Bethesda Handbook of Clinical Oncology, 2nd Edition

Targeted Treatments and Complimentary and Alternative Medicine


Targeted Therapies

James L. Gulley*

Gregory Curt

*Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

AstraZeneca Oncology, Garrett Park, Maryland

The ideal pharmaceutical agent acts on the target tissue without being toxic to other tissues, thereby having a wide therapeutic index. Initial anticancer agents fell far short of this ideal, with limited antitumor activity and considerable toxicity to normal tissues. Newer classes of promising drugs that target molecular structures or pathways unique to tumors are being developed. This chapter provides a brief overview on U.S. Food and Drug Administration (FDA)–approved targeted therapies.


Monoclonal antibodies (MABs) take advantage of the exquisite specificity inherent in the immune system. The first generation of murine MABs had disappointing clinical results despite the ability to target tumors appropriately. This was caused by a lack of effector function of murine antibodies in humans (i.e., inability to facilitate antibody-dependent cellular cytotoxicity or to complement mediated lysis) that was attributable to lack of murine Fc (constant fragment of an antibody molecule) functionality in humans and to significant induction of human anti–mouse-antibodies (HAMAs). This was overcome either by adding functionality to the antibodies (e.g., adding a radioisotope or toxin) or by “humanizing” the antibody to gain effector function and to decrease immunogenicity. Some MABs are completely human except for select segments of the hypervariable domain of the antibody (see Fig. 43.1). Several MABs have been FDA approved for either diagnostic testing or cancer therapy (see Table 43.1).

TABLE 43.1. U.S. Food and Drug Administration (FDA)-approved Monoclonal Antibodies (MABs) for Cancer Treatment

Generic name

Trade name


FDA indication

NHL, non-Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; VEGF, vascular endothelial growth factor; 5-FU, 5-fluorouracil; EGFR, epidermal growth factor receptor.
Unlabeled antibody is given first followed by labeled antibody. (131)I is both a β and γ emitter.
Rituxumab is given first then (111)In labeled antibody (to assess biodistribution), then therapeutic (90)Y labeled antibody. (90)Y is a β emitter.




Relapsed or refractory, low-grade or follicular, CD20+ NHL

Tositumomab and I-131 tositumomaba



Refractory to rituximab, relapsed, CD20+ follicular NHL

(90)Y-ibritumomab tiuxetanb



Relapsed or refractory, low-grade, or transformed B-cell lymphoma




Salvage B-cell CLL

Gemtuzumab ozogamicin



Relapsed acute myeloid leukemia




HER-2+ metastatic breast cancer




Metastatic colorectal cancer, frontline with 5-FU




Second line for metastatic colorectal cancer in combination with irinotecan


FIG. 43.1. Fully human and fully murine antibodies have all regions from their respective species. Chimeric antibodies generally have the constant regions from humans and variable regions from other species, whereas humanized antibodies generally have only select regions (such as the hypervariable region) from another species.

The nomenclature of MABs has a few unique rules. Generic names of MABs or fragments end in “mab.” In addition, an MAB with the suffix “omab” indicates a murine antibody, “ximab” indicates a chimeric antibody, and “zumab” indicates a humanized antibody.

Rituximab (Rituxan)

  • Rituximab (Rituxan) is a chimeric MAB that targets CD20, a marker found on B cells.
  • It is indicated for relapsed or refractory, low-grade or follicular, CD20+non-Hodgkin lymphoma (NHL).
  • Overall response (OR) rate of single-agent rituximab was 48%, with 6% complete response (CR) in a multicenter, open-label, single-arm study of 166 patients with relapsed or refractory low-grade or follicular B-cell NHL (1). The median duration of response was 11.2 months (range, 1.9 to more than 42.1 months). See Chapter 28 for details about use.
  • Toxicities include asthenia, dizziness, headache, nausea, vomiting, pruritus, and rash (common), and infection and hematologic, cardiac, and renal toxicity (serious).



Trastuzumab (Herceptin)

  • Trastuzumab (Herceptin) is a humanized antibody that targets the human epidermal growth factor receptor (HER-2), which is overexpressed in a variety of cancers.
  • It is indicated in patients with breast cancer who overexpress HER-2, either in combination with paclitaxel as up-front treatment for disease, or as a single agent for those who have failed earlier chemotherapy.



  • In a pivotal phase III trial of 469 patients with HER-2–positive breast cancer who had not previously received chemotherapy for metastases, the patients were randomized to receive chemotherapy with or without traztuzumab. In contrast to the arm that received chemotherapy without traztuzumab, the combination arm had a longer median time to disease progression (TTP) (7.4 versus 4.6 months; p<0.001), higher OR rate (50% versus 32%; p <0.001), longer median duration of response (9.1 versus 6.1 months; p<0.001), longer median time to treatment failure (6.9 versus 4.5 months; p <0.001), and longer median overall survival (25.1 versus 20.3 months; p = 0.046) (2).
  • The clinical benefit of trastuzumab has been seen largely for those patients who have 3+ HER-2 overexpression.
  • The single-agent objective response rate of 24% in first-line therapy is somewhat higher than the rate seen for salvage therapy (3).
  • Toxicities include anemia/leukopenia and diarrhea (common), and cardiomyopathy, infusion-associated symptoms, hypersensitivity reactions, and pulmonary events (serious).
  • Combination therapy of trastuzumab and anthracyclines resulted in a high rate of cardiotoxicity (4). See Chapter 12 for details about use.

Tositumomab and Iodine-131 Tositumomab (Bexxar)

  • Tositumomab and Iodine-131 Tositumomab (Bexxar) is a murine MAB that targets CD20.
  • It is indicated for relapsed, CD20+, follicular NHL that is refractory to rituxumab therapy.
  • In a phase III study, 60 patients with chemotherapy-refractory low-grade or transformed low-grade B-cell NHL who have failed to respond to at least two chemotherapeutic regimens were treated with a single course of I-131 tositumomab (5). An OR rate of 65% (20% CR) was achieved with a median response duration of 6.5 months. These clinical parameters were a statistically significant improvement on the responses to the patients' previous qualifying chemotherapy.
  • Toxicities include asthenia, headache, fever, infection, and hematologic toxicity (common), and pleural effusion and dehydration (serious).

(90)Y-ibritumomab Tiuxetan (Zevalin)

  • Ibritumomab is a murine MAB that targets CD20.
  • It is indicated for relapsed or refractory, low-grade, or transformed B-cell lymphoma.
  • In a randomized, comparative phase III study involving 143 patients with relapsed or refractory NHL (low-grade, follicular, or transformed), an overall objective response rate of 80% (30% CR) and 56% (16% CR) was reported in patients treated with Y-90 ibritumomab tiuxetan radioimmunotherapy and rituximab immunotherapy, respectively (p= 0.002) (6). Durable responses of 6 months were 64% in contrast to 47% (p = 0.030) favoring radioimmunotherapy.
  • Toxicities include asthenia, dizziness, headache, and arthralgia (common), and myelosuppression, angioedema, and infection (serious).

Alemtuzumab (Campath)

  • Alemtuzumab (Campath) is a humanized antibody that targets CD52, a cell surface marker found on essentially all T and B lymphocytes.
  • It is indicated for B-cell chronic lymphocytic leukemia (CLL) in the salvage setting.
  • In a phase II, open-label study, patients with previously treated, symptomatic CLL (n= 29) were assigned to receive intravenous alemