Molecular targeted therapy (MTT) is a new approach to cancer treatment that resulted from the plethora of molecular and biologic discoveries into the etiology of cancer over the last quarter of a century. Several agents have been approved by the U.S. Food and Drug Administration (FDA) for clinical use and have replaced traditional chemotherapy in the treatment of some cancers. Many more are currently being tested in clinical trials, and their widespread integration into the mainstream for cancer treatment is expected to increase at an accelerated pace during the next decade.
Agents in this type of therapy are vastly different from the traditional chemotherapeutic agents that constitute the majority of therapy described throughout the chapters of this book. These drugs are designed with the intention to specifically target molecules that are uniquely or abnormally expressed within cancer cells while sparing normal cells. In this chapter, we discuss drugs that are already available for clinical use and provide a brief description of the mechanism of action of these agents, the pathways they target, and some of their clinical uses. This chapter also addresses promising agents currently in clinical trials that may be available soon in the clinic.
A. Characteristics of MTT
The ideal molecule for targeted therapy should have the following characteristics:
Uniquely expressed in cancer cells but not in normal cells.
Important for the maintenance of the malignant phenotype; therefore, once the targeted molecule has been effectively disabled, the cancer cell will not be able to develop resistance against the therapeutic agent by suppressing its function or expelling the targeted molecule from the cell.
The degree to which target molecules do not embody these characteristics coupled with nonspecificity of the therapeutic agent determines the limitations of the current targets and agents.
B. Classification and type of MTT
The classification of MTT is a moving target. In this chapter, we classify MTT based on the targeting strategy of each molecule. There are two targeting strategies for MTT.
1. Function-directed therapy
This therapeutic strategy is intended to restore the normal function or abrogate the abnormal function of the defective molecule or a pathway in the tumor cell. This is accomplished by the following:
Reconstituting the normal molecule
Inhibiting the production of a defective molecule
Aborting, altering, or reversing a newly acquired function by targeting the defective molecule, its function, and its downstream effect
Agents under this category are classified based on the mechanism of action and subclassified based on the known affected targeted pathway.
2. Phenotype-directed therapy
This is a therapeutic strategy that is intended to target the unique phenotype of the cancer cell where killing the cell is more dependent on nonspecific mechanisms rather than targeting a specific pathway. Accordingly, agents under this category are classified based on the type of therapy and subclassified based on the targeted pathway or molecule.
Table 2.1 summarizes the classification and FDA-approved indications of molecular-targeted agents.
II. FUNCTION-DIRECTED THERAPY
Agents under this category target specific cellular pathways (e.g., signal transduction pathways, angiogenesis, protein degradation, etc.).
A. Cell signaling-targeted therapy
Signal transduction pathways are crucial for delivering messages from the extracellular environment into the nucleus and enabling the cell to carry on cellular processes including survival, proliferation, and differentiation. These signals are initiated from the cell surface by the interaction of molecules (ligands) such as hormones, cytokines, and growth factors with cell receptors. Cell receptors, in turn, transfer the signal through a network of molecules to the nucleus, which leads to the transcription of new molecules responsible for engineering the desired outcome.
