Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy.

Introduction

The proof-of-concept that high amounts of antibodies exhibiting the same antigen specificity can be produced in a cost-effective manner has been first been provided in 1975 by the German biologist Georges Köhler and the Argentinian biochemist César Milstein. 1 This milestone discovery, which granted to Köhler and Milstein the 1984 Nobel Prize for Medicine or Physiology, not only has revolutionized countless experimental applications and diagnostic procedures, but also has generated a growing armamentarium of highly specific therapeutic agents. 2 , 3 Indeed, a large panel of monoclonal antibodies (mAbs) is nowadays approved by the US Food and Drug Administration (FDA) and other international regulatory agencies, including the European Medicines Agency (EMA), for the treatment of disorders as diverse as autoimmune diseases and cancer. 2 , 3 In 1997, rituximab, a chimeric (meaning that it contains both human and murine domains) molecule specific for the B-cell lineage marker CD20 was the first mAb to be licensed for use in cancer patients, i.e., individuals with non-Hodgkin’s lymphoma (NHL) relapsing upon conventional chemotherapy. 4 Since then, no less than 15 distinct mAbs have been approved for the treatment of hematopoietic and solid neoplasms, encompassing: (1) mAbs that exert an antineoplastic activity as they primarily bind to proteins preferentially expressed on the surface of neoplastic, as opposed to non-malignant, cells; (2) mAbs that neutralize trophic signals provided by the tumor stroma; and (3) so-called immunostimulatory mAbs, i.e., mAbs that mediate therapeutic effects as they bind to, and hence modulate the activity of, cells of the immune system, de facto eliciting a novel or reactivating a pre-existing immune response against malignant cells. In 2 previous issues of OncoImmunology , 5 , 6 we have discussed the scientific rationale behind the use of mAbs, all types confounded, in cancer therapy, as well as the clinical development of (1) mAbs that have not yet been approved by the US FDA for use in humans, and (2) FDA-approved mAbs employed as off-label therapeutic interventions. As this area of clinical investigation is continuously expanding, here we will maintain the approach that we adopt in our Trial Watch series, 7 - 10 but we will restrict our attention on mAbs that mediate antineoplastic effects by primarily targeting cancer cells and/or the trophic support that they receive from the tumor stroma, which we cumulatively refer to as “tumor-targeting” mAbs ( Table 1 ). Recent advances on the use of immunostimulatory antibodies in cancer therapy 11 - 16 will be discussed in the next Trial Watch.

For illustrative purposes, tumor-targeting mAbs can be sub-grouped into 6 non-mutually exclusive classes, 17 based on functional considerations: (1) mAbs that inhibit cancer cell-intrinsic signal transduction pathways that are required for survival and/or proliferation, such as cetuximab, a chimeric IgG1 specific for the epidermal growth factor receptor (EGFR), which is currently approved for the treatment of head and neck cancer and colorectal carcinoma (CRC); 18 , 19 (2) mAbs that activate cytotoxic receptors expressed by cancer cells (e.g., tumor necrosis factor receptor superfamily, member 10B, TNFRSF10B, best known as TRAILR2 or DR5), hence actively triggering their apoptotic demise, such as the fully human TRAILR2-specific IgG1 conatumumab; 20 (3) mAbs that bind (but not necessarily inhibit the activity of) tumor-associated antigens (TAAs) and exert antineoplastic effects as they engage effector mechanisms of innate immunity, including antibody-dependent cell-mediated cytotoxicity (ADCC), 3 , 21 - 24 antibody-dependent cellular phagocytosis (ADCP), 25 and complement-dependent cytotoxicity (CDC), 26 , 27 such as rituximab, which is widely employed for the treatment of chronic lymphocytic leukemia (CLL) and NHL; 28 - 30 (4) trifunctional (bispecific) mAbs, which can crosslink 2 distinct antigens (generally, one TAA and one T-cell marker) while preserving the capacity of activating immune effector functions via their constant fragment, such as catumaxomab, a chimeric (mouse and rat) mAb specific for CD3 and epithelial cell adhesion molecule (EPCAM) that is currently licensed for the therapy of malignant ascites in patients with EPCAM + tumors; 31 , 32 (5) immunoconjugates, i.e., TAA-specific mAbs coupled to toxins or radionuclides, such as the CD20-targeting molecules 90 Y-ibritumomab tiuxetan and 131 I-tositumomab, which are nowadays used in the treatment of NHL; 33 , 34 and (6) mAbs that interfere with the trophic interaction between neoplastic cells and the tumor stroma, such as the vascular endothelial growth factor (VEGF)-directed mAb bevacizumab, which is currently approved for use in patients affected by CRC as well as lung and renal cancer. 35 , 36 It should be kept in mind that several tumor-targeting mAbs exert antineoplastic effects via multiple of these mechanisms. For instance, cetuximab not only inhibits EGFR signaling, but also triggers ADCC, 37 and has a direct immunostimulatory activity. 38

