cancer before and during whole brain radiation therapy.
      although contradictory clinical data have been reported after WBRT in patients with BMs from NSCLC.
      • Fang L.
      • Sun X.
      • Song Y.
      • et al.
      Whole-brain radiation fails to boost intracerebral gefitinib concentration in patients with brain metastatic non–small cell lung cancer: a self-controlled, pilot study.

      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.
      • Liang K.
      • Ang K.K.
      • Milas L.
      • Hunter N.
      • Fan Z.
      The epidermal growth factor receptor mediates radioresistance.
      • Akimoto T.
      • Hunter N.R.
      • Buchmiller L.
      • Mason K.
      • Ang K.K.
      • Milas L.
      Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas.
      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 ligand
      • Dent P.
      • Yacoub A.
      • Contessa J.
      • et al.
      Stress and radiation-induced activation of multiple intracellular signaling pathways.
      leads to accelerated repopulation via the Ras/MAP kinase pathway.
      • Reardon D.B.
      • Contessa J.N.
      • Mikkelsen R.B.
      • et al.
      Dominant negative EGFR-CD533 and inhibition of MAPK modify JNK1 activation and enhance radiation toxicity of human mammary carcinoma cells.
      • Schmidt-Ullrich R.K.
      • Mikkelsen R.B.
      • Dent P.
      • et al.
      Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation.
      Secondly, there is increased cell survival by means of the phosphoinositide 3-kinase (PI3K)/AKT pathway,
      • Toulany M.
      • Dittmann K.
      • Krüger M.
      • Baumann M.
      • Rodemann H.P.
      Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway.
      as well as EGFR ligand synthesis (transforming growth factor-α and amphiregulin), which in turn activates the PI3K/AKT pathway in an autocrine loop.
      • Gangarosa L.M.
      • Sizemore N.
      • Graves-Deal R.
      • Oldham S.M.
      • Der C.J.
      • Coffey R.J.
      A raf-independent epidermal growth factor receptor autocrine loop is necessary for Ras transformation of rat intestinal epithelial cells.
      Third, radiation-induced nuclear translocation of wild-type EGFR in turn activates the nonhomologous end-joining DNA double-strand break repair pathway.
      • Dittmann K.
      • Mayer C.
      • Fehrenbacher B.
      • et al.
      Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase.
      • Dittmann K.
      • Mayer C.
      • Rodemann H.-P.
      Inhibition of radiation-induced EGFR nuclear import by C225 (cetuximab) suppresses DNA-PK activity.
      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).
      • Bianco C.
      • Tortora G.
      • Bianco R.
      • et al.
      Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa).
      • Chinnaiyan P.
      • Huang S.
      • Vallabhaneni G.
      • et al.
      Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva).
      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.
      • Das A.K.
      • Chen B.P.
      • Story M.D.
      • et al.
      Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) abrogate EGFR-mediated radioprotection in non–small cell lung carcinoma.
      • Das A.K.
      • Sato M.
      • Story M.D.
      • et al.
      Non–small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation.
      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.
      • Bokobza S.M.
      • Jiang Y.
      • Weber A.M.
      • Devery A.M.
      • Ryan A.J.
      Short-course treatment with gefitinib enhances curative potential of radiation therapy in a mouse model of human non–small cell lung cancer.
      • Zhang S.
      • Zheng X.
      • Huang H.
      • et al.
      Afatinib increases sensitivity to radiation in non–small cell lung cancer cells with acquired EGFR T790M mutation.
      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.
      • Webb T.R.
      • Slavish J.
      • George R.E.
      • et al.
      Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy.
      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.
      • Dai Y.
      • Wei Q.
      • Schwager C.
      • et al.
      Synergistic effects of crizotinib and radiotherapy in experimental EML4-ALK fusion positive lung cancer.
      • Sun Y.
      • Nowak K.A.
      • Zaorsky N.G.
      • et al.
      ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non–small cell lung cancer expressing EML4-ALK.
      With regard to antiangiogenic agents, their radiosensitizing effects on both the microenvironment and tumor cells have been widely described.
      • Wachsberger P.
      • Burd R.
      • Dicker A.P.
      Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction.
      First, a hypoxic tumor microenvironment stimulates upregulation, through hypoxia-inducible factor-1α, of angiogenic factors such as vascular endothelial growth factor.
      • Maxwell P.H.
      • Dachs G.U.
      • Gleadle J.M.
      • et al.
      Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth.
      • Hanahan D.
      • Folkman J.
      Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.
      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”
      • Jain R.K.
      Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.
      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.
      • Truman J.-P.
      • García-Barros M.
      • Kaag M.
      • et al.
      Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery.
      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.
      • O’Reilly M.S.
      • Holmgren L.
      • Chen C.
      • Folkman J.
      Angiostatin induces and sustains dormancy of human primary tumors in mice.
      • Masood R.
      • Cai J.
      • Zheng T.
      • Smith D.L.
      • Hinton D.R.
      • Gill P.S.
      Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors.
      • Kirsch M.
      • Strasser J.
      • Allende R.
      • Bello L.
      • Zhang J.
      • Black P.M.
      Angiostatin suppresses malignant glioma growth in vivo.
      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.
      • Chalmers A.J.
      • Lakshman M.
      • Chan N.
      • Bristow R.G.
      Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets.
      Table 1Ongoing and/or Unpublished Clinical Trials Combining Radiation and Novel Targeted Agents for NSCLC BMs
      Data from ClinicalTrials.gov.

      US National Institutes of Health. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/home. Accessed February 5, 2016.

      StudyTrial PhaseEstimated EnrollmentEstimated Primary Completion DateSelected Mutation GroupPrimary SiteArmsPrimary End Point(s)Secondary End Point(s)
      EGFR inhibitors
       Erlotinib
      NCT025565932116August 2019EGFR wild typeNSCLCWBRT (45 Gy in 15 fx) + errlotinib (150 mg/d)2-y CNS PFS
      NCT015186212150December 2017UnselectedNSCLCWBRT (30 Gy in 10 fx) + erlotinib (150 mg/d) vs. WBRT aloneMedian OSToxicity, LC, TNP
      NCT018877953224August 2016EGFR mutantNSCLCWBRT (40 Gy in 20 fx) + erlotinib (150 mg/d) vs. WBRT aloneTNPOS, tumor response, QOL
      NCT002686843381UnselectedNSCLCWBRT + SRS + TMZ vs. WBRT + SRS + erlotinib vs. WBRT+SRS aloneOS
       Gefitinib
      NCT023380112/3210November 2017EGFR mutantNSCLCWBRT (30 Gy in 10 fx) + gefitinib (250 mg/d) vs. gefitinib alonePFSOS, QOL, MMSE
      NCT01363557
      Study terminated.
      21August 2012EGFR mutantLung NOSWBRT (30 Gy in 10 fx) + gefitinib (250 mg/d) vs. gefitinib aloneTumor responseToxicity, PFS, OS
       Icotinib
      NCT01926171480September 2016UnselectedNSCLCWBRT (40 Gy in 20 fx) + icotinibTumor responseDC, PFS, toxicity
       Vandetanib
      NCT00807170
      Study terminated.
      15August 2010UnselectedNSCLCWBRT (30 Gy in 10 fx) + vandetanib (100 mg/d, 200 mg/d, 300 mg/d)MTDClinical and radiographic PFS
       Lapatinib
      NCT01218529
      Study completed.
      282August 2014UnselectedLung NOS, breastWBRT (30 Gy in 10 fx) + lapatinib (1250 mg/d)Tumor responseDC, PFS, toxicity
       Nimotuzumab
      NCT00872482
      Study terminated.
      221July 2011UnselectedNSCLCWBRT (30 Gy in 10 fx) + nimotuzumab (200 mg/wk) vs. WBRT aloneTumor responseOS, TNP, PFS, OS
      ALK inhibitors
       TKI (NOS)
      NCT02314364230November 2021EGFR mutant, ALK+ or ROS1 mutantNSCLCSRS + TKI12-mo DFToxicity, PFS, OS, patterns of failure
      Antiangiogenic agents
       Cediranib
      NCT00937482
      Study completed.
