Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy

Erika Vacchelli; Fernando Aranda; Alexander Eggermont; Jérôme Galon; Catherine Sautès-Fridman; Laurence Zitvogel; Guido Kroemer; Lorenzo Galluzzi

doi:10.4161/onci.27048

. 2014 Jan 1;3:e27048. doi: 10.4161/onci.27048

Trial Watch

Tumor-targeting monoclonal antibodies in cancer therapy

Erika Vacchelli ^1,^2,^3,^4,^†, Fernando Aranda ^1,^2,^3,^†, Alexander Eggermont ¹, Jérôme Galon ^5,^6,^7,⁸, Catherine Sautès-Fridman ^6,^7,⁹, Laurence Zitvogel ^1,¹⁰, Guido Kroemer ^11,^12,^2,^3,^5,^‡,^*, Lorenzo Galluzzi ^1,^5,^3,^‡,^*

PMCID: PMC3937194 PMID: 24605265

Abstract

In 1997, for the first time in history, a monoclonal antibody (mAb), i.e., the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug Administration for use in cancer patients. Since then, the panel of mAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has not stopped to expand, nowadays encompassing a stunning amount of 15 distinct molecules. This therapeutic armamentarium includes mAbs that target tumor-associated antigens, as well as molecules that interfere with tumor-stroma interactions or exert direct immunostimulatory effects. These three classes of mAbs exert antineoplastic activity via distinct mechanisms, which may or may not involve immune effectors other than the mAbs themselves. In previous issues of OncoImmunology, we provided a brief scientific background to the use of mAbs, all types confounded, in cancer therapy, and discussed the results of recent clinical trials investigating the safety and efficacy of this approach. Here, we focus on mAbs that primarily target malignant cells or their interactions with stromal components, as opposed to mAbs that mediate antineoplastic effects by activating the immune system. In particular, we discuss relevant clinical findings that have been published during the last 13 months as well as clinical trials that have been launched in the same period to investigate the therapeutic profile of hitherto investigational tumor-targeting mAbs.

Keywords: bevacizumab, brentuximab vedotin, cetuximab, nimotuzumab, trastuzumab, tumor-associated antigen

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 therapy¹¹^-¹⁶ will be discussed in the next Trial Watch.

Table 1. Tumor-targeting mAbs currently approved for cancer therapy.*^,**.

mAb	Target	Approved	Type	Indication(s)
Alemtuzumab	CD52	2001	Hzed IgG1	Chronic lymphocytic leukemia
Bevacizumab	VEGF	2004	Hzed IgG1	Glioblastoma multiforme, colorectal, renal and lung cancer
Brentuximab vedotin	CD30	2011	C IgG1	Hodgkin's and anaplastic large cell lymphoma (coupled to MMAE)
Catumaxomab	CD3 EPCAM	2009	M-R hybrid	Malignant ascites in patients with EPCAM⁺ cancer
Cetuximab	EGFR	2004	C IgG1	HNC and colorectal carcinoma
Denosumab	RANKL	2011	H IgG2	Breast cancer, prostate carcinoma and giant cell tumors of the bone
Gemtuzumab ozogamicin	CD33	2000	Hzed IgG4	Acute myeloid leukemia (coupled with calicheamicin)
Ibritumomab tiuxetan	CD20	2002	M IgG1	Non-Hodgkin lymphoma (coupled with ⁹⁰Y or ¹¹¹In)
Panitumumab	EGFR	2006	H IgG2	Colorectal carcinoma
Pertuzumab	HER2	2012	Hzed IgG1	Breast carcinoma
Ofatumumab	CD20	2009	H IgG1	Chronic lymphocytic leukemia
Rituximab	CD20	1997	C IgG1	Chronic lymphocytic leukemia and non-Hodgkin lymphoma
Tositumomab	CD20	2003	H IgG1	Non-Hodgkin lymphoma (naked or coupled with ¹³¹I)
Trastuzumab (emtansine)	HER2	1998	Hzed IgG1	Breast carcinoma (naked or coupled to mertansine) and gastric or gastresophageal junction cancer