Since the submission of our latest Trial Watch on this topic (October 2012), 5 the US FDA has approved bevacizumab for use in combination with fluoropyrimidine/irinotecan- or fluoropyrimidine/oxaliplatin-based chemotherapy for the treatment of patients with metastatic CRC whose disease has progressed in spite of first-line bevacizumab-based therapy. 39 Of note, bevacizumab had been licensed by the US FDA as first- or second-line therapeutic intervention in subjects affected by metastatic CRC as early as in 2004 and 2006, respectively. 40 - 42 During the last 13 mo, the US FDA has also extended the approval of denosumab, a human IgG2 specific for receptor activator of NF-κB ligand (RANKL), to unresectable giant cell tumors of the bone in adults and skeletally mature adolescents. 43 , 44 Besides being employed in postmenopausal women at risk for osteoporosis, denosumab is licensed by the US FDA since 2011 for use in patients at high risk of bone fracture as they undergo androgen-deprivation therapy for non-metastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer. 45 On 2013, February, 22nd, the US FDA approved trastuzumab emtansine, a humanized IgG1 specific for v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2, best known as HER2) coupled to the cytotoxic agent mertansine, for use in women bearing HER2 + metastatic breast carcinoma who previously received naked trastuzumab (which is approved for use in breast carcinoma patients since 1998) and a taxane, separately or in combination. 46 , 47 Finally, no earlier than on 2013, September 30th, the US FDA granted accelerated approval to pertuzumab (a humanized IgG1 specific for HER2) for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2 + , locally advanced, inflammatory, or early-stage breast cancer. 48 Of note, pertuzumab had previously (on 2012, June 8th) been licensed for use in combination with trastuzumab and docetaxel for the treatment of patients with metastatic HER2 + breast carcinoma who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 49 However, the recent regulatory extension granted to this tumor-targeting mAB is relevant as pertuzumab in combination with trastuzumab and docetaxel has now become the first FDA-approved neoadjuvant treatment for patients with breast cancer (source http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm370393.htm ).

Update on Clinical Reports

Since the submission of our previous Trial Watch dealing with this topic (October 2012), 5 the preclinical and clinical development of mAbs for cancer therapy has proceeded at an unprecedented speed. Indeed, querying PubMed with the string “antibody AND cancer AND patients” as of 2013, October 21st returned more than 3200 entries indexed later than 2012, October 1st. Narrowing down the search to “antibody AND cancer AND patients AND trial” resulted in approximately 600 entries (source http://www.ncbi.nlm.nih.gov/pubmed ). Although this figure (1) refers to mAbs all types confounded and (2) is expected to comprise a number of review articles, commentaries and false-positive hits (i.e., scientific reports that do not deal with the clinical development of mAb although they do contain all these keywords), it is representative of the huge interest that this therapeutic modality continues to attract. Obviously, a significant fraction of the clinical reports published during the last 13 mo on the use of tumor-targeting mAbs in cancer patients refers to the use of FDA-approved molecules as on-label interventions. This is the case of studies comparing experimental regimens to gold standard therapeutic approaches, when the latter involves a tumor-targeting mAb, as well as of studies that investigated whether some FDA-approved tumor-targeting mAbs can be safely and effectively administered at different doses and/or via different routes and/or according to alternative schedules. In line with the scope of our Trial Watch (see above), we will not consider these studies further. Rather, we will focus on experimental mAbs or FDA-approved mAbs employed as off-label interventions.

