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Targeted drugs in combination with radiotherapy for the treatment of solid tumors: current state and future developments Expert Rev. Clin. Pharmacol. 6(6), 663–676 (2013)

Edgar Selzer*1 and Gabriela Kornek2 1 Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria 2 Department of Medicine I, Division of Medical Oncology, Medical University of Vienna, Vienna, Austria *Author for correspondence: Tel.: +43 140 400 7672 Fax: +43 140 400 2666 [email protected]

The continuously rising use of novel drugs, especially of molecules belonging to the group of targeted drugs is now shaping the therapeutic landscape. However, treatment combinations of targeted drugs with radiotherapy are still rare. Only the monoclonal antibody cetuximab (Erbitux1) has been approved for the treatment of locally advanced squamous cell cancer of the head and neck in combination with radiotherapy. Several targeted compounds are in advanced stages of clinical development for combination treatments with radiotherapy, of which substances with either anti-EGFR or anti-angiogenic mechanisms, such as trastuzumab, panitumumab, erlotinib, cilengitide and bevacizumab are the most promising. Aim of this article is to provide, mainly from a radio-oncological point of view, an overview about the current state as well as to give an outlook on the near future of the most advanced targeted combined treatment concepts for solid tumors. KEYWORDS: clinical study • radiation oncology • solid tumor • targeted drugs

Current state: targeted therapies & radiation therapy

The last two decades are characterized by an increasing use of a variety of novel targeted compounds. This development is shaping the oncological as well as the non-oncological medical landscape as a whole. Targeted therapy is characterized by different concepts as compared with classical pharmaceutical approaches that were dominated the development of drugs in the last century. Nowadays, the design of novel medicaments is regarded as incomplete if the specific target of the molecule and if the underlying biological function is not known before initiation of clinical studies. The history of targeted therapies and the importance of the underlying concepts have been discussed in a plethora of excellent reviews and have been summarized recently in an overview article for

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10.1586/17512433.2013.841540

this journal [1]. The interested reader is therefore referred to this article and to references therein. Currently, more than 40 US FDAand/or EMA-approved cancer therapeutics are known, that belong into the category of targeted drugs (TABLE 1). More detailed information about approved targeted cancer drugs may be found, for example, on the website of the National Cancer Institute at the NIH [101]. Most of the drugs now in use were approved during the past 15 years at an average rate of 2–3 new drugs per year. However, the fact that some targeted drugs, such as selective estrogen receptor modulators (tamoxifen and toremifene), or aromatase inhibitors (anastrozole or letrozole) were already designed several decades before the term ‘targeted’ has been introduced is often overlooked. Far more compounds – the exact number is difficult to evaluate – are now in clinical or preclinical development. It


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Table 1. The US FDA-approved targeted drugs in oncology.

Table 1. The US FDA-approved targeted drugs in oncology (cont.).

Drug

Mechanism – primary target

Drug

Mechanism – primary target

Aflibercept (Zaltrap1)

VEGF-A, PlGF

Sorafenib (Nexavar1)

Raf, KIT, FLT-3, VEGFR-2,3, PDGFR-B

Sunitinib (Sutent1)

PDGFR, VEGFR 1 to 3, KIT, FLT, CSF-1R

1

Axitinib (Inlyta )

VEGFR-1 to 3, PDGFR, KIT

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1

Abiraterone acetate (Zytiga )

Androgen biosynthesis inhibitor

Bevacizumab (Avastin1)

VEGF

Bortezomib (Velcade1)

Proteasome inhibitor

Brentuximab vedotin (Adcretris1)

CD30

Bosutinib (Bosulif1)

Bcr-Abl

Brentuximab vedotin (Adcetris1)

CD30

Cabozantinib (Cometriq

1

)

Pan-tyrosine kinase inhibitor

1

)

Carfilzomib (Kyprolis

Proteasome inhibitor

Catumaxomab (Removab1)

CD3, EpCAM

Cetuximab (Erbitux1)

EGFR type I

1

Crizotinib (Xalkori )

ALK and ROS 1

Dasatinib (Sprycel1)

BCR-ABL, SRC family)

1

GnRH receptor

1

RANKL

Degarelix (Degarelix ) Denosumab (Xgeva ) 1

Enzalutamide (Xtandi )

Androgen receptor

Gemtuzumab ozogamicin (Mylotarg1)

CD 33 antigen

1

)

EGFR type I

1

Everolimus (Afinitor )

mTOR pathway

Gefitinib (Iressa1)

EGFR

Imatinib (Glivec1)

Bcr-Abl, PDGF, KIT

Erlotinib (Tarceva

1

Imatinib (Glivec )

CTLA-4 1

Ipilimumab (Yervoy )

EGFR type I/II 1

Lapatinib ditosylate (Tykerb ) Nilotinib (Tasigna

1

)

Mechanism unclear Bcr-Abl, PDGF-R, KIT

1

Ofatumumab (Arzerra ) 1

Panitumumab (Vectibix ) 1

CD 20 EGFR type I

Pazopanib (Votrient )

VEGFR-1 to 3, PDGFR-a/b, KIT

Ponatinib (Iclusig1)