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Abbreviations: C, chimeric; EGFR, epidermal growth factor receptor; EPCAM, epithelial cell adhesion molecule; H, human; HNC, head and neck cancer; Hzed, humanized; M, murine; mAb, monoclonal antibody; MMAE, monomethyl auristatin E; R, rat; RANKL, receptor activator of NF-κB ligand; VEGF, vascular endothelial growth factor. *by the US Food and Drug Administration or European Medicines Agency at the day of submission. **updated from ref.12

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 ⁹⁰Y-ibritumomab tiuxetan and ¹³¹I-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.

Table 2. Recently published clinical trials assessing the therapeutic profile of hitherto investigational tumor-targeting mAbs.^*,**.

mAb	Target(s)	Indication(s)	Phase	Note	Ref.
1D09C3	HLA-DR	CLL Lymphoma	I	As single agent	94
AGS-1C4D4	PSCA	Pancreatic cancer	II	Combined with gemcitabine	95
AVE1642	IGF1R	Solid tumors	I	Combined with docetaxel	60
AVE1642	IGF1R	Solid tumors	I	Combined with docetaxel, gemcitabine, erlotinib or doxorubicin	59
Blinatumomab (MEDI-538)	CD3 CD19	Acute lymphoblastic leukemia	II	As single agent or followed by HSCT	96
Carlumab (CNTO 888)	CCL2	Prostate cancer	II	As single agent	88
Carlumab (CNTO 888)	CCL2	Solid tumors	I	As single agent	86
Cixutumumab (IMC-A12)	IGF1R	Bone or soft-tissue sarcomas	II	Combined with temsirolimus	56
Cixutumumab (IMC-A12)	IGF1R	Renal cell carcinoma	I	Combined with temsirolimus	249
Clivatuzumab tetraxetan	MUC1	Pancreatic cancer	I	Coupled with ⁹⁰Y and combined with low-dose gemcitabine	117
Conatumumab (AMG 655)	TRAILR2	Colorectal carcinoma	II	Combined with bevacizumab plus folinic acid-, 5-FU- and oxaliplatin-based chemotherapy	65
		Lung cancer	II	Combined with paclitaxel plus carboplatin	64
		Pancreatic cancer	II	Combined with ganitumab and gemcitabine	57
Drozitumab (PRO95780)	TRAILR2	Colorectal carcinoma	Ib	Combined with bevacizumab plus folinic acid-, 5-FU- and oxaliplatin-based chemotherapy	67
Farletuzumab (MORAb-003)	FOLR1	Ovarian carcinoma	II	As single agent or combined with platinum- or taxane-based chemotherapy	97
GC33 (RO5137382)	GPC3	Hepatocellular carcinoma	I	As single agent	98
Ganitumab (AMG 479)	IGF1R	Breast carcinoma	II	As single agent	58
Ganitumab (AMG 479)	IGF1R	Pancreatic cancer	II	Combined with conatumumab and gemcitabine	57
Inotuzumab ozogamicin (CMC-544)	CD22	Non-Hodgkin’s lymphoma	I/II	Combined with rituximab	99
Intetumumab (CNTO 95)	ITGA5	Prostate cancer	II	Combined with docetaxel and prednisone	100
KRN330	GPA33	Colorectal cancer	I	As single agent	101
L19	FN1	Solid tumors	I/II	As a shuttle to deliver TNFα to the tumor vasculature	120
Lexatumumab (HGS-ETR2)	TRAILR2	Solid tumors	I	As single agent	66
Lintuzumab (SGN-33)	CD33	Acute myeloid leukemia	IIb	Combined with low-dose cytarabine	108
MIK-β1 (MA1–35896)	IL2RB	T-LGL leukemia	I	As single agent	93
Nimotuzumab (h-R3)	EGFR	NSCLC	I	Combined with gefitinib	102
Obinutuzumab (GA101)	CD20	Non-Hodgkin’s lymphoma	I	As single agent	103
Rilotumumab (AMG 102)	HGF	Prostate cancer	II	Combined with mitoxantrone plus prednisone	91
Ramucirumab (IMC-1121B)	VEGFR2	Hepatocellular carcinoma	II	As single agent	77
		Gastresophageal adenocarcinoma	III	As single agent	76
		Lung cancer	III	Combined with docetaxel	78
Trebananib (AMG 386)	ANGPT1 ANGPT2	Solid tumors	I	As single agent	87
Volociximab (M200)	ITGA5 ITGB1	NSCLC	Ib	Combined with carboplatin and paclitax	107