Experimental mAbs

The results of no less than 33 clinical studies investigating the safety and efficacy of hitherto experimental tumor-targeting mAbs in cancer patients have been published during the last 13 mo ( Table 2 ). The therapeutic paradigms investigated by these studies are relatively heterogeneous, encompassing the inhibition of cancer cell-intrinsic survival pathways, the active elicitation of endogenous signal transduction cascades with pro-apoptotic effects, the engagement of immune effectors, the selective delivery to neoplastic cells of cytotoxic agents or radionuclides as well as the blockade of trophic molecules produced by the tumor stroma and/or their receptors. Among the strategies that nowadays appear to attract more interest is the mAb-mediated inhibition of insulin-like growth factor 1 receptor (IGF1R), an anti-apoptotic signal transducer that is overexpressed by a large panel of tumors. 50 Thus, 3 distinct IGF1R-specific mAbs, namely, ganitumab (a fully human IgG1 also known as AMG 479), 51 cixutumumab (a fully human IgG1 also known as IMC-A12), 52 and AVE1642 (a humanized IgG1), 53 , 54 have recently been tested, either as a standalone intervention, either combined with conventional chemotherapeutic agents (e.g., docetaxel, doxorubicin, and gemcitabine), or given together with temsirolimus (an inhibitor of the mammalian target of rapamycin currently approved by FDA for the treatment of renal cell carcinoma), 55 in cohorts of patients affected by bone and soft tissue sarcomas, 56 pancreatic tumors, 57 locally advanced or metastatic breast carcinomas, 58 and advanced solid tumors. 59 - 61 In all these studies, anti-IGF1R antibodies were well tolerated and displayed promising clinic activity, at least in a subset of patients.

Another approach that has been investigated in several recent clinical studies is the therapeutic activation of TRAILR2. 62 Indeed, although both normal and malignant cells express TRAILR2, the latter appear to be more susceptible to TRAILR2 agonists than the former, for hitherto unclear reasons. 62 , 63 During the last 13 mo, the results of 5 distinct studies investigating the safety and clinical profile of TRAILR2-activating mAbs in cancer patients have been published. 57 , 64 - 67 In particular, these studies tested (1) conatumumab (a human IgG1 also known as AMG 655) 20 , 68 , 69 in combination with gemcitabine-based chemotherapy for the treatment of pancreatic cancer, 57 with paclitaxel plus carboplatin for the first-line treatment of advanced non-small-cell lung carcinoma (NSCLC), 64 or with bevacizumab plus a folinic acid-, 5-fluorouracil, and oxaliplatin-based chemotherapeutic regimen (generally known as mFOLFOX6) for the first-line treatment of metastatic CRC; 65 (2) drozitumab (a human IgG1 also known as PRO95780 ) 70 , 71 in combination with bevacizumab plus mFOLFOX6 as a first-line intervention against metastatic CRC; 67 and (3) lexatumumab (a human IgG1 also known as HGS-ETR2) 72 - 74 as a standalone intervention in pediatric patients affected by solid tumors. 66 In these clinical cohorts, TRAILR2-activating mAbs were well tolerated. The therapeutic potential of this approach, however, seems limited, as poor (if any) clinical responses have been documented among patients receiving TRAILR2 activating mAbs.

There are several means for blocking the trophic support that stromal cells normally provide to their malignant counterparts. By antagonizing VEGF receptor 2 (VEGFR2) signaling, ramucirumab (a human IgG1 also known as IMC-1121B), blocks perhaps the most prominent of these interactions, i.e. , neoangiogenesis. 75 Ramucirumab has recently been tested as a standalone intervention in patients affected by advanced gastric or gastresophageal junction adenocarcinoma and hepatocellular carcinoma, 76 , 77 as well as in combination with docetaxel for the treatment of stage IV NSCLC patients progressing upon one cycle of platinum-based therapy. 78 More frequently, however, mAbs are devised to block the crosstalk between neoplastic cells and their stroma by neutralizing soluble mediators. The precursor of this class of tumor-targeting mAbs is bevacizumab (which targets VEGF), but several other molecules operate in a similar fashion, including carlumab (a human IgG1 also known CNTO 888), which neutralizes chemokine (C-C motif) ligand 2 (CCL2); 79 trebananib (also known AMG 386), a peptibody ( i.e. , a fusion between a biologically active peptide and the constant fragment of a mAb) that blocks angiopoietin 1 and 2; 80 - 82 and rilotumumab (a human IgG2 also known as AMG 102), which binds to—hence neutralizing—hepatocyte growth factor (HGF). 83 - 85 During the last 13 mo, carlumab and trebananib have been employed for dose-escalation studies in patients affected by advanced solid tumors, 86 - 88 while rilotumumab has been tested in combination with mitoxantrone (an anthracycline that induces the immunogenic demise of cancer cells) 8 , 89 , 90 and prednisone in patients with progressive, taxane-refractory castration-resistant prostate cancer. 91 , 92 All these agents were well tolerated, yet only trebananib was associated with durable antitumor activity in a fraction of patients. 87