      118March 2011UnselectedNSCLCWBRT + cediranibMTDNeurologic PFS, OS
       Sunitinib
      NCT00981890
      Study completed.
      122July 2014UnselectedAny cancerSRS + sunitinibMTD, toxicityToxicity, PFS
       Sorafenib
      NCT01276210123January 2018UnselectedAny cancer, excluding SCLC and lymphomaSRS + sorafenibMTDPFS, OS
      NCT00639262
      Study completed.
      135September 2012UnselectedAny cancerRT + sorafenib (200 mg twice daily)MTDTumor response, PFS, toxicity
       Endostar
      NCT01410370280UnknownUnselectedAny cancerWBRT (30 Gy in 10 fx) + endostar (7.5 mg/m2/d) vs. WBRT aloneORROS, VEGF levels, toxicity
       Cilengitide
      NCT00884598121UnknownUnselectedLung (SCLC or NSCLC)WBRT + cilengitideMTD, toxicityORR, OS, PFS, toxicity
      PARP inhibitors
       Veliparib (ABT-888)
      NCT01657799
      Study completed.
      2307January 2015UnselectedNSCLCWBRT (30 Gy in 10 fx) + veliparib (low and high dose) vs. WBRT + placeboOSTumor response, PFS
       Iniparib (BSI-201)
      NCT01551680
      Study terminated.
      13February 2014UnselectedAny cancerWBRT (37.5 Gy in 15 fx) + iniparib (2.8, 4, 5.6, 8, or 11.2 mg/kg)MTDToxicity, QOL, ORR, PFS
      mTOR inhibitors
       Everolimus
      NCT00892801
      Study terminated.
      15February 2011UnselectedNSCLCWBRT (30 Gy in 10 fx) + everolimus (5 or 10 mg/d)MTD, median OSTumor response, toxicity, TNP, PFS
      ATR inhibitors
       VX-970
      NCT02589522146June 2017UnselectedNSCLCWBRT + VX-970MTD, toxicityQOL, toxicity, PFS, OS
      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.
      a Study terminated.
      b Study completed.

      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.
      • Lind J.S.W.
      • Lagerwaard F.J.
      • Smit E.F.
      • Senan S.
      Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non–small-cell lung cancer.
      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.
      • Welsh J.W.
      • Komaki R.
      • Amini A.
      • et al.
      Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non–small-cell lung cancer.
      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.
      • Sperduto P.W.
      • Wang M.
      • Robins H.I.
      • et al.
      A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non–small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.
      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 2Published Prospective Trials Combining Radiation and Novel Targeted Agents for NSCLC BMs
      StudyTrial PhaseNo. of PatientsMutation StatusArmsOutcomes
      EGFR inhibitors
       Erlotinib
      Lind et al.
      • Lind J.S.W.
      • Lagerwaard F.J.
      • Smit E.F.
      • Senan S.
      Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non–small-cell lung cancer.
      111EGFR status not reportedErlotinib (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)
      • Sperduto P.W.
      • Wang M.
      • Robins H.I.
      • et al.
      A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non–small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.
      3126EGFR status not reportedWBRT (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 + SRSmOS: 13.4, 6.3, 6.1 mo (NS) Grade ≥3 toxicity: 11%, 41%, 49% (SS)
      Welsh et al.
      • Welsh J.W.
      • Komaki R.
      • Amini A.
      • et al.
      Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non–small-cell lung cancer.
      240EGFR 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.
      • Lee S.M.
      • Lewanski C.R.
      • Counsell N.
      • et al.
      Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases.
      280EGFR 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.
      • Zhuang H.
      • Yuan Z.
      • Wang J.
      • Zhao L.
      • Pang Q.
      • Wang P.
      Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma.
      254EGFR 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)
      • Pesce G.A.
      • Klingbiel D.
      • Ribi K.
      • et al.
      Outcome, quality of life and cognitive function of patients with brain metastases from non–small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Ca.
      259EGFR status not reportedGefitinib (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.
      • Zhou L.
      • He J.
      • Xiong W.
      • et al.
      Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non–small cell lung cancer patients with brain metastases: results of phase I dose-escalation study.