Dual Abl/Src protein inhibitor

Pertuzumab (Perjeta1) 1

Pralatrexate (Folotyn ) 1

HER2 Dihdrofolate reductase

Regorafenib (Stivarga )

VEGFR, TIE2, PDGFR, RET, KIT, RAF

Rituximab (Mabthera1)

CD 20

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Temsirolismus (Torisel1) 1

Trametinib (Mekinist )

mTOR MEK

1

Trastuzumab (Herceptin ) 1

Vandetanib (Caprelsa ) 1

Vorinostat (Zolinza )

EGFR type II VEGFR, EGFR, RET HDAC inhibitor

1

Vemurafenib (Zelboraf ) 1

Vismodegib (Erivedge )

Activated BRAFV600E gene Hedgehog pathway

FDA-approved drugs for oncology. List was generated from a database containing a listing of drugs approved by the FDA for sale in the USA. Data taken from [102].

would be completely beyond the scope of any serious review to present a valid overview covering the entire field. The discrepancy between the huge number of compounds and the low number of final approvals reflects the risk and uncertainties that are inherently associated with the drug development process [1]. Even initially very promising drugs may fail in advanced clinical study phases, as very recent examples have shown (e.g., cilengitide; see further below). At the moment, the market of targeted drugs is dominated, at least in terms of sales, by only a handful of compounds. Among these, four monoclonal antibodies – bevacizumab (Avastin1; Roche), rituximab (Rituxan1/MabThera1; Biogen Idec/Roche), trastuzumab (Herceptin1; Roche) and cetuximab (Erbitux; Eli Lilly/Bristol-Myers Squibb) – and one small-molecule drug–imatinib (Gleevec1; Novartis) contribute to the majority of sales. Of note, apart from rituximab, for which the primary indication is the treatment of lymphoma, the majority of drugs of potential interest for the radiation oncologist have their most likely field of indication in the treatment of solid tumors [2]. Hematological tumors, at least for the time being, do not seem to play an equivalent important role with respect to radiotherapeutic treatment combinations. It is the intention of the authors of this review to provide an outlook as robust as possible on the probable future of drugs that are now in advanced clinical stage of development in combination with radiotherapy (RT). The sheer quantity of novel compounds that have not been evaluated in combination with RT represents a major opportunity of unexploited potential for research and development of novel combinations. Many of the approved targeted drugs have, at least in preclinical and cellular models, the potential to increase the sensitivity of tumor cells towards ionizing as well as non-ionizing radiation. Oncology has become one of

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Targeted drugs in combination with radiotherapy for the treatment of solid tumors

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the major focus areas for pharmaceuti• EGF receptor-genotype and expression levels: activation state of EGF receptordependent signaling cascades (e.g., MAPK, AKT, PKC, STAT3) – in colorectal cancer, cal and biotechnology companies and lung cancer, pancreatic cancer, head and neck cancer, and other cancer types thousands of cancer-related Phase I, II • Hypoxia and underlying factors and III trials are listed on Clinical• HPV, p16 expression (e.g., in head and neck cancer) Trials.gov. • MGMT-methylation state (glioblastoma) The introduction of novel targeted • RAS and B-RAF signaling pathways therapies, however, requires concomi• TP53 status tant research and development of biomarkers at an early stage of drug • Bioimaging: PET and other functional imaging diagnostics based on selective in-vivo imaging of relevant molecular (target) structures. For example: integrin ligands coupled development, an aspect of drug with PET tracers for imaging of neo-angiogenesis: hypoxia markers (e.g., misonidazole); research that has been underrepresented imaging of specific and therapeutically relevant cellular structures in most clinical studies of the past [1]. Biomarkers should not only be able to Figure 1. Biomarkers and modulators of importance for radiosensitivity. verify the expression of the molecular target in the patient per se, but also be able to monitor therapy response and to predict outcome. In targeting K-RAS by RNA interference or the PI3K-AKT case of need to assess and predict the response to combination pathway increased radiosensitivity in non-small cell lung and treatments, the situation may be more complex. In some other cancer cell lines [12,13]. A summary of targeted drugs cases, the targeted drug may interfere with a pathway that is that are used in combination with RT in clinical studies is also directly involved in the extent of the cellular response shown in TABLE 2. Only approved drugs (for any indication) toward radiation, such as temozolomide [3-7]. Response to that are in evaluation in radio-therapeutic (EORTC or radiation therapy has been linked in HNSCC cancer to the RTOG) clinical trials for solid tumors at any stage (Phase II HPV/p16 status [8,9]. FIGURE 1 shows a selection of targets and and III; recruiting, completed or planned) are listed. The list biomarkers of potential importance for both radioresponse as was assembled from data provided on the EORTC [103], the well as for direct pharmacological targeting. Examples of bio- RTOG [104] and the US NIH [105] homepages. markers for selecting therapy regimen containing targeted drugs are EGF receptor (EGFR) mutations (non-small cell Targeted drugs & targeted radiotherapy lung cancer [NSCLC]), steroid receptors and HER2 status (in Clinical and preclinical development and use of targeted therabreast cancer), B-RAF mutation state (in melanoma) and K- pies in combination with RT is at the moment most advanced RAS mutations in colon cancer [1]. It will be of interest to in the field of treatment of solid tumors. This article will focus investigate whether in these patients an infection with HPV on concomitant applications of targeted drugs with radiation may also be associated with a differential response toward sys- therapy that are either approved for other indications than for temic therapy, such as cetuximab combined with RT. In combination therapies with RT or are at least in Phase III clintumors in which the biological target of the drug is also ical trials (FIGURE 2). It is important to note that for many of involved in modulating radiation effects, evaluating the these substances evidence is available from experimental as well expression level and/or functional state of the target may yield as preclinical studies for their principal capability to enhance simultaneous predictive information for both treatment regi- radiation effects. These properties provide a rationale for their mens. Use of biomarkers in order to predict treatment use as combination partners in the clinic. However, synergistic response and/or prognosis is now continuously evolving, and effects with radiation should be, under optimal conditions, determination of, for example, EGFR phenotype and geno- restricted to the tumor tissue and spare normal cells. In clinical type, HPV-infection status, RAS- and B-RAF mutation state practice, this may be difficult to achieve. Since most of the taror O-6-methylguanine-DNA methyltransferase (MGMT)- geted regimens are relatively novel, unexpected acute and late methylation status, hypoxia and other markers, will be helpful side effects may emerge especially in combination with RT. to further optimize the use of standard and/or targeted thera- Particularly, the introduction of radiation treatment techniques, pies in combination with RT. A recent overview on predictive such as intensity modulated radiation therapy (IMRT), which as well as prospective biomarkers was published by are associated with larger irradiated volumes as well as with Chung et al. [10]. For example, in colorectal cancer, determi- altered fractional doses compared with older conventional nation of the RAS genotype that serves as a biomarker for irradiation techniques, may lead to side effects in an unpreresistance against EGFR inhibitors is now almost regarded as dictable manner. For example, in head and neck cancer patients, sparing of the parotids by irradiation techniques a standard procedure [11]. However, for many types of treatments the connection such as IMRT may lead to increases in doses to previously between genotype and/or phenotype of certain genes and untreated regions, such as the brain. Most of the drugs that clinical relevance is less clear. Therefore, much more research dominate field and that are in advanced stages of combinaon this aspect of targeted combination treatments is needed, tion studies either act via inhibition of VEGFR- or EGFRespecially with respect to radiation therapy. For example, dependent signaling pathways. 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Table 2. Approved targeted drugs in evaluation in radiotherapeutic clinical trials for solid tumors. Drug