Among several other therapeutic strategies based on hitherto experimental tumor-targeting mAbs, 93 - 108 great interest is attracted by immunoconjugate-based regimens. This approach is very flexible, as it can be harnessed to shuttle chemicals, 109 radionuclides, 110 as well as biologically active factors (e.g., cytokines) 111 - 113 to virtually any cellular component of neoplastic lesions, provided that these components express (ideally in a restricted manner) an antigenic moiety on their surface. 114 Recently, 90 Y-conjugated clivatuzumab tetraxetan, a humanized mAb specific for mucin 1 (MUC1, which is frequently overexpressed or aberrantly glycosylated in multiple carcinomas), 115 , 116 has been employed in combination with low-dose gemcitabine (an immunostimulatory therapeutic regimen) 11 , 12 in patients bearing advanced pancreatic neoplasms. 117 On a slightly different note, a tumor necrosis factor α (TNFα)-armed variant of L19, a human single chain variable fragment targeting the extra domain B (EDB) of fibronectin (which is predominantly expressed by the tumor-associated vasculature), 118 , 119 has been tested as a standalone therapeutic intervention in patients with advanced solid tumors. 120 Interestingly, these studies demonstrated some clinical activity for 90 Y-conjugated clivatuzumab tetraxetan, 117 but not for the TNFα-L19 fusion. 120 However, the maximal tolerated dose of TNFα-L19 was not attained in this trial, leaving room for further tests at increased doses and/or in combination with conventional therapeutic regimens.

FDA-approved mAbs tested as off-label interventions

Testing FDA-approved drugs on indications for which they have not yet been licensed is advantageous in that safety concerns are generally limited. Accordingly, there is an intense wave of clinical investigation that aims at determining whether FDA-approved tumor-targeting mAbs employed as off-label interventions may provide clinical benefits to cancer patients. During the last 13 mo, the results of no less than 60 clinical trials of this type have been published in peer-reviewed scientific journals ( Table 3 ). The largest fraction of these studies involved the VEGF-targeting mAb bevacizumab, which has been tested, most often in combination with conventional chemotherapy and/or targeted anticancer agents, in cohorts of patients affected by acute myeloid leukemia, 121 multiple myeloma, 122 head and neck squamous cell carcinoma (HNSCC), 123 , 124 breast carcinoma, 48 , 125 - 130 melanoma, 131 hepatocellular carcinoma, 132 - 136 pancreatic cancer, 137 ovarian carcinoma, 138 - 143 prostate cancer, 144 and several other advanced or metastatic solid tumors. 145 - 154 Moreover, 89 Zr-conjugated bevacizumab has been investigated as a means to visualize neoplastic lesions by positron emission tomography (PET) in women with primary breast carcinomas, which often secrete high levels of VEGF. 155 In the context of a randomized Phase III clinical trial, the addition of bevacizumab to docetaxel and trastuzumab failed to improve the progression-free survival of HER2 + metastatic breast cancer patients. 156 Along similar lines, in patients with HER2 - metastatic or locally recurrent breast carcinoma, the combination of bevacizumab with capecitabine (a precursor of 5-fluorouracil) failed to meet the non-inferiority criterion as compared with a therapeutic regimen involving bevacizumab and paclitaxel (a microtubular poison of the taxane family). 127 Earlier, the addition of bevacizumab had been suggested to improve the efficacy of multiple taxanes, including paclitaxel and docetaxel, against breast carcinoma. 157 , 158 Thus, the clinical profile of specific, but not all, chemotherapeutics employed for the treatment of breast carcinoma may be ameliorated from the co-administration of bevacizumab. Nonetheless, on 2011, November 18th, the US FDA revoked the authorization that was given to bevacizumab for use in metastatic breast cancer patients (in combination with paclitaxel) in February 2008 (which was originally granted under the FDA accelerated approval program) (source http://www.cancer.gov/cancertopics/druginfo ). Of note, plasmatic VEGF may constitute a predictive biomarker for bevacizumab efficacy among breast cancer patients. 125 , 156 A finding is being prospectively validated in the context of the MERiDiAN trial, a study in which patients will be treated with bevacizumab and paclitaxel upon stratification based on the circulating levels of short VEGF-A isoforms. 159 Finally, the addition of bevacizumab to cytotoxic chemotherapeutics including paclitaxel and carboplatin (a DNA-damaging platinum derivative), 160 - 162 has been associated with a small but quantifiable decrease in the quality of life of ovarian carcinoma patients. 141 This combinatorial regimen had previously been shown to prolong the disease-free survival of ovarian cancer patients (in particular individuals at high risk for progression) as compared with conventional paclitaxel- or carboplatin-based chemotherapy. 163 Thus, clinicians will have to carefully consider on a per-patient basis whether such a prolongation in disease-free survival is warranted in exchange of a decline in quality of life.