In cancer cells, these pathways are found to be altered through the mutation of some of their components. This leads to the functional dysregulation of the affected pathways resulting in uncontrolled proliferation and inhibition of apoptosis. Accordingly, targeting the components of these pathways is a prime goal for the development of MTT. The components of these pathways include the following:
The ligand
The receptors for these ligands, the majority of which are receptor kinases
The cascade of proteins that form these pathways, the majority of which are protein kinases
TABLE 2.1 Classification and FDA-Approved Indications of Molecular-Targeted Agents
Agent
Target
Cancer Type
Patient Population
Blocking of the Ligand-Receptor Binding
Cetuximab
EGFR1
KRAS-WT metastatic colon
First line + FOLFIRI+ Irinotecan if failed or intolerant to irinotecanbased chemotherapy Single agent if failed both irinotecan- and oxaliplatinbased chemotherapy
Locally advanced, recurrent or metastatic SCCHN
First line + XRT or + platinum and 5-FU Second line after progression on platinum
Panitumumab
EGFR1
KRAS-WT metastatic colon
Single agent after 5-FU, oxaliplatin, and irinotecan chemotherapy failure
Trastuzumab
HER2
Adjuvant HER2+ breast
First line + doxorubicin, cyclophosphamide, and paclitaxel
Metastatic HER2+ breast
First line + paclitaxel Single agent after one prior chemotherapy
HER2+ metastatic gastric or GEJ
First line + cisplatin and either capecitabine or 5-FU
Pertuzumab
HER2
HER2+ metastatic breast
First line + trastuzumab and docetaxel
Bevacizumab
VEGF
Metastatic colon
First or second line + FOLFOX or FOLFIRI
Locally advanced, recurrent, or metastatic nonsquamous NSCLC
First line + carboplatin and paclitaxel
Metastatic RCC
+ IFN-α
Glioblastoma
Second line after chemoradiation
Persistent, recurrent or metastatic cervical
+ Paclitaxel and cisplatin or topotecan
Ovarian, fallopian, or primary peritoneal
+ Paclitaxel, doxorubicin, or topotecan after platinum failure
Ramucirumab
VEGFR2
Advanced gastric or GEJ
Single agent or + paclitaxel after platinum- or 5-FU-based regimen failure
Metastatic colorectal
After 5-FU-, oxaliplatin-, and bevacizumab-based regimen failure
Locally advanced or metastatic NSCLC
+ Docetaxel after platinum-based chemotherapy failure
Axitinib
VEGFR, PDGFR, c-KIT
Metastatic RCC
Second line after at least one prior therapy
Ziv-aflibercept
VEGFR
Metastatic colorectal
+ FOLFIRI after oxaliplatinbased chemotherapy failure
Lenvatinib
VEGFR1-3 PDGFR, c-KIT, RET, FGF
Recurrent or metastatic thyroid
Second line after radioactive iodine failure
Inhibition of Receptor Tyrosine Kinases
Erlotinib
EGFR
Locally advanced or metastatic NSCLC with exon 19 deletion or exon 21 mutation (L858R)
First line as a single agent Second line after
progression on a platinum doublet
Maintenance following first-line platinum-based
Locally advanced or metastatic pancreatic
First line + gemcitabine
Gefitinib
EGFR
Locally advanced or metastatic NSCLC
Patients who showed prior benefit
Afatinib
EGFR
Metastatic NSCLC with exon 19 deletion or exon 21 mutation (L858R)
First line as a single agent
Sunitinib
VEGFR, PDGFR, c-KIT
Advanced RCC
First line as a single agent
GIST
Second line after imatinib failure
Unresectable or metastatic PNET
First line as a single agent
Lapatinib
HER2
HER2+ metastatic breast
Second line + capecitabine in patients who failed trastuzumab
ER+/PR+ metastatic breast
First line + letrozole
Pazopanib
VEGFR, PDGFR, c-KIT
Advanced RCC
First line as a single agent
Advanced softtissue sarcoma
First line if unfit for chemotherapy Second line after chemotherapy failure
Vandetanib
EGFR, VEGFR2, RET
Unresectable, metastatic medullary thyroid
First line as a single agent
Cabozantinib
RET, MET, VEGFR1-3
Metastatic medullary thyroid
After progression on prior treatment
Ibrutinib
BTK
MCL
In previously treated patients
Relapsed or refractory CLL
In previously treated patients
Crizotinib
ALK, c-MET, ROS1
ALK+ locally advanced or metastatic NSCLC
First line as a single agent
Ceritinib
ALK
ALK+ locally advanced or metastatic NSCLC
Second line after crizotinib failure
Imatinib
BCR-ABL, PDGF, c-KIT
Chronic-, accelerated-, or blast-phase Ph+ CML
First line as a single agent Second line after IFN-α failure