      115EGFR mut onlyIcotinib (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.
      • Fan Y.
      • Huang Z.
      • Fang L.
      • et al.
      A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non–small cell lung cancer.
      220EGFR 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.
      • Lévy C.
      • Allouache D.
      • Lacroix J.
      • et al.
      REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours.
      119VEGF status not reportedBevacizumab (5, 10, 15 mg/kg every 2 wk) + WBRT (30 Gy in 15 fx) d 153-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).
      • Lee S.M.
      • Lewanski C.R.
      • Counsell N.
      • et al.
      Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases.
      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.
      • Zhuang H.
      • Yuan Z.
      • Wang J.
      • Zhao L.
      • Pang Q.
      • Wang P.
      Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma.
      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.
      • Pesce G.A.
      • Klingbiel D.
      • Ribi K.
      • et al.
      Outcome, quality of life and cognitive function of patients with brain metastases from non–small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Ca.
      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.
      • Luo S.
      • Chen L.
      • Chen X.
      • Xie X.
      Evaluation on efficacy and safety of tyrosine kinase inhibitors plus radiotherapy in NSCLC patients with brain metastases.
      Icotinib has also demonstrated tolerable side effects and efficacy in association with brain RT NSCLC,
      • Zhou L.
      • He J.
      • Xiong W.
      • et al.
      Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non–small cell lung cancer patients with brain metastases: results of phase I dose-escalation study.
      • Fan Y.
      • Huang Z.
      • Fang L.
      • et al.
      A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non–small cell lung cancer.
      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.
      • Crombet T.
      • Osorio M.
      • Cruz T.
      • et al.
      Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients.
      Unlike other anti-EGFR mAbs, nimotuzumab is not associated with a severe acneiform rash.
      • Bebb G.
      • Smith C.
      • Rorke S.
      • et al.
      Phase I clinical trial of the anti-EGFR monoclonal antibody nimotuzumab with concurrent external thoracic radiotherapy in Canadian patients diagnosed with stage IIb, III or IV non–small cell lung cancer unsuitable for radical therapy.
      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.
      • Macias A.
      • Neninger E.
      • Santiesteban E.
      • et al.
      Preliminary results of a phase II clinical trial of the anti EGFR monoclonal antibody nimotuzumab in combination with whole brain radiation therapy in patients diagnosed with advanced non–small cell lung cancer tumors unresectable brain metastases.
      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]).
      • Johung K.L.
      • Yeh N.
      • Desai N.B.
      • et al.
      Extended survival and prognostic factors for patients with ALK-rearranged non–small-cell lung cancer and brain metastasis.
      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).
      • Lévy C.
      • Allouache D.
      • Lacroix J.
      • et al.
      REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours.
      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 growth
      • O’Reilly M.S.
      • Boehm T.
      • Shing Y.
      • et al.
      Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.
      ); 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,
      • Albert J.M.
      • Cao C.
      • Geng L.
      • Leavitt L.
      • Hallahan D.E.
      • Lu B.
      Integrin alpha v beta 3 antagonist cilengitide enhances efficacy of radiotherapy in endothelial cell and non–small-cell lung cancer models.
      probably through tumor vasculature normalization and tumor hypoxia regulation.
      • Skuli N.
      • Monferran S.
      • Delmas C.
      • et al.
      Activation of RhoB by hypoxia controls hypoxia-inducible factor-1alpha stabilization through glycogen synthase kinase-3 in U87 glioblastoma cells.

      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.
      • Miwa M.
      • Masutani M.
      PolyADP-ribosylation and cancer.
      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.
      • Mehta M.P.
      • Curran W.J.
      • Wang D.
      • et al.
      Phase I safety and pharmacokinetic (PK) study of veliparib in combination with whole brain radiation therapy (WBRT) in patients (pts) with brain metastases.
      • Mehta M.P.
      • Wang D.
      • Wang F.
      • et al.
      Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study.
      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.
      • Chabot P.
      • Ryu J.-S.
      • Gorbunova V.
      • et al.
      Results of a randomized, global, multi-center study of whole-brain radiation therapy (WBRT) plus veliparib or placebo in patients (pts) with brain metastases (BM) from non–small cell lung cancer (NSCLC).