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Abbreviations: 5-FU, 5-fluorouracil; ANGPT, angiopoietin; CCL2, chemokine (C-C motif) ligand 2; CLL; chronic lymphocytic leukemia; EGFR, epidermal growth factor receptor; FN1, fibronectin 1; FOLR1, folate receptor 1 (adult); GPA33, glycoprotein A33; GPC3, glypican 3; HGF, hepatocyte growth factor; HSCT, hematopoietic stem cell transplantation; IGF1R, insulin-like growth factor 1 receptor; IL2RB, IL-2 receptor β; ITGA5, integrin α5; ITGB1, integrin β1; mAb, monoclonal antibody; MUC1, mucin 1; NSCLC, non-small cell lung carcinoma; PSCA, prostate stem cell antigen; T-LGL, T-cell large granular lymphocytic; TRAILR2, TNFα-related apoptosis-inducing ligand receptor 2; VEGFR2, vascular endothelial growth factor receptor 2. *between 2012, October 1st and the day of submission. **refers to mAbs that directly bind cancer cells or block trophic signals provided by the tumor stroma.

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, ⁹⁰Y-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 ⁹⁰Y-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, ⁸⁹Zr-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.

Table 3. Recently published clinical trials assessing the therapeutic profile of FDA-approved tumor-targeting mAbs employed as off-label anticancer interventions.^*,**.