After stem cell transplant (in pediatrics)
Relapse or refractory Ph+ ALL
First line in pediatrics Second line in adults
PDGFR+ MDS
First line
ASM without D816V c-KIT mutated or status unknown
First line
HES/CEL
First line
Unresectable, recurrent, or metastatic DFSP
First line
Unresectable or metastatic c-KIT+ GIST, and postresection
First line
Dasatinib
BCR-ABL, c-KIT, PDGFR
Ph+ CML
Chronic phase as first line Chronic, accelerated, and blast phases after imatinib failure
Ph+ ALL
Second line
Nilotinib
BCR-ABL
Ph+ CML
Chronic phase as first line Chronic, accelerated, and blast phases after imatinib failure
Ponatinib
BCR-ABL
Ph+ CML
Chronic, accelerated, and blast phases after prior TKI failure Ph+ ALL Second line
Bosutinib
BCR-ABL
Ph+ CML
Chronic, accelerated, and blast phases after prior TKI failure
Ruxolitinib
JAK2
Intermediate or high-risk myelofibrosis
First line
Polycythemia vera
Second line after hydroxyurea failure
Sorafenib
Raf/MEK/ERK, VEGFR2, PDGF
Advanced RCC
First line
Unresectable HCC
First line
Recurrent or metastatic, progressive, differentiated thyroid cancer
Second line after iodine-131 (I131) failure
Trametinib
MEK1,2
BRAFV600E– or BRAFV600K-mutated unresectable or metastatic melanoma
First line with dabrafenib Second line as a single agent after prior BRAF inhibitor
Dabrafenib
MEK1,2
BRAFV600E– or BRAFV600K-mutated unresectable or metastatic melanoma
First line as a single agent or in combination with trametinib
Vemurafenib
MEK1
BRAFV600E-mutated unresectable or metastatic melanoma
First line
Regorafenib
VEGFR1-3
KRAS-WT metastatic colorectal
Fourth line after 5-FU-, oxaliplatin-, and irinotecan-based chemotherapy
Advanced GIST
Refractory or intolerant to imatinib
Everolimus
mTOR
Advanced RCC
Failed sunitinib or sorafenib
ER+/PR+ metastatic breast
+ Exemestane after letrozole or anastrozole failure
Locally advanced or metastatic PNET
First line
SEGA associated with TS
First line if unresectable
Temsirolimus
mTOR
Advanced RCC
First line for high-risk patients
Idelalisib
PI3K
Relapsed CLL
+ Rituximab
Relapsed FL
Third line
Relapsed SLL
Third line
Vismodegib
Hedgehog
Metastatic basal cell carcinoma
First line
Olaparib
PARP
BRCA-mutated advanced ovarian cancer
Fourth line after chemotherapy
Panobinostat
HDAC
MM
+ Bortezomib and dexamethasone after two prior regimens
Vorinostat
HDAC
CTCL
After at least two prior therapies
Romidepsin
HDAC
CTCL
Second line
Protein Degradation-Targeted Therapy
Bortezomib
26S proteasome
MM
First line and beyond in combination with MP
MCL
Second line and beyond as a single agent
Carfilzomib
26S proteasome
MM
Third line after bortezomib and an immunomodulator
Immune Modulation-Targeted Therapy
Lenalidomide
Nonspecific immunomodulator
MM
Second line in combination with dexamethasone
Transfusiondependent MDS, 5q deletion
First line
MCL
Third line after two prior therapies including bortezomib
Pomalidomide
Nonspecific immunomodulator
MM
Third line after lenalidomide and bortezomib
Phenotype-Targeted Therapy
Rituximab
CD20
CD20+ FL
First line + CVP Second line post-CVP
CD20+ DLBCL
First line + CHOP or other anthracycline-based chemotherapy Maintenance in patient who achieved response to rituximab
CD20+ CLL
First line + fludarabine and cyclophosphamide
Alemtuzumab
CD52
CLL
First line or beyond
Ofatumumab
CD20
CLL
First line + chlorambucil Third line after fludarabine and alemtuzumab failure
Blinatumomab
CD19, CD3
Ph- ALL
Second line and beyond
Gemtuzumab
CD33+ calicheamicin
CD33+ AML
After first relapse in 60 years or older not candidate for chemotherapy
Adotrastuzumab emtansine
HER2+ DM1
HER2+ metastatic breast
After trastuzumab and a taxane failure
Brentuximab
CD30+ MMAE
HL
Relapse after ASCT
ALCL
After multiagent chemotherapy failure
Ibritumomab
CD20+90Y
CD20+ FL or transformed B-cell NHL
Relapsed or refractory after chemotherapy and rituximab
Tositumomab
CD20+131I
CD20+ low-grade or transformed low-grade NHL
Relapsed or refractory to chemotherapy and rituximab
Accordingly, strategies targeting signal transduction pathways include the following:
Blocking the ligand-receptor interaction. This leads to the prevention of the initiation of the signal and can be accomplished by either blocking circulating ligands or blocking ligand binding to the extracellular domain of the receptor.