Type of trial 1

Aflibercept (Zaltrap )

Brain tumors, rectal cancer

1

Axitinib (Inlyta )

GBM

Abiraterone acetate (Zytiga1)

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1

Prostate cancer

Bevacizumab (Avastin )

Pancreatic cancer, brain tumors, HNSCC, CRC, NSCLC, cervical cancer, esophageal, prostate and endometrial cancer

Bortezomib (Velcade1)

NSCLC, HNSCC, brain tumors, rectal cancer

Cabozantinib (Cometriq1)

Cervical cancer

Cetuximab (Erbitux1)

GBM, esophageal, HNSCC, CRC, pancreatic, brain and anal cancer

1

Crizotinib (Xalkori )

NSCLC

1

Dasatinib (Sprycel )

GBM, HNSCC, NSCLC

1

Degarelix (Degarelix )

Prostate cancer

1

Erlotinib (Tarceva )

Brain metastases, NSCLC, HNSCC, pancreatic, esophageal, cervical cancer, brain tumors 1

Everolimus (Afinitor )

HNSCC, GBM, prostate cancer, NSCLC, brain metastases, esophageal cancer

1

Gefitinib (Iressa )

GBM, HNSCC, NSCLC, esophageal cancer, skin cancer, brain metastases, prostate cancer, pancreatic cancer

Imatinib (Glivec1)

Glioma 1

Ipilimumab (Yervoy )

Melanoma, CRC 1

Lapatinib ditosylate (Tykerb ) 1

Nilotinib (Tasigna )

Breast cancer, HNSCC, brain metastases from lung or breast cancer Chordoma

1

Panitumumab (Vectibix )

HNSCC, NSCLC, salivary gland tumors, esophageal, anal, pancreatic, rectal and cervical cancer

Pazopanib (Votrient1)

Anaplastic thyroid cancer

Sorafenib (Nexavar1)

Pancreatic, hepatocellular and bladder, brain tumors, NSCLC, brain metastases, cervical cancer, HNSCC, rectal cancer

Sunitinib (Sutent1)

Sarcoma, prostate cancer, GBM, HNSCC, brain metastases, metastatic solid cancer

Temsirolismus (Torisel1)

HNSCC, GBM, NSCLC

Trametinib (Mekinist1)

Rectal cancer 1

Trastuzumab (Herceptin ) 1

Vandetanib (Caprelsa ) 1

Vorinostat (Zolinza )

Breast, cancer, brain metastases (breast cancer), bladder cancer, esophageal cancer, gastric cancer GBM, NSCLC and brain metastases, glioma, HNSCC Brain metastases, NSCLC, glioma, GBM, pancreatic cancer, palliative radiotherapy

1

Vemurafenib (Zelboraf )

Melanoma

CRC: Colorectal cancer; GBM: Glioblastoma multiforme; HNSCC: Head and neck squamous cell carcinoma; NSCLC: Non-small cell lung cancer.

play a physiologically and therefore clinically relevant role and are expressed on normal cells as well as on tumor cells. There is sufficient scientific rationale for targeting EGFRand VEGFR-dependent biological processes, as both are involved in the regulation, for example, of tumor growth, angiogenesis and cellular survival [14]. In addition, inhibition of both signaling pathways has been found to act synergistically with irradiation [4,5,7]. For the time being, only a few additional drugs are in a state advanced enough in order to be regarded as serious and likely candidates for a potential successful introduction into clinical practice in the near 666

future. Examples of targeted drugs in Phase III clinical studies in combination with RT are discussed below. Examples of targeted drugs in use or in an advanced stage of development–major candidates

As has been noted before, only a few groups of targeted compounds deserve to be mentioned as advanced with respect to their development status. Most notably, and possibly of highest importance, is the group of EGFR inhibitors. The leading compound in this group is cetuximab (Erbitux), a monoclonal antibody, which is the only approved drug yet for use as a Expert Rev. Clin. Pharmacol. 6(6), (2013)

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combination partner with radiation in Combinations with primary RT head and neck cancer patients [15,16]. RTOG 0522 (accelerated RT + cisplatin ± cetuximab – for H & N cancer) Cetuximab is a recombinantly produced RTOG 1016 (RT + cetuximab versus RT + CHT – in HPV positive oropharyngeal chimeric, human and mouse sequences cancer) containing, monoclonal antibody. It is RTOG 0617/ECOGR0617 (RT + CHT ± cetuximab – for NSCLC) composed of the Fv regions of a murine RTOG 0436 (RT + cisplatin/paclitaxel ± cetuximab – for esophageal cancer) anti-EGFR antibody with human RTOG 1010 (RT + paclitaxel/carboplatin/trastuzumab vs RT + paclitaxel/carboplatIgG1 heavy and kappa light chain conin/trastuzumab followed by surgery – in HER2-expressing adenocarcinoma of the esophagus) stant regions. The antibody functions by Prophylactic RT binding to the EGFR type I (also desigACCOG-HER-PCI (Anglo Celtic Cooperative Oncology Group trial; NCT00639366) nated as HER1 or c-ErbB-1), which is (trastuzumab/taxane ± prophylactic cranial irradiation for metastatic breast cancer) expressed on both normal and tumor Combinations with adjuvant (postoperative) RT (PORT) cells. By binding to the EGFR, cetuxiEORTC 22071 (PORT- CHT ± panitumumab – for high risk H & N cancer) mab competitively inhibits the association RTOG 0920 (PORT (IMRT) ± cetuximab – in locally-advanced resected H & N cancer) of EGF and other endogenous ligands, RTOG 1216 (PORT + cisplatin versus docetaxel versus docetaxel/cetuximab – for high such as TGF-a, to its cognate receptor. risk H & N cancer patients (p16-negative oropharyngeal cancer) Cetuximab is highly specific for the RTOG 0974/NSABPB-43 (PORT ± trastuzumab – for HER2-positive DCIS after human EGFR and does not bind to lumpectomy) EGFR from other species. In addition, RTOG 0825 (PORT + TMZ ± bevacizumab - for GBM) other EGFR inhibitors, such as panituRTOG 0320 (whole brain RT & stereotactic RT +/- temozolomide and erlotinib – for mumab, erlotinib and gefitinib deserve to NSCLC with 1–3 brain metastases) be mentioned as compounds that are fairly advanced but still not approved in Figure 2. Combinations of radiotherapy with approved agents in Phase III studies combination with RT. The most impor(ongoing and closed). tant groups of compounds selected CHT: Chemotherapy; GBM: Glioblastoma multiforme; H & N: Head and neck; RT: Radiotherapy. according to their underlying molecular mechanisms are discussed below. Experimental as well as clinical evidence providing the basis for target- advance head and neck cancer patients is still a platinum-based ing EGFR with inhibitors – the majority of data are available chemoradiotherapy [22]. This combination often leads to severe radiation-induced mucositis, while chemotherapy is potentially for cetuximab, erlotinib, gefitinib and lapatinib [17,18]. associated with additional systemic and potential fatal side effects on the renal and hematopoietic system. Taken together, the curEGFR inhibitors Cetuximab has been approved for the primary treatment of rent consensus is that a combination of primary RT with cetuxiadvanced head and neck patients with squamous cell cancer, mab may be used in all patients with advanced (stage III/IV) where it now plays a central role and competes with classical che- carcinomas of the head and neck region (squamous cell carcimotherapy regimens [1,15,16]. The approval is based on a successful noma) that are not eligible for a treatment combination containPhase III study that showed an impressive response of patients ing cisplatin in combination with RT [16,23]. Cetuximab treated with definitive RT and cetuximab [19]. The 5-year overall combined with RT has not been compared in prospective clinical survival (OS) rates showed a median increase from 29 to trials with chemoradiotherapy [16,23]. For this reason, the standard 49 months in the cetuximab group [20]. In addition, cetuximab is treatment for patients with locoregionally advanced SCCHN, also indicated, in combination with irinotecan, for the treatment who are not eligible for surgery, is radio-chemotherapy. Of note, of K-RAS wild-type metastatic colorectal cancer (mCRC) in novel combinations of cetuximab with RT in combination with combination with chemotherapy, as well as a single agent in other compounds than cisplatin are under investigation in patients who have failed oxaliplatin- and irinotecan-based therapy clinical trials. Panitumumab (Vectibix1, Amgen, Inc.) was initially and in patients who are intolerant to irinotecan. In addition, cetuximab plus platinum-based chemotherapy is also of value in approved by the FDA in 2006 for the treatment of patients first-line treatment in patients with recurrent or metastatic squa- with EGFR-positive mCRC who progressed after first-line chemous cell carcinoma of the head and neck [21]. In this study, the motherapy (fluoropyrimidine-, oxaliplatin- and irinotecanauthors could demonstrate that combining cetuximab with cispla- containing chemotherapy regimens). Based on two randomized tin and fluorouracil prolonged the median OS from 7.4 to Phase III trials, panitumumab is now approved as a first-line 10.1 months. One major question that was recently resolved in a treatment in combination with Folfox and as second-line treatprospective clinical study (RTOG 0522) was whether addition of ment of patients (combined with Folfiri) with KRAS wild-type cetuximab to cisplatin in combination with RT would improve mCRC. Potential side effects of panitumumab resemble survival for patients with stage III-IV head and neck squamous cetuximab-related toxicities (skin rash and acne, systemic allercell cancers (see further below). The current standard of care for gic infusion reactions, hypomagnesemia and in rare cases www.expert-reviews.com