Recently, the safety and efficacy of cetuximab as an off-label therapeutic intervention, most often in combination with conventional chemotherapeutic agents, chemical EGFR inhibitors (such as erlotinib), 164 , 165 or radiation therapy, have been investigated in patients affected by a large panel of neoplasms, including breast carcinoma, 166 esophageal and gastric cancer, 167 - 169 NSCLC, 170 , 171 pancreatic carcinoma, 172 - 174 and other solid tumors. 175 - 179 In addition, the tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded liposomes coupled to the antigen-binding fragment of cetuximab have been evaluated in patients with EGFR-overexpressing advanced solid tumors what were no longer amenable to standard treatments. 180 Only one of these studies was a large, open-label randomized Phase III trial, assessing the addition of cetuximab to capecitabine/cisplatin-based chemotherapy in patients with advanced gastric or gastresophageal junction cancer (EXPAND trial). 169 In this context, 904 patients (followed at 164 cancer centers in 25 distinct countries) were randomized at a 1:1 ratio to receive 3-wk cycles of twice-daily capecitabine (on days 1–14) plus intravenous cisplatin (on day 1), with or without weekly cetuximab (starting on day 1). 169 Grade 3–4 adverse events were significantly more frequent among patients treated with cetuximab than among individuals receiving chemotherapy only. Moreover, the addition of cetuximab to chemotherapy provided no additional benefits to advanced gastric cancer patients as compared with the use of capecitabine plus cisplatin alone. 169

The results of a few other clinical trials testing FDA-approved tumor-targeting mAbs in off-label indications have been published during the last 13 mo. 181 - 186 In particular, denosumab has been shown to improve the overall survival of lung cancer patients with bone metastases as compared with zoledronic acid. 181 The addition of panitumumab (a EGFR-specific human IgG2 currently approved for the treatment of CRC) 187 - 189 to cisplatin- or 5-fluorouracil-based chemotherapy has been demonstrated to improve the progression-free survival (but not the overall) survival of unselected HNSCC patients. 182 Along similar lines, the combination of panitumumab with pegylated liposomal doxorubicin has been associated with clinical efficacy in patients with platinum-refractory ovarian carcinoma, though skin toxicity was considerable. 183 Conversely, panitumumab failed to improve the therapeutic profile of conventional chemotherapy in an unselected population of patients with advanced gastresophagic adenocarcinoma. 185 Finally, the co-administration of rituximab and recombinant interleukin (IL)-21 to patients with indolent B-cell malignancies has been reported to be well tolerated and clinically active, warranting further investigation. 184

Additional studies

Although in our Trial Watch series we never discuss clinical studies that evaluate the therapeutic profile of anticancer agents employed as on-label interventions, a mention here goes to the CLEOPATRA trial, a randomized, double-blind, placebo-controlled, Phase 3 study investigating the safety and efficacy of pertuzumab, 49 , 190 in combination with trastuzumab and docetaxel, in patients with HER2 + first-line metastatic breast carcinoma. 106 In the context of this study, 808 women with HER2 + metastatic breast cancer who had not received previous chemotherapy or biological treatments (enrolled at 204 distinct cancer centers in 25 countries) were randomized at a 1:1 ratio to receive either pertuzumab, trastuzumab, and docetaxel or the same regimen with a matching placebo replacing pertuzumab. 106 At data cutoff (when the median follow-up was 30 mo for both groups), intention-to-treat analyses revealed a significant improvement in both disease-free and overall survival among patients receiving pertuzumab, trastuzumab, and docetaxel as compared with patients treated with trastuzumab and docetaxel only, with no marked differences in the incidence and severity of side effects. 106 As it stands, the first wave of results from the CLEOPATRA trial (which has been published in January 2012) underpinned the approval of pertuzumab for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2 + metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 49 Conversely, the recent approval of pertuzumab for use in patients with HER2 + , locally advanced, inflammatory, or early-stage breast cancer (see above) was supported by the results of the NeoSphere study, a Phase II, randomized clinical trial involving no less than 417 patients. 48