mAb	Target(s)	Indication(s)	Phase	Note	Ref.
Bevacizumab	VEGF	Angiosarcoma and epithelioid hemangioendotheliomas	II	As a single agent	154
		Breast carcinoma	n.a.	Coupled to ⁸⁹Zr as a diagnostic tool	155
			II	Combined with docetaxel plus capecitabine	126
			II	Combined with docetaxel plus cisplatin	128
			II	Combined with gemcitabine	129
			II	Combined with trastuzumab plus docetaxel	48
			III	Combined with docetaxel	125
			III	Combined with capecitabine or paclitaxel	130
			III	Combined with capecitabine or paclitaxel	127
			III	Combined with trastuzumab plus docetaxel	156
		Cervical cancer	II	Combined with topotecan plus cisplatin	147
		Colorectal carcinoma	II/III	Combined with folinic acid, 5-FU, oxaliplatin and irinotecan	145
		Endometrial carcinoma	II	Combined with temsirolimus	150
		Gastresophageal adenocarcinoma	II/III	Combined with epirubicin, cisplatin and capecitabine	152
		Hepatocellular carcinoma	n.a.	Combined with erlotinib	133
			I	Combined with rapamycin	132
			II	Combined with erlotinib	135
			II	Combined with erlotinib	134
			II	After transhepatic arterial chemoembolization	136
		HNSCC	II	Combined with cisplatin plus IRMT	123
		HNSCC	II	Combined with cetuximab	124
		Leukemia	II	Combined with cytarabine	121
		Melanoma	II	Combined with temozolomide or albumin-bound paclitaxel plus carboplatin	131
		Multiple myeloma	II	Combined with bortezomib	122
		Ovarian carcinoma	n.a.	As a single agent	139
			n.a.	Combined with gemcitabine plus oxaliplatin	140
			II	Combined with docetaxel within 12 months of platinum-based therapy	138
			II	Combined with PLD	143
			II	Combined with albumin-bound paclitaxel	142
			III	Combined with carboplatin plus paclitaxel	141
		Pancreatic cancer	II	Combined with gemcitabine plus 5-FU	137
		Prostate cancer	II	Combined with docetaxel	144
		Urothelial carcinoma	II	Combined with gemcitabine plus carboplatin	149
		Metastatic solid tumors	I	Combined with vincristine, irinotecan and temozolomide	146
			I	Combined with albumin-bound paclitaxel plus gemcitabine	148
			I	Combined with sorafenib plus low-dose cyclophosphamide	151
			I	Combined with temsirolimus plus liposomal doxorubicin	153
Cetuximab	EGFR	Bone or soft-tissue sarcomas	II	As a single agent	179
		Breast carcinoma	II	Combined with cisplatin	166
		Cervical cancer	I	Combined with cisplatin	177
		Esophageal cancer	I	As part of a chemoradiotherapeutic regimen	168
		Esophageal cancer	II/III	As part of a chemoradiotherapeutic regimen	167
		Gastric cancer	III	Combined with capecitabine plus cisplatin	169
		Lung cancer	I	Combined with bevacizumab plus erlotinib	170
		Lung cancer	II	Combined with bevacizumab, paclitaxel and carboplatin	171
		Pancreatic cancer	n.a.	Combined with gemcitabine plus IRMT	172
			II	Combined with gemcitabine plus oxaliplatin	173
			I/II	Combined with everolimus plus capecitabine	174
		Prostate cancer	II	Combined with docetaxel	176
		Urothelial carcinoma	II	Combined with paclitaxel	178
		Solid tumors	n.a.	As a single agent	175
		Solid tumors	I	As a carrier for doxorubicin-loaded immunoliposomes	180
Denosumab	RANKL	Lung cancer	III	As a single agent	181
Ofatumumab	CD20	Small lymphocytic lymphoma	I	As single agent	186
Panitumumab	EGFR	Gastresophagic cancer	III	Combined with epirubicin, oxaliplatin and capecitabine	185
		HNSCC	III	Combined with cisplatin plus 5-FU	182
		Ovarian carcinoma	II	Combined with PLD	183
Pertuzumab	HER2	NSCLC	Ib	Combined with erlotinib	104
Pertuzumab	HER2	Ovarian carcinoma	II	Combined with carboplatin	105
Rituximab	CD20	B-cell malignancies	I	Combined with rIL-21	184

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Abbreviations: 5-FU, 5-fluorouracil; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell carcinoma; IL, interleukin; IMRT, intensity-modulated radiation therapy; mAb, monoclonal antibody; n.a., not available; NSCLC, non-small cell lung carcinoma; PLD, pegylated liposomal doxorubicin; r, recombinant; RANKL, receptor activator of NF-κB ligand; VEGF, vascular endothelial growth factor. *between 2012, October 1st and the day of submission. **refers to mAbs that directly bind cancer cells or block trophic signals provided by the tumor stroma.

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 investigation¹⁹²^-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 ⁹⁰Y-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 peptidomimetic²¹⁷^,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 ²²⁵Ac 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 dexamethasone²²² 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 (⁶⁸Ga)-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).

Table 4. Clinical trials recently launched to evaluate the therapeutic profile of tumor-targeting monoclonal antibodies in investigational settings.^*,**.