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nausea, vomiting and constipation). Panitumumab is currently in evaluation in a Phase III trial (EORTC 22071) in combination with RT. In a recently presented randomized Phase III (CONCERT) trial, the addition of panitumumab to cisplatinbased chemoradiotherapy resulted in a significant shorter OS (hazard ratio [HR]: 1.63; [24]) compared with standard chemoradiation. Several Phase II trials investigating RT in combination with panitumumab are ongoing and may be found at the website provided by the US NIH [105]. Erlotinib is an oral tyrosine kinase inhibitor of EGFR. It has been approved in the USA for advanced pancreatic and NSCLC [25,26]. Preclinical models suggest a significant RTsensitizing effect and a potential synergism with cisplatin. In a recently published Phase II trial, however, erlotinib failed to improve response rates and progression-free survival when added to RT plus cisplatin in patients with advanced squamous cell carcinoma of the head and neck [27]. VEGFR inhibition

The term angiogenesis is generally applied to the growth of micro-vessel sprouts of the size of capillary blood vessels and is characterized by the expansion of pre-existing vascular networks. Once a network is established (VEGF-dependent), it is expanded by sprouting as well as by non-sprouting mechanisms. Angiogenesis plays an important and possibly even indispensable role for the growth of tumors and also represents one of the so-called hallmarks of cancer [28]. In general, the relative impact of neo-angiogenesis increases as tumors become clinically larger. The principal importance of angiogenesis for tumor growth is supported by multiple pre-clinical and clinical studies that showed a positive correlation between tumor angiogenesis and tumor stage. Several growth factors have been shown to contribute to this process, of which the so-called VEGF is regarded as one of the most important factors involved. VEGF and its receptor are now one of the most important targets for anticancer treatment [29–31]. Because of the essential role VEGF and its receptors and their downstream signaling pathways play in angiogenesis, tumor progression and metastasis, various therapeutic strategies (‘lines of attack’) have been developed to interfere with these pathways. Among the various approaches are the development of antibodies and soluble receptors that inhibit the binding of VEGF to its receptors. In addition, tyrosine kinase inhibitors, antisense constructs targeting various genes, mammalian target of rapamycin (mTOR) inhibitors and hypoxia-inducible factor (HIF) antagonists agents are in early clinical development. The effects of RT on tumors are regarded as being dependent on the functional state of the vascular tumor bed and vascular-dependent supply of nutrients and oxygen [32]. The endothelial cell as a central target of radiation effects

The endothelial cell (EC) plays a central role as a primary target responsible for several clinical consequences of RT [33]. This relates not only to antitumor effects of RT, but also to treatment-associated side effects in normal tissues [34]. The 668