Inhibition of receptor kinases. This leads to the prevention of phosphorylation of the intracellular kinase domain of the receptor, resulting in the abortion of protein cascade in the cell signaling pathways.
Inhibition of intracellular signaling proteins.
1. Blocking of the ligand-receptor binding
Blocking receptors and ligand-receptor interaction is currently achieved by utilizing specific monoclonal antibodies (MoAbs) directed against the ligand or the receptor. MoAbs are biologic agents designed with the intention to specifically target soluble proteins or membrane proteins with an extracellular domain. The MoAbs can exert their antitumor effect through multiple potential mechanisms including blocking the targeted receptor or ligand and preventing its function in transmitting signals to the nucleus, activating antibody-dependent cellular cytotoxicity, or helping to internalize the receptor and hence deliver toxic agents into the cells. The MoAb technology has considerably improved in the last decade by humanizing these agents partially in chimeric or fully humanized constructs. Substituting the murine Fc portion of the MoAb with a human equivalent leads to a significant decrease in the generation of a human anti-mouse antibody (HAMA) immune reaction. Although generation of human anti-chimeric antibodies (HACAs) may still occur for those MoAbs, it does not occur with fully humanized MoAbs. This technology to humanize MoAbs has made these molecules more usable in the treatment of cancer, particularly when repetitive dosing is required.
2. Epidermal growth factor receptor family
Epidermal growth factor receptors (EGFRs) are a small family of proteins belonging to the larger receptor tyrosine kinase (RTK) family. The EGFR family includes at least four described receptors: EGFR1, HER-2-neu (erbB2), HER3 (erbB3), and HER4 (erbB4). These receptors are glycoproteins consisting of three domains: an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with a tyrosine kinase activity. Binding of the ligands to the receptor leads to the activation of the intracellular tyrosine kinase and the phosphorylation of the receptor, which, in turn, leads to activation of the downstream signal transduction pathway. The activation of this pathway promotes cell activation, proliferation, and enhanced survival. Agents have been developed against the receptors EGFR1 and HER-2-neu.
3. EGFR1-targeted therapy
EGFR1 was the first member of the EGFR family to be identified. It is activated by binding to epidermal growth factor (EGF) and to transforming growth factor-α (TGF-α). EGFR1 is found to be overexpressed in many cancers, including 50% to 70% of colon, lung, and breast cancers. Several antibodies targeting EGFR have been approved by the FDA.