      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.
      • Yom S.S.
      • Diehn M.
      • Raben D.
      Molecular determinants of radiation response in non–small cell lung cancer.
      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,
      • Porta R.
      • Sánchez-Torres J.M.
      • Paz-Ares L.
      • et al.
      Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.
      • Wu Y.-L.
      • Zhou C.
      • Cheng Y.
      • et al.
      Erlotinib as second-line treatment in patients with advanced non–small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803).
      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.
      • Gow C.-H.
      • Chang Y.-L.
      • Hsu Y.-C.
      • et al.
      Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non–small-cell lung cancer.
      • Kalikaki A.
      • Koutsopoulos A.
      • Trypaki M.
      • et al.
      Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC.
      • Italiano A.
      • Vandenbos F.B.
      • Otto J.
      • et al.
      Comparison of the epidermal growth factor receptor gene and protein in primary non–small-cell-lung cancer and metastatic sites: implications for treatment with EGFR-inhibitors.
      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,
      • Welsh J.W.
      • Komaki R.
      • Amini A.
      • et al.
      Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non–small-cell lung cancer.
      • Sperduto P.W.
      • Wang M.
      • Robins H.I.
      • et al.
      A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non–small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.
      • Lee S.M.
      • Lewanski C.R.
      • Counsell N.
      • et al.
      Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases.
      • Zhuang H.
      • Yuan Z.
      • Wang J.
      • Zhao L.
      • Pang Q.
      • Wang P.
      Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma.
      whereas Lind et al. initiated erlotinib 1 week before the start of RT.
      • Lind J.S.W.
      • Lagerwaard F.J.
      • Smit E.F.
      • Senan S.
      Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non–small-cell lung cancer.
      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,
      • Zhuang H.
      • Wang J.
      • Zhao L.
      • Yuan Z.
      • Wang P.
      The theoretical foundation and research progress for WBRT combined with erlotinib for the treatment of multiple brain metastases in patients with lung adenocarcinoma.
      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.
      • Welsh J.W.
      • Komaki R.
      • Amini A.
      • et al.
      Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non–small-cell lung cancer.
      • Sperduto P.W.
      • Wang M.
      • Robins H.I.
      • et al.
      A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non–small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.
      • Lee S.M.
      • Lewanski C.R.
      • Counsell N.
      • et al.
      Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases.
      • Pesce G.A.
      • Klingbiel D.
      • Ribi K.
      • et al.
      Outcome, quality of life and cognitive function of patients with brain metastases from non–small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Ca.
      • Shen C.J.
      • Kummerlowe M.N.
      • Redmond K.J.
      • Rigamonti D.
      • Lim M.K.
      • Kleinberg L.R.
      Stereotactic radiosurgery: treatment of brain metastasis without interruption of systemic therapy.
      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.
      • Weickhardt A.J.
      • Scheier B.
      • Burke J.M.
      • et al.
      Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non–small-cell lung cancer.
      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,
      • Khuntia D.
      • Brown P.
      • Li J.
      • Mehta M.P.
      Whole-brain radiotherapy in the management of brain metastasis.
      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.
      • Soon Y.Y.
      • Leong C.N.
      • Koh W.Y.
      • Tham I.W.K.
      EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non–small cell lung cancer with brain metastases: a systematic review and meta-analysis.
      Chemotherapy alone for newly diagnosed NSCLC with asymptomatic BM results in significant intracranial response rates, with no impact of delayed WBRT on patient outcome.
      • Barlesi F.
      • Gervais R.
      • Lena H.
      • et al.
      Pemetrexed and cisplatin as first-line chemotherapy for advanced non–small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01).
      • Lee D.H.
      • Han J.-Y.
      • Kim H.T.
      • et al.
      Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first: result of a randomized pilot study.
      • Robinet G.
      • Thomas P.
      • Breton J.L.
      • et al.
      Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non–small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) protocol 95-1.
      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.
      • Berger L.A.
      • Riesenberg H.
      • Bokemeyer C.
      • Atanackovic D.
      CNS metastases in non–small-cell lung cancer: current role of EGFR-TKI therapy and future perspectives.