signaling pathways underlying the inflammatory response are now focus of intense investigation most notably in the field of rheumatology which has led to the recent introduction of novel targeted compounds capable of modulating TNF-a and IL-bdependent signaling [35]. The principal clinical relevance of targeting vasculature in the treatment of cancer by pharmacological means is undisputed by most scientists and many vascular targeting agents are currently in clinical issue or in advanced preclinical development [36,37]. Also, the principal importance of ECs for anti-tumor effects as well as for normal tissue responses (side effects) against RT has been demonstrated. Several studies define a similar pattern of tissue response, for example, in the GI tract and tumors. This pattern of changes is characterized by rapid endothelial apoptosis (within days) followed by tissue and/or tumor regression. It was suggested that this time course of events sustains microvascular dysfunction and regulates tumor stem cell dysfunction in response to low-dose irradiation as is being used in the treatment of cancer patients [33]. Not only the antitumor, but also some of the side effects of RT may be directly related to EC dysfunction and not primarily, as has been thought before, to damage at the stem cell level [38,39]. Higher doses than those used during conventionally fractionated RT (>2.0 Gy) are believed to preferentially target the tumor vasculature [40]. The notion that the microvasculature, besides the clonogenic component, might be an additional target for radiation provides a basis for exploring new methods for pharmacological modification of radiation effects on tumors as well as on normal tissues. The link between tumor growth and angiogenesis provides the basis for combining antivascular therapy and RT. Of note, inflammatory processes also play an important pathophysiological role both for tumor growth, tumor angiogenesis and lymphatic angiogenesis [31–43]. Functional vasculature is required for adequate cancer cell oxygenation that is important during fractionated RT and hence for an adequate treatment response. However, persistent functional vessels and viable ECs are undesirable after irradiation as they allow remaining tumor clonogenic cells to survive and regrow. It has been hypothesized that tumor vasculature may be restored after treatment by bone marrow-derived cells and that this process may be blocked by inhibition of specific cytokine pathways. It should be noted in this context, that inhibition of angiogenesis has been linked with several potentially negative effects on treatment outcome. Undesirable effects of treatment with anti-angiogenic agents, such as increased tumor hypoxia or invasiveness as well as an increase in the number of breast cancer stem cells have been discussed in the literature [43–45]. The sequence of progression (premalignant state, followed by the angiogenic switch to the malignant state) of proangiogenic factors under pathological conditions is well characterized and has been summarized [46]. Several growth factors are involved, such as VEGF, bFGF, TGFb-1, PIGF, PD-ECGF and pleiotrophin. Each of the activities of these growth factors may serve directly or indirectly as a potential target for inhibiting tumor growth under pathological conditions. Tumor Expert Rev. Clin. Pharmacol. 6(6), (2013)

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Targeted drugs in combination with radiotherapy for the treatment of solid tumors

growth is accompanied by several stages at which angiogenesis plays an important role leading finally to metastasis that also relies on formation of blood vessels (secondary angiogenesis) [47]. There is evidence for an association between EGFR function and expression and angiogenesis. For example, upregulation of VEGF-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy [48]. In preclinical experiments as well as in clinical trials, EGFR inhibitors in combination with anti-angiogenic agents have shown additive efficacy [49]. Furthermore, EGFR expression may be upregulated in proliferating tumor ECs, which provides a further potential linkage between EGFR signaling and enhanced angiogenesis [50]. It has also been shown in several publications that blocking EGFR function may inhibit VEGF expression and angiogenesis in tumor cells [51–59]. Integrin inhibition

Integrins are heterodimeric transmembrane receptors that play an important role for cellular and extracellular matrix interactions. In the cellular context, integrins act as heterodimeric transmembrane glycoproteins consisting of two subunits termed a and b. At the moment, 24 different heterodimeric configurations (18 a and 8 b subunits) are known. Several reviews are available discussing the role of this class of proteins in processes such as cell migration, differentiation, survival, angiogenesis, wound healing, hemostasis and there general importance in the field of oncology [54–57]. The potentially clinical importance of therapeutics targeting integrins is also based on the fact that several diseases are known which are characterized by excessive angiogenesis for which no effective treatments are available. The integrins involved in angiogenesis comprise a1b1, a2b1, a4b1, a5b1, a6b1, a6b4, a9b1, avb3, avb5 and avb8 [54,55]. Especially integrins avb3, avb5 and a5b1 have been shown to be involved in processes such as angiogenesis and in the metastasis of solid tumors that play an important role in cancer therapy [42,54–56]. The currently most advanced integrin antagonist in clinical development is cilengitide, which is or has been evaluated in several clinical Phase III studies for various types of tumors, such glioblastoma or head and neck cancer [60-62]. The fact that brain tumors are typically well vascularized, and therefore potentially more susceptible to anti-angiogenic treatment with integrin antagonists compared with other types of tumors, the lack of effective treatments for glioblastoma, and the synergy observed for integrin antagonists in combination with RT – at least in preclinical studies – spurred the development of clinical trials especially for the treatment of glioblastoma [63]. Preclinical data suggest that cell adhesion mediated by integrins contributes to radioresistance [64,65]. In contrast to this, another group recently published that cilengitide modulates attachment and survival of glioblastoma cells, but is not a radiosensitizer [66]. Apart from brain tumors, inhibitory peptides and monoclonal antibodies targeting integrins are currently being investigated in clinical trials in patients with colorectal cancer, renal cell carcinoma and melanoma. The first reports in Phase I trials demonstrating clinical activity with an integrin antagonist was www.expert-reviews.com