mAb	Target(s)	Indication(s)	Phase	Status	Note	Ref.
Alemtuzumab	CD52	Hematological malignancies	I/II	Not yet recruiting	In combination with genetically modified T cells	NCT01875237
Alemtuzumab	CD52	Peripheral T-cell lymphoma	II	Completed	As a consolidation regimen upon cyclophosphamide-based chemotherapy	NCT01806337
BC8	CD45	Hematological malignancies	I/II	Not yet recruiting	Followed by BEAM chemotherapy and ASCT	NCT01921387
Bevacizumab	VEGF	Brain tumors	II	Recruiting	As single agent	NCT01767792
		Breast carcinoma	0	Not yet recruiting	As ⁸⁹Zr-bevacizumab radiotracer	NCT01894451
			II	Not yet recruiting	Combined with carboplatin, cyclophosphamide or paclitaxel	NCT01898117
			II	Not yet recruiting	Combined with eribulin	NCT01941407
			II	Not yet recruiting	Combined with cyclophosphamide, doxorubicin and paclitaxel	NCT01959490
			II	Recruiting	Combined with paclitaxel	NCT01722968
		Glioma	I/II	Recruiting	Combined with temozolomide and vitamin C	NCT01891747
		Glioma	II	Recruiting	Combined with radiation therapy	NCT01743950
		Lymphoma	II	Recruiting	Combined with gemcitabine-based chemotherapy	NCT01921790
		Melanoma	II	Not yet recruiting	Combined with paclitaxel-based chemotherapy	NCT01879306
		Melanoma	II	Not yet recruiting	Combined with ipilimumab	NCT01950390
		MM	n.a.	Recruiting	As ⁸⁹Zr-bevacizumab radiotracer	NCT01859234
		Ovarian cancer	II	Not yet recruiting	Combined with trabectedin ± carboplatin	NCT01735071
			II	Recruiting	Combined with carboplatin and paclitaxel	NCT01739218
			II	Recruiting	Combined with paclitaxel	NCT01770301
			II	Recruiting	Combined with carboplatin and paclitaxel	NCT01838538
			II	Recruiting	Combined with carboplatin and paclitaxel	NCT01847677
			III	Active not recruiting	Combined with carboplatin and PLD	NCT01837251
			III	Not yet recruiting	Combined with carboplatin and gemcitabine or paclitaxel or PLD	NCT01802749
		Reproductive tract cancers	II	Recruiting	Combined with carboplatin and paclitaxel	NCT01770171
			II	Recruiting	Combined with gemcitabine ± platinum based chemotherapy	NCT01936974
			II	Terminated with results	Followed by abraxane infusion	NCT01821859
		Rhabdomyosarcoma	II	Recruiting	Combined with cyclophosphamide-based chemotherapy	NCT01871766
		Sarcoma	I	Recruiting	Combined with doxorubicin and radiation therapy	NCT01746238
		Sarcoma and neuroectodermal tumors	II	Not yet recruiting	Combined with cyclophosphamide-based chemotherapy	NCT01946529
		Advanced or metastatic solid tumors	I	Not yet recruiting	Combined with lurbinectedin and paclitaxel	NCT01831089
			I	Recruiting	Combined with tivantinib	NCT01749384
			I	Recruiting	As single agent	NCT01847118
			II	Not yet recruiting	As single agent	NCT01898130
			II	Recruiting	Combined with cisplatin and pemetrexed	NCT01951482
Blinatumomab	CD3 CD19	DLBCL	II	Recruiting	As single agent	NCT01741792
Brentuximab vedotin	CD30	AML	I	Recruiting	Combined with immunogenic chemotherapy	NCT01830777
		DLBCL	II	Recruiting	Combined with cyclophosphamide-based chemotherapy	NCT01925612
		Germ cell tumors	II	Not yet recruiting	As single agent	NCT01851200
		Lymphoma	I/II	Recruiting	Combined with rituximab	NCT01805037