a. Cetuximab (Erbitux) is a humanized immunoglobulin-G1 (IgG1) chimeric MoAb that binds to the external ligand-binding domain of EGFR1. It also binds with much lower affinity to EGF and TGF-α. The combination of cetuximab and irinotecan was found to improve disease response rate (RR) and progression-free survival (PFS) over the use of cetuximab alone in patients with metastatic colorectal carcinoma (CRC) who have previously failed irinotecan therapy. Recent studies have shown an improved PFS by 1.4 months and median overall survival (OS) by 4 months in patients with KRAS wildtype (WT) metastatic CRC with the addition of cetuximab to either FOLFIRI (folinic acid, fluorouracil [5-FU], and irinotecan) or FOLFOX (folinic acid, 5-FU, and oxaliplatin). An increased RR was also observed in this patient population (46% vs. 38% in all patients, 57% vs. 39% in patients with KRAS-WT). Additionally, cetuximab has been studied in patients with metastatic CRC previously treated with irinotecan, with an improved OS of 1.5 months in all patients and 3.6 months in patients with KRAS-WT. These studies have led to its approval in the first-line setting for patients with KRAS-WT metastatic CRC in combination with FOLFIRI, patients who failed both irinotecan- and oxaliplatin-based chemotherapy regimens as a single agent, and patients who are refractory or intolerant to irinotecan-based chemotherapy in combination with irinotecan. Recently, the combination of cetuximab and FOLFIRI in patients with untreated KRAS-WT metastatic CRC was compared to FOLFIRI plus bevacizumab and showed an improved rate of carcinoembryonic antigen (CEA) decline, which correlated with an improved OS, favoring the cetuximab arm. Cetuximab is also approved for the treatment of squamous cell carcinoma of head and neck (SCCHN). It has been shown to improve local-regional control by 9.5 months and OS by 19.7 months in patients with stage III or IV previously untreated SCCHN when combined with radiation therapy (RT) compared to RT alone. It was also shown to improve RR (35.6% vs. 19.5%), PFS by 2.2 months, and OS by 2.7 months in patients with stage III or IV SCCHN when combined with 5-FU and either carboplatin or cisplatin. Additionally, cetuximab alone showed a RR of 13% with duration of response of 5.8 months in patients with recurrent or metastatic SCCHN who progressed within 30 days of a platinum agent. These studies have led to its approval as a first line in combination with either radiation or platinum-based therapy and 5-FU in patients with recurrent, locally advanced, or metastatic SCCHN and as a second line in SCCHN patients who progressed on a platinum agent. Common adverse effects include rash and diarrhea. Although very uncommon, cardiac arrest and myocardial infarction (MI) were reported among the serious side effects.
b. Panitumumab (Vectibix) is a fully humanized MoAb that binds to EGFR1 with higher affinity than cetuximab. A randomized phase III study demonstrated that patients with refractory EGFR-expressing metastatic CRC treated with panitumumab plus best supportive care (BSC) had a better PFS compared to patients who received BSC alone. The patients who benefited from the treatment were those with tumors that did not express KRAS mutations. Therefore, panitumumab was approved by the FDA as a monotherapy for chemotherapy-refractory KRAS-WT metastatic CRC. It was also shown to improve PFS by 1.6 months and OS by 4.4 months in combination with FOLFOX in patients with untreated KRAS-WT metastatic CRC compared to FOLFOX alone. Importantly, it was found to be noninferior to cetuximab in patients with metastatic CRC previously treated with FOLFOX or FOLFIRI. It was also studied in patients with metastatic SCCHN in combination with cisplatin and 5-FU compared to chemotherapy alone and had a nonsignificant trend toward improved OS and modest, but significant, improvement in PFS of 1.2 months. Other diseases with promising results using panitumumab include non-small-cell lung cancer (NSCLC) and renal cancer. Common adverse effects include rash, peripheral edema, fatigue, and diarrhea. Serious toxicity, including bronchospasm, has been reported only rarely.
4. HER-2-neu (HER2, erbB2)-targeted therapy
HER2 is the second member of the EGFR family. This receptor has the same basic structure as the other family members; however, no conjugate ligand has been identified for HER2. There have been no mutations identified in the HER2 gene in human cancers, yet it is overexpressed in many epithelial cancers, including colon, pancreas, genitourinary, and breast cancers. HER2 signals through the phosphoinositide-3 kinase (PI3K)/Akt and mitogen-activated protein (MAP) kinase pathways, and HER2 overexpression leads to inhibition of apoptosis and increase in cell proliferation.