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documented for cilengitide in patients with recurrent malignant glioblastoma and in children with refractory brain tumors [67,68]. In this study, cilengitide displayed activity as a single agent and was not associated with significant toxicity. Cilengitide in combination with RT and temozolomide in patients with newly diagnosed glioblastoma has been explored in clinical trials [62,69]. The standard care of treatment for glioblastoma usually consists of surgical resection, if possible, followed by RT in combination with chemotherapy (temozolomide) [70]. Addition of temozolomide to RT improves outcome in glioblastoma [70,71]. The next logical step was therefore to combine cilengitide with a treatment combination consisting of RT and temozolomide. Stupp et al. reported in a Phase I/IIa study on 52 patients treated with cilengitide at a dose of 500 mg twice weekly in association with RT and concomitant and adjuvant temozolomide [72]. The 6-month progression-free survival was 69% and the median OS was 16.1 months, as compared with 53.9% and 14.6 months, respectively for standard treatment. Temozolomide is an orally active alkylating agent, the activity of which depends on its ability to chemically modify DNA. In patients, the presence of a methylated MGMT gene promoter (a promoter is regulatory element of gene transcription), whose gene product (O6-alkylguanine DNA alkyltransferase) is capable of repairing temozolomideinduced DNA damage, is associated with a significantly longer progression-free survival and OS as compared with the presence of unmethylated MGMT ([70,73] and references therein). Methylation of genes is a general molecular mechanism for control of gene activity. Additional positive results utilizing RT in combination with cilengitide were reported from a randomized Phase II trial (new agents brain tumor treatment (NABTT) cooperative group (NABTT 0306) [74]. In this study, 112 patients with newly diagnosed glioblastoma were randomized to receive cilengitide in combination with standard RT plus temozolomide treatment. Median survival and 1-year survival rates were 18.9 months and 79.5%, respectively. OS was 30 months for patients who had methylated MGMT status, and 17.4 months for patients who had unmethylated MGMT status. Cilengitide has been evaluated in several Phase III studies for the treatment of glioblastoma (CENTRIC-study: cilengitide, temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma and methylated gene promoter status). CENTRIC was initiated in 2008 with the primary aim of investigating the efficacy and safety of cilengitide in combination with RT plus temozolomide versus RT and temozolomide alone in patients with newly diagnosed glioblastoma displaying a methylated MGMT gene promoter status. The study was recently concluded and an analysis of outcome measures was presented. However, Merck announced this Phase III trial failed to meet the primary end points as in a news release. Detailed trial results were presented at the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting. Apart from cetuximab, the only targeted compound that is currently approved for combination with RT, several recent or ongoing clinical studies have investigated or are in the process of evaluating RT as a combination partner. A select list of major Phase III studies (ongoing or closed) is presented in FIGURE 2 and 669

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is discussed briefly in the following chapter regarding their underlying scientific rationale and clinical outcome. Studies are subdivided into protocols that combine definitive, prophylactic or postoperative radiotherapy (PORT, adjuvant RT) with targeted drugs that are already approved for at least one other oncological indication. Of note, only a small number of targeted drugs are currently in Phase III studies (cetuximab, trastuzumab, panitumumab, bevacizumab and erlotinib), demonstrating the still untapped potential for possible future studies in this field. Clinical studies – active or recently closed of radiotherapy (primary, prophylactic or postoperative) in combination with targeted drugs Combinations with definitive RT

Definitive RT plays a potentially curative role for many types of tumors. One of the most prominent examples is the locally advanced stage of head and neck cancer, where primary (definitive) RT plays an eminent role almost equal to primary surgical treatment, depending among others, on the exact localization, operability and also on quality of life issues [22]. The approval of cetuximab for head and neck cancer is based on one multinational, randomized study that was previously published and widely cited [19,20]. In this study [106], RT alone versus RT plus cetuximab was compared for the treatment of locoregionally advanced squamous cell carcinoma of the head and neck. Primary end point was the duration of loco-regional control. The results clearly favored the combination treatment. Median duration of locoregional control was 24.4 months (RT plus cetuximab group) compared with 14.9 months among patients treated with RT alone. Importantly, the improvement in outcome was not associated with a higher incidence of common toxic effects. Based on this study, novel protocols combining cetuximab with RT have been developed. RTOG 0617 (randomized Phase III comparison of standarddose [60 Gy] versus high-dose [74 Gy] conformal RT with concurrent and consolidation carboplatin/paclitaxel ± cetuximab (IND #103444) in patients with stage IIIA/IIIB NSCLC) is a four-arm study in which half of patients are assigned to treatment with cetuximab. Recruitment of patients for the cetuximab arms is still ongoing. The currently accepted ‘standard of care’ for treatment of locally advanced NSCLC is radiation plus chemotherapy. In recent years, research has been concentrated on the type of chemotherapy drugs to use and how to combine them with RT. Targeting the EGFR pathway has been shown to be of relevance in NSCLC. The role of EGFR inhibitors in the treatment of NSCLC with wild-type EGFR has been recently reviewed by Laurie and Goss [79]. The discovery of activating mutations of the EGFR in NSCLCs has spurred research on the use of EGFR inhibitors in mutationpositive patients. However, only a minority is of the patient’s tumors contain mutations in the EGFR gene ([79], and references therein). EGFR inhibitors can induce a typical, acneiform rash. The relationship between rash and outcomes has been evaluated in several studies. In the FLEX study (cetuximab plus 670