		Lymphoma	III	Recruiting	Combined with cyclophosphamide-based chemotherapy	NCT01777152
		Mast cell leukemia	n.a.	Not yet recruiting	As single agent	NCT01807598
		Peripheral T-cell lymphoma	n.a.	Not yet recruiting	As single agent	NCT01841021
Catumaxomab	CD3 EPCAM	Gastric peritoneal carcinomatosis	II	Recruiting	As single agent	NCT01784900
Catumaxomab	CD3 EPCAM	Ovarian cancer	II	Recruiting	As single agent	NCT01815528
Cetuximab	EGFR	Brain tumors	I/II	Recruiting	Combined with bevacizumab	NCT01884740
		Esophageal cancer Gastric cancer	II	Recruiting	Combined with cisplatin, 5-FU and radiotherapy	NCT01787006
		Esophageal cancer Gastric cancer	II	Completed	Combined with carboplatin, paclitaxel and radiotherapy	NCT01904435
		Advanced solid tumors	I	Recruiting	Combined with erlotinib	NCT01727869
		Advanced solid tumors	I	Recruiting	Combined with irinotecan and vemurafenib	NCT01787500
Ch14.18	GD2	Neuroblastoma	II	Recruiting	Combined with irinotecan and temozolomide	NCT01767194
Conatumumab	TRAILR2	Reproductive tract cancers	I	Not yet recruiting	Combined with birinapant	NCT01940172
Denosumab	RANKL	NSCLC	II	Not yet recruiting	As single agent	NCT01951586
Lintuzumab	CD33	Leukemia	I/II	Recruiting	Combined with cytarabine	NCT01756677
Necitumumab	EGFR	NSCLC	I/II	Recruiting	Combined with cisplatin and gemcitabine	NCT01763788
			II	Recruiting	Combined with carboplatin and paclitaxel	NCT01769391
			II	Recruiting	Combined with cisplatin and gemcitabine	NCT01788566
Nimotuzumab	EGFR	Breast carcinoma	II	Not yet recruiting	Combined with capecitabine and docetaxel	NCT01939054
		Cervical cancer	II	Recruiting	Combined with chemoradiotherapy	NCT01938105
		Gastric cancer	III	Recruiting	Combined with irinotecan	NCT01813253
		NSCLC	I/II	Not yet recruiting	Combined with afatinib	NCT01861223
		Rectal cancer	II	Recruiting	Combined with radiotherapy, capecitabine and oxaliplatin	NCT01899118
Ofatumumab	CD20	Leukemia	II	Not yet recruiting	Combined with cyclophosphamide and fludarabine	NCT01762202
Ofatumumab	CD20	NHL	I	Recruiting	Combined with rIL-18	NCT01768338
Panitumumab	EGFR	Anal cancer	II	Recruiting	Combined with capecitabine, mitomycin and radiotherapy	NCT01843452
Panitumumab	EGFR	Bladder cancer	II	Recruiting	Combined with carboplatin and gemcitabine	NCT01916109
Pertuzumab	HER2	Gastric cancer Gastresophageal cancer	III	Recruiting	Combined with capecitabine, cisplatin, 5-FU and trastuzumab	NCT01774786
Rituximab	CD20	B-cell malignancies	I	Recruiting	Combined with a PI3K inhibitor	NCT01905813
		Hodgkin's lymphoma	0	Not yet recruiting	Combined with brentuximab vedotin	NCT01900496
		Neuroblastoma	III	Recruiting	Combined with dexamethasone	NCT01868269
		Prostate cancer	0	Recruiting	As single agent	NCT01804712
SAR650984	CD38	MM	I	Recruiting	Combined with lenalidomide and dexamethasone	NCT01749969
TF2	CEA	Breast cancer	I/II	Recruiting	As single agent	NCT01730612
TF2	CEA	Medullary thyroid carcinoma	I/II	Recruiting	As single agent	NCT01730638
Trastuzumab	HER2	Bladder cancer	II	Active, not recruiting	Combined with carboplatin, cisplatin and gemcitabine	NCT01828736
Trastuzumab	HER2	Recurrent or metastatic tumors	II	Recruiting	Combined with lapatinib	NCT01771458