a. Trastuzumab (Herceptin) was one of the first MTTs to be introduced in the clinic. It is a humanized (chimeric) MoAb that binds to HER2. Although the mechanism of action of trastuzumab is not entirely clear, it is believed to act through one or more of the following mechanisms: inhibiting the tyrosine kinase signaling of the receptor, activating antibody-dependent cellular cytotoxicity, inducing apoptosis, inducing G1 arrest by modulating the cyclin-dependent kinases, inhibiting angiogenesis, and enhancing chemotherapy-induced cytotoxicity. The FDA approved trastuzumab in 1998 for use in patients with metastatic breast cancer overexpressing HER2 protein. In a large, multicenter phase III study in patients with metastatic breast cancer overexpressing HER2, it was demonstrated that trastuzumab, when used as a firstline therapy in combination with chemotherapy (with either the combination of anthracyclines and cyclophosphamide or paclitaxel as a single agent), can significantly increase both the duration of response and OS.1 Trastuzumab is currently used in three settings for patients with breast cancer overexpressing HER2: as a first-line therapy in combination with paclitaxel; as a second-line monotherapy in patients who have received at least one prior chemotherapy regimen; or in an adjuvant setting in combination with doxorubicin, cyclophosphamide, and paclitaxel. It is also approved for patients with metastatic HER2+ gastric or gastroesophageal junction (GEJ) adenocarcinoma. This is based on an improved OS of 4.8 months when used in combination with cisplatin and either capecitabine or 5-FU compared to chemotherapy alone. Patients with HER2- disease showed no benefit when treated with trastuzumab. Common adverse effects are asthenia, rash, and diarrhea. Serious side effects are ventricular dysrhythmia, decreased left ventricular ejection fraction (LVEF), and thromboembolism.
b. Pertuzumab (Perjeta) is a fully humanized MoAb directed against the extracellular domain of HER2. It prevents dimerization of the HER2 receptor that is necessary for its activity and is a potential mechanism of resistance to trastuzumab. When combined with trastuzumab and docetaxel in patients with untreated metastatic HER2+ breast cancer, pertuzumab improved RR from 12.5% to 20.2%, median PFS by 6.3 months, and median OS by 15.7 months.2 This led to its FDA-approval for untreated HER2+ breast cancer in combination with trastuzumab and docetaxel. It has also been studied in the neoadjuvant setting and showed an improved pathologic complete response (pCR) rate of 46% when combined with docetaxel and trastuzumab (compared to 29% for docetaxel and trastuzumab). Common side effects include diarrhea, nausea, rash, and peripheral neuropathy. Serious effects include febrile neutropenia, severe diarrhea, and left ventricular dysfunction. Importantly, the combination of pertuzumab and trastuzumab does not seem to increase cardiotoxicity compared to trastuzumab alone.
5. Vascular endothelial growth factor
Vascular endothelial growth factor (VEGF) family of proteins is one of the specific positive regulators of angiogenesis. It is composed of five different growth factors: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor. Of these, VEGF-A exerts the most influence on the angiogenesis process. The VEGF proteins bind to three tyrosine kinase receptors: VEGF receptor 1 (VEGFR-1/FLT-1), VEGFR-2 (kinase insert domain receptor/fetal liver kinase 1, FLK-1), and VEGFR-3 (FLT-1). VEGFR-2, through its interaction with VEGF, is thought to be the main mediator of tumor-associated angiogenesis and metastatic processes, whereas VEGFR-1 plays a role in hematopoiesis. The VEGF-A is expressed or overexpressed in many tumors, including lung, breast, and ovarian cancer tumors, as well as gastrointestinal stromal tumors (GISTs) and renal cell carcinoma (RCC). Accordingly, targeting these molecules to block tumor-associated angiogenesis constitutes a logical therapeutic strategy to control cancer. Both antibodies and small molecules have been developed as targeted therapies utilizing this pathway. Here, we discuss the antibodies. The small molecules are discussed later in the chapter.