chemotherapy in patients with advanced NSCLC (FLEX): an open-label randomized Phase III trial), an analysis was performed on patients in the cetuximab arm who had developed any grade of rash by the end of the first cycle [80]. Patients developing a rash with cetuximab had improved outcomes while patients treated with cetuximab who did not develop early rash had outcomes equivalent to patients receiving chemotherapy alone, suggesting that the lack of a rash by might be a marker of lack of benefit [80]. Similar correlations were seen in patients treated with RT and cetuximab in head and neck cancer patients. One of the next most obvious steps was to combine RT with standard chemotherapy and to compare this regimen with an identical treatment plus additional cetuximab (RTOG 0522 – a randomized Phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III–IV head and neck squamous cell carcinomas [HNSCC]). The scientific rationale for this trial was based on the fact that the addition of both cisplatin as well as cetuximab alone was found to improve survival in patients with locally advanced stage III–IV HNSCC [19,20,75]. However, the analysis of the RTOG 0522 study showed that patients with locally advanced head and neck cancer gained no survival benefit with the addition of cetuximab to chemoradiation. OS improved only slightly with cetuximab, but the difference did not achieve statistical significance, according to the data presented by Ang K, the principal investigator, at the American Society of Clinical Oncology (ASCO) meeting in Chicago (IL, USA, June 2011). The study included nearly 150 sites and 940 patients with stage III–IV cancer of the oropharynx, larynx and hypopharynx, of which 895 patients were eligible for analysis. One of the most significant recent findings in the treatment of head and neck cancer patients was the finding that infection with the human papilloma virus (HPV) is associated with an improved treatment outcome in head and neck cancer patients [9,76]. This observation, in conjunction with the rise in the incidence of HPV-associated carcinoma, which is primarily confined to the oropharynx, has now prompted a re-evaluation of standard treatment regimen based on previous trial outcomes that did not consider HPV/p16 status. It is unclear at the moment, whether HPV infection would necessitate or allow the introduction of altered (HPV-adapted) treatment concepts and how this would potentially affect combinations of RT with chemotherapy or with targeted drugs, such as cetuximab. One ongoing trial (RTOG-1016 – a Phase III trial of RT plus cetuximab versus chemoradiotherapy in HPV-associated oropharynx cancer) aims to identify a less toxic approach in HPV-associated cancer of the oropharynx by comparing accelerated RT (IMRT) plus high dose cisplatin (100 mg/ m2 on days 1 and 22) with accelerated RT (IMRT) plus concomitant cetuximab in patients positive for p16. Targeting the EGFR by monoclonal antibodies is one possible strategy to improve outcome in patients with NSCLC. Besides the EGFR, several other targets may be of importance in the treatment of this type of cancer, including Expert Rev. Clin. Pharmacol. 6(6), (2013)

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Targeted drugs in combination with radiotherapy for the treatment of solid tumors

ALK, MET, RAS and PI3K [77]. In the Phase III FLEX trial, cetuximab added to chemotherapy resulted in a modest OS benefit (1.2 months) compared with the same chemotherapy alone in patients with advanced EGFR-expressing NSCLC [78]. Both RTOG 0436 and RTOG 1010 explore the role of RT in combination with targeted drugs in esophageal cancer. RTOG 0436 evaluates the addition of cetuximab to RT combined with chemotherapy in patients who are treated without surgery while in RTOG 1010 RT is investigated in combination with chemotherapy with or without trastuzumab followed by surgery. Prophylactic RT

Prophylactic cranial irradiation in combination with targeted therapy is investigated in a trial sponsored by the Anglo Celtic Cooperative Oncology Group (radiation therapy to the head in preventing brain metastases in women receiving trastuzumab and chemotherapy for metastatic or locally advanced breast cancer). Patients in treatment arm 1 receive a taxane plus trastuzumab therapy for 6 weeks. While continuing taxane and trastuzumab therapy, patients then undergo concurrent prophylactic cranial RT. In the second arm, taxane plus trastuzumab therapy without concurrent prophylactic cranial RT is applied. Inclusion criteria are histologically proven breast carcinoma (HER2-positive tumors plus the presence of C-erB2 gene amplification is a precondition for inclusion into the study) without known or suspected brain metastases or CNS disease). The study results are not published yet. Of interest in the context of cranial irradiation is a recent publication describing that the presence of EGFR mutations is associated with favorable intracranial response and progressionfree survival following brain irradiation in NSCLC patients [81]. Postoperative (adjuvant) RT

In the adjuvant or postoperative setting, several prospective clinical trials are of interest, which are combining RT with targeted compounds of which EORTC 22071 and RTOG 0920 are noteworthy. EORTC 22071 and RTOG 0920 are noteworthy. The rationale for performing these studies is based on the fact, that adjuvant management of completely resected SCCHN with certain risk factors is still controversial. In general, postoperative radiotherapy (PORT) is indicated and regarded as a standard of care for most stage III/IV cases. In the last years, randomized trials have shown that the addition of concurrent chemotherapy to PORT improves outcomes for selected patients. In a widely cited meta-analysis, it was revealed that patients who benefited significantly from the addition of chemotherapy were those with positive resection margins and/ or nodal extracapsular extension [82]. Patients with other tumor characteristics did not benefit significantly from high-dose concurrent cisplatin. EORTC 22071 is a randomized, Phase III trial of the EGFR-antibody panitumumab combined with adjuvant RT plus chemotherapy for patients with HNSCC at high risk of recurrence. High-risk patients are defined as those with the www.expert-reviews.com

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presence of close resection margins (