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Abbreviations: 5-FU, 5-fluorouracil; AML, acute myeloid leukemia; ASCT, autologous stem cell transplantation; BEAM, carmustine + etoposide + cytarabine + melphalan; CEA, carcinoembryonic antigen; DLBCL, diffuse large B-cell lymphoma; EGFR, epidermal growth factor receptor; EPCAM, epithelial cell adhesion molecule; IL, interleukin; mAb, monoclonal antibody; MM, multiple myeloma; n.a., not available; NHL, non-Hodgkin's lymphoma; NSCLC, non-small cell lung carcinoma; PI3K, phosphoinositide-3-kinase; PLD, pegylated liposomal doxorubicin; r, recombinant; RANKL, receptor activator of NF-κB ligand; TRAILR2, TNFα-related apoptosis-inducing ligand receptor 2; VEGF, vascular endothelial growth factor. *between 2012, October 1st and the day of submission. **refers to hitherto investigational tumor-targeting mAbs as well as to FDA-approved tumor-targeting mAbs employed as off-label interventions.

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 ⁸⁹Zr-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).

Glossary

Abbreviations:

ADCC: antibody-dependent cell-mediated cytotoxicity
ADCP: antibody-dependent cellular phagocytosis
CDC: complement-dependent cytotoxicity
CLL: chronic lymphocytic leukemia
CRC: colorectal carcinoma
DLBCL: diffuse large B-cell lymphoma
EGFR: epidermal growth factor receptor
EMA: European Medicines Agency
EPCAM: epithelial cell adhesion molecule
FDA: Food and Drug Administration
HNSCC: head and neck squamous cell carcinoma
IGF1R: insulin-like growth factor 1 receptor
IL: interleukin
mAb: monoclonal antibody
MMAE: monomethyl auristatin E
NHL: non-Hodgkin’s lymphoma
NSCLC: non-small cell lung carcinoma
TAA: tumor-associated antigen
TNFα: tumor necrosis factor α
VEGF: 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

Footnotes

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

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PERMALINK

Trial Watch

Erika Vacchelli

Fernando Aranda

Alexander Eggermont

Jérôme Galon

Catherine Sautès-Fridman

Laurence Zitvogel

Guido Kroemer

Lorenzo Galluzzi

Abstract

Introduction

Table 1. Tumor-targeting mAbs currently approved for cancer therapy.*^,**.

Update on Clinical Reports

Experimental mAbs

Table 2. Recently published clinical trials assessing the therapeutic profile of hitherto investigational tumor-targeting mAbs.^*,**.

FDA-approved mAbs tested as off-label interventions

Table 3. Recently published clinical trials assessing the therapeutic profile of FDA-approved tumor-targeting mAbs employed as off-label anticancer interventions.^*,**.

Additional studies

Update on Clinical Trials Testing Tumor-Targeting Monoclonal Antibodies

Table 4. Clinical trials recently launched to evaluate the therapeutic profile of tumor-targeting monoclonal antibodies in investigational settings.^*,**.

Concluding Remarks

Disclosure of Potential Conflicts of Interest

Acknowledgments

Glossary

Abbreviations:

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Trial Watch

Erika Vacchelli

Fernando Aranda

Alexander Eggermont

Jérôme Galon

Catherine Sautès-Fridman

Laurence Zitvogel

Guido Kroemer

Lorenzo Galluzzi

Abstract

Introduction

Table 1. Tumor-targeting mAbs currently approved for cancer therapy.*,**.

Update on Clinical Reports

Experimental mAbs

Table 2. Recently published clinical trials assessing the therapeutic profile of hitherto investigational tumor-targeting mAbs.*,**.

FDA-approved mAbs tested as off-label interventions

Table 3. Recently published clinical trials assessing the therapeutic profile of FDA-approved tumor-targeting mAbs employed as off-label anticancer interventions.*,**.

Additional studies

Update on Clinical Trials Testing Tumor-Targeting Monoclonal Antibodies

Table 4. Clinical trials recently launched to evaluate the therapeutic profile of tumor-targeting monoclonal antibodies in investigational settings.*,**.

Concluding Remarks

Disclosure of Potential Conflicts of Interest

Acknowledgments

Glossary

Abbreviations:

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table 1. Tumor-targeting mAbs currently approved for cancer therapy.*^,**.

Table 2. Recently published clinical trials assessing the therapeutic profile of hitherto investigational tumor-targeting mAbs.^*,**.

Table 3. Recently published clinical trials assessing the therapeutic profile of FDA-approved tumor-targeting mAbs employed as off-label anticancer interventions.^*,**.

Table 4. Clinical trials recently launched to evaluate the therapeutic profile of tumor-targeting monoclonal antibodies in investigational settings.^*,**.