a. Bevacizumab (Avastin) is a humanized murine anti-VEGF MoAb. It functions by blocking VEGF-A binding to its receptors (VEGFR), thereby inhibiting the tumor-induced angiogenesis process. Given the ubiquitous nature of angiogenesis in cancer, bevacizumab is used in many cancers, including colon, lung, glioblastoma, RCC, ovarian, and uterine cancers. Bevacizumab was found to improve RR, PFS, and OS when combined with first-line chemotherapy of FOLFOX or FOLFIRI in patients with metastatic CRC. Even in patients with metastatic CRC who received bevacizumab in the first-line setting, its addition to second-line chemotherapy showed an improved PFS of 1.7 months compared to second-line chemotherapy alone. However, bevacizumab use in the adjuvant setting did not improve OS. These studies have led to its approval for metastatic CRC as a first-line treatment in combination with FOLFOX or FOLFIRI and as a second-line treatment with similar regimens, but not in the adjuvant setting. In previously untreated patients with metastatic, recurrent, or locally advanced nonsquamous NSCLC, bevacizumab plus paclitaxel and carboplatin (PC) was shown to improve OS by 2 months compared to PC alone.3 A similar study combining bevacizumab with gemcitabine and cisplatin failed to show an improvement in PFS or OS. This led to its approval for patients with previously untreated metastatic, recurrent, or locally advanced nonsquamous NSCLC in combination with PC. Squamous-type histology was excluded from these studies given an unacceptably high risk of massive hemoptysis with bevacizumab use. Bevacizumab is also approved for the use in patients with glioblastoma previously treated with either temozolomide or irinotecan with radiation. This was based on an improvement of RR of 26% and 20%, respectively, on two separate studies but with no survival advantage. Bevacizumab is also approved for the use in patients with previously untreated metastatic RCC in combination with interferon (IFN)-α2a, based on improvement of 18% in RR and 4.8 months in PFS with no difference in OS. Recently, bevacizumab was also studied in both cervical and ovarian cancer patients. Patients with refractory metastatic cervical cancer following initial chemotherapy received bevacizumab in combination with paclitaxel and cisplatin or paclitaxel and topotecan. Bevacizumab with either chemotherapy doublet improved RR by 11% and OS by 3.9 months. Patients with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer had an improved PFS of 6.8 months when received bevacizumab in combination with paclitaxel, doxorubicin, or topotecan, compared to 3.4 months with chemotherapeutic agent alone. Accordingly, bevacizumab was approved in combination with chemotherapy in patients with persistent, recurrent or metastatic cervical cancer and patients with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer. Bevacizumab was approved by the FDA in 2008 for use as a first-line therapy in combination with paclitaxel in patients with metastatic HER2- breast cancer, based on an improvement in PFS of 5.9 months in patients receiving the combination compared to those receiving paclitaxel alone. However, the FDA Oncology Drugs Advisory Committee recommended that approval be withdrawn based on the new trials that did not show any improvement in OS and minimal improvement in PFS. Serious adverse effects include arterial and venous thrombosis, hypertension (HTN), gastrointestinal perforation, and delayed wound healing following surgery. Up to 31% of patients with squamous cell lung cancer (SCLC) were found to have serious or fatal pulmonary hemorrhage, restricting its use in this patient population.
b. Ramucirumab (Cyramza) is a recombinant human IgG1 MoAb against VEGFR-2 that is approved in multiple settings. In patients with locally advanced or metastatic gastric or GEJ adenocarcinoma previously treated with either platinum-based or 5-FU-based regimen, ramucirumab showed an improvement of PFS by 0.8 months and OS by 1.4 months compared to placebo. In the same patient population, ramucirumab was combined with paclitaxel and compared to placebo in combination with paclitaxel. This study showed that ramucirumab improved RR by 12%, PFS by 1.5 months, and OS by 2.2 months. These studies had led to its approval in these disease settings. In addition, ramucirumab is approved for patients with locally advanced or metastatic NSCLC after progression on a platinum-based regimen. This was based on a phase III study comparing it in combination with docetaxel to docetaxel in combination with placebo showing an improvement of PFS by 1.5 months, with a nonsignificant trend toward improved OS. Recently, ramucirumab was approved in patients with metastatic colorectal cancer after 5-FU-, oxaliplatin-, bevacizumab-based chemotherapy failure, based on improved OS by 1.6 months and PFS by 1.2 months compared to placebo. Common adverse effects include HTN and diarrhea when used as a single agent. When used in combination with a taxane, adverse effects include neutropenia, neuropathy, and fatigue. Serious effects are similar to those of bevacizumab.
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