Taken together, the findings of recently published clinical studies testing the safety and efficacy of tumor-targeting mAbs reinforce the notion that this approach is generally well tolerated and has the potential to elicit robust therapeutic responses, at least in subsets of patients. Among a huge amount of preclinical studies demonstrating the efficacy of tumor-targeting mAbs in a large panel of experimental paradigms (source http://www.ncbi.nlm.nih.gov/pubmed ), we have found of particular interest the work by Boross and colleagues, demonstrating that IgAs and the corresponding Fc receptor (CD89) may be harnessed to achieve robust antineoplastic effects in vivo. 191 These observations pave the way to the development of novel tumor-targeting mAbs of the IgA, rather than IgG, isotype and strategies for the therapeutic targeting of CD89.

Update on Clinical Trials Testing Tumor-Targeting Monoclonal Antibodies

When this Trial Watch was being redacted (October 2013), official sources listed 74 clinical trials launched after 2012, October 1st to evaluate the therapeutic profile of hitherto investigational tumor-targeting mAbs in cancer patients (16 studies) or the efficacy of FDA-approved tumor-targeting mAbs employed as off-label anticancer interventions (58 studies) (source http://www.clinicaltrials.gov ).

Among the investigational tumor-targeting mAbs that continue to attract considerable clinical interest are nimotuzumab and necitumumab. Nimotuzumab (a humanized IgG1) and necitumumab (a fully human IgG1) target the EGFR and have been the subject of an intense wave of clinical investigation 192 - 205 During the last 13 mo, no less than 8 clinical trials have been launched to evaluate the safety and therapeutic potential of these EGFR-targeting mAbs, including 7 Phase I-II studies testing nimotuzumab or necitumumab in combination with conventional chemo(radio)therapeutic regimens in patients with breast carcinoma ( NCT01939054 ); NSCLC ( NCT01763788 ; NCT01769391 ; NCT01788566 ; NCT01861223 ), cervical carcinoma ( NCT01938105 ) and rectal cancer ( NCT01899118 ), as well as 1 Phase III trial assessing the therapeutic potential of nimotuzumab plus irinotecan (an inhibitor of topoisomerase I) in individuals with EGFR-overexpressing gastric or gastresophageal junction cancer ( NCT01813253 ).

Alongside, multiple clinical studies have recently been initiated to investigate the therapeutic profile of a relatively heterogeneous group of investigational tumor-targeting mAbs. These mAbs include (1) BC8, a CD45-targeting murine IgG1 usually coupled to radionuclides, 206 , 207 which is now being tested (in its 90 Y-conjugated form) together with combinatorial chemotherapy in patients with high-risk lymphoid malignancies allocated to undergo hematopoietic stem cells transplantation ( NCT01921387 ); (2) blinatumomab, a bispecific T-cell engager (BiTE) targeting CD3 and CD19 (also known as MEDI-538), 96 , 208 - 210 now under evaluation as a standalone therapeutic measure in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ( NCT01741792 ); (3) Ch14.18, a chimeric IgG1 specific for disialoganglioside GD2, 211 - 216 which is currently being assessed in combination with irinotecan and temozolomide (an alkylating agent) in young patients with relapsed or refractory neuroblastoma ( NCT01767194 ); (4) conatumumab (see above), which is now being investigated in combination with a small SMAC peptidomimetic 217 , 218 in women with relapsed ovarian cancer ( NCT01940172 ); (5) lintuzumab, a humanized IgG1 targeting the cell surface myelomonocytic differentiation antigen CD33, 219 , 220 which is currently being tested (as an 225 Ac conjugate) in combination with cytarabine (an inhibitor of DNA synthesis) in old leukemia patients (NCT01756677); (6) SAR650984, a humanized IgG1 targeting CD38, 221 now under evaluation together with lenalidomide and dexamethasone 222 in patients with relapsed or refractory multiple myeloma ( NCT01749969 ); and (7) TF2, a bispecific molecule that binds carcinoembryonic antigen (CEA) while providing a platform for the highly targeted delivery of a second, radionuclide ( 68 Ga)-coupled peptide, 223 - 225 which is currently being tested as a diagnostic tool in subjects affected by HER2 - breast carcinoma ( NCT01730612 ) or medullary thyroid carcinoma ( NCT01730638 ) ( Table 4 ).