      Two phase II trials were included in this review.
      • Park 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.
      • Wu Y.-L.
      • Zhou C.
      • Cheng Y.
      • et al.
      Erlotinib as second-line treatment in patients with advanced non–small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803).
      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.
      • Park 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.
      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.
      • Wu Y.-L.
      • Zhou C.
      • Cheng Y.
      • et al.
      Erlotinib as second-line treatment in patients with advanced non–small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803).
      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.
      • Schuler M.
      • Wu Y.-L.
      • Hirsh V.
      • O’Byrne K.
      • 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.
      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.
      • Nanjo 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.
      • Yates J.
      • Ballard P.
      • Ashton S.
      • et al.
      301 Using PK/PD/efficacy modeling to predict potential of AZD9291 to target brain metastases from advanced NSCLC with EGFR sensitizing mutations (EGFRm+).
      • Sequist L.V.
      • Soria J.-C.
      • Goldman J.W.
      • et al.
      Rociletinib in EGFR-mutated non–small-cell lung cancer.
      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.
      • Solomon B.J.
      • Mok T.
      • Kim D.-W.
      • et al.
      First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
      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.
      • Costa D.B.
      • Shaw A.T.
      • Ou S.-H.I.
      • et al.
      Clinical experience with crizotinib in patients with advanced alk-rearranged non–small-cell lung cancer and brain metastases.
      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.
      • Johung K.L.
      • Yeh N.
      • Desai N.B.
      • et al.
      Extended survival and prognostic factors for patients with ALK-rearranged non–small-cell lung cancer and brain metastasis.
      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%.
      • Toyokawa G.
      • Seto T.
      • Takenoyama M.
      • Ichinose Y.
      Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary?.
      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.
      • Socinski M.A.
      • Langer C.J.
      • Huang J.E.
      • et al.
      Safety of bevacizumab in patients with non–small-cell lung cancer and brain metastases.
      • Besse B.
      • Le Moulec S.
      • Mazières J.
      • et al.
      Bevacizumab in patients with nonsquamous non–small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study.
      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).
      • Socinski M.A.
      • Langer C.J.
      • Huang J.E.
      • et al.
      Safety of bevacizumab in patients with non–small-cell lung cancer and brain metastases.
      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.
      • Besse B.
      • Le Moulec S.
      • Mazières J.
      • et al.
      Bevacizumab in patients with nonsquamous non–small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study.
      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.
      • Ilhan-Mutlu A.
      • Osswald M.
      • Liao Y.
      • et al.
      Bevacizumab prevents brain metastases formation in lung adenocarcinoma.

      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.
      • Yamamoto M.
      • Serizawa T.
      • Shuto T.
      • et al.
      Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study.
      In patients not suitable for local treatments, new developments in WBRT techniques with hippocampal sparing may reduce neurocognitive toxicity.
      • Gondi V.
      • Pugh S.L.
      • Tome W.A.
      • et al.
      Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial.
      New systemic therapies and particularly targeted therapies have improved the prognosis of metastatic patients with NSCLC.
      • Minguet J.
      • Smith K.H.
      • Bramlage P.
      Targeted therapies for treatment of non–small cell lung cancer—recent advances and future perspectives.
      • Shea M.
      • Costa D.B.
      • Rangachari D.
      Management of advanced non–small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches.
      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,
      • Golberg S.B.
      • Gettinger S.N.
      • Mahajan A.
      • et al.
      Activity and safety of pembrolizumab in patients with metastatic non–small cell lung cancer with untreated brain metastases.
      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.
      • Wersäll P.J.
      • Blomgren H.
      • Pisa P.
      • Lax I.
      • Kälkner K.-M.
      • Svedman C.
      Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma.
      • Postow M.A.
      • Callahan M.K.
      • Barker C.A.
      • et al.
      Immunologic correlates of the abscopal effect in a patient with melanoma.
      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.
      • Sperduto P.W.
      • Yang T.J.
      • Beal K.
      • et al.
      The effect of gene mutations on survival in patients with adenocarcinoma of the lung following the development of brain metastases.
      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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