For obvious safety reasons, the largest fraction of clinical trials initiated during the last 13 mo to test tumor-targeting mAbs aims at determining whether FDA-approved molecules might exert therapeutic effects in off-label indications. Thus, bevacizumab is currently being tested as a diagnostic tool (in its 89 Zr-conjugated form) or as a therapeutic intervention, most frequently in combination with standard chemo(radio)therapeutic regimens, in patients with hematological malignancies ( NCT01859234 ; NCT01921790 ), various forms of sarcoma ( NCT01746238 ; NCT01871766 ; NCT01946529 ), glioma ( NCT01743950 ; NCT01891747 ), breast carcinoma ( NCT01722968 ; NCT01894451 ; NCT01898117 ; NCT01941407 ; NCT01959490 ), melanoma (NCT01879306; NCT01950390 ), ovarian carcinoma ( NCT01735071 ; NCT01739218 ; NCT01770301 ; NCT01802749 ; NCT01837251 ; NCT01838538 ; NCT01847677 ), neoplasms of the reproductive tract ( NCT01770171 ; NCT01821859 ; NCT01936974 ), and other (advanced or metastatic) solid tumors ( NCT01749384 ; NCT01767792 ; NCT01831089 ; NCT01847118 ; NCT01898130 ; NCT01951482 ; NCT01946529 ). Brentuximab vedotin, an anti-CD30 monomethyl auristatin E (MMAE) conjugate approved for the treatment of relapsed Hodgkin’s lymphoma and relapsed systemic anaplastic large cell lymphoma, 226 , 227 is being investigated, either as a single therapeutic agent or combined with (often cyclophosphamide-based) chemotherapy, in patients affected by acute myeloid leukemia ( NCT01830777 ), mast cell leukemia or systemic mastocytosis ( NCT01807598 ); DLBCL or other forms of lymphoma ( NCT01777152 ; NCT01805037 ; NCT01841021 ; NCT01925612 ), and CD30 + germ cell tumors ( NCT01851200 ). The clinical profile of cetuximab, invariably in combination with chemotherapy or multimodal therapy, is being evaluated in subjects bearing esophageal or gastric carcinoma ( NCT01787006 ; NCT01904435), brain neoplasms ( NCT01884740 ) or other advanced solid tumors ( NCT01727869 ; NCT01787500 ). Rituximab, given as a standalone therapeutic regimen or combined with brentuximab vedotin, dexamethasone or INCB040093 (an orally available inhibitor of the δ isoform of the 110 kDa catalytic subunit of class I phosphoinositide-3-kinases) 228 , 229 is under investigation for its therapeutic potential in cohorts of individuals with various B-cell malignancies ( NCT01905813 ), Hodgkin’s lymphoma ( NCT01900496 ), neuroblastoma-associated opsoclonus myoclonus syndrome (a rare neurological disorder of unclear origin) 230 ( NCT01868269 ), and prostate carcinoma ( NCT01804712 ). The clinical profile of trastuzumab, in combination with either conventional chemotherapy or lapatinib (a tyrosine kinase inhibitor currently approved in HER2 + breast carcinoma patients), 231 is being assessed in patients bearing bladder neoplasms ( NCT01828736 ) or other solid tumors ( NCT01771458 ). Pertuzumab is being tested in combination with trastuzumab as a first-line therapeutic intervention in patients with gastric or gastresophageal carcinoma ( NCT01774786 ). Catumaxomab is now being evaluated as a standalone therapeutic agent in patients with gastric peritoneal carcinomatosis ( NCT01784900 ) or ovarian carcinoma ( NCT01815528 ). Denosumab plus standard chemotherapy is under investigation as a first-line intervention against metastatic NSCLC ( NCT01951586 ). Ofatumumab, a human IgG1 targeting CD20 that is approved by FDA for the treatment of CLL, 232 , 233 is currently being tested, in combination with cyclophosphamide-based chemotherapy or human recombinant IL-18, 234 in patients with other forms of leukemia ( NCT01762202 ) or NHL ( NCT01768338 ). Alemtuzumab, a CD52-specific humanized IgG1 that is licensed for use in CLL patients, 235 , 236 is being evaluated as a consolidation regimen upon cyclophosphamide-based chemotherapy in patients with peripheral T-cell lymphoma ( NCT01806337 ) or in combination with donor lymphocyte infusions in subjects with multiple hematological malignancies ( NCT01875237 ). Finally, panitumumab, an EGFR-specific humanized IgG2 currently licensed for use in CRC patients, 237 , 238 is under investigation as a therapeutic measure against anal cancer ( NCT01843452 ) and bladder carcinoma ( NCT01916109 ) ( Table 4 ).

As for the clinical trials listed in our previous Trial Watches dealing with this topic, 5 , 6 the following studies have changed status: NCT00560794 , NCT00848926 , NCT00866047 , and NCT00986674 , now listed as “Active, not recruiting”; NCT00563680 , NCT00947856 , NCT00778167 , and NCT00838201 , now listed as “Completed”; NCT01614795 , now listed as “Temporarily closed to accrual”; NCT00385827 , NCT01335204 , and NCT01513317 , now listed as “Terminated”; and NCT01034787 , whose status is now “Unknown.” NCT01513317 , comparing siltuximab (a chimeric mAb that neutralizes IL-6, also known as CNTO 328) 239 , 240 plus best supportive care to placebo plus best supportive care in anemic patients with low/intermediate-risk myelodysplastic syndrome, has been stopped after the interim analysis, based on lack of efficacy (although there were no safety concerns). Conversely, the reasons underlying the suspension of NCT01614795 and the termination of both NCT00385827 and NCT01335204 are not available. Among “Active, not recruiting” and “Completed” studies, (preliminary or definitive) results appear to be available for NCT00560794 ; 241 NCT00778167 ; NCT00838201 ; NCT00848926 ; NCT00866047 ; NCT00947856 ; 242 and NCT00986674 (source http://www.clinicaltrials.gov ).

Concluding Remarks

The interest of clinicians in harnessing the specificity of mAbs for cancer therapy remains very high, as demonstrated by the consistent number of clinical trials that have been initiated during the last 13 mo to test this immunotherapeutic paradigm in oncological settings. As discussed here, a large fraction of these studies involves tumor-targeting mAbs, i.e., mAbs that primarily bind to malignant cells or interrupt the trophic support provided to developing tumors by the stroma. Such an intense wave of clinical development is paralleled by the relatively frequent approval by FDA of (1) novel tumor-targeting mAbs, or (2) novel oncological indications for previously licensed molecules. As some (but not all) tumor-targeting mAbs exert antineoplastic effects by engaging immune effector functions, it will be interesting to see whether and in which circumstances the clinical benefits of mAbs can be improved by combining these immunotherapeutic agents with broad or targeted immunostimulatory interventions, including selected cytokines, 111 , 112 Toll-like receptor agonists, 243 - 245 immunogenic chemotherapy; 246 - 248 and irradiation. 110

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Authors are suppported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; AXA Chair for Longevity Research; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).

Previously published online: www.landesbioscience.com/journals/oncoimmunology/article/27048

Abbreviations:

antibody-dependent cell-mediated cytotoxicity

antibody-dependent cellular phagocytosis

complement-dependent cytotoxicity

chronic lymphocytic leukemia

colorectal carcinoma

diffuse large B-cell lymphoma

epidermal growth factor receptor

European Medicines Agency

epithelial cell adhesion molecule

Food and Drug Administration

head and neck squamous cell carcinoma

insulin-like growth factor 1 receptor

interleukin

monoclonal antibody

monomethyl auristatin E

non-Hodgkin’s lymphoma

non-small cell lung carcinoma

tumor-associated antigen

tumor necrosis factor α

vascular endothelial growth factor

Citation: Vacchelli E, Aranda F, Eggermont A, Galon J, Sautès-Fridman C, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy. OncoImmunology 2014; 3:e27048; 10.4161/onci.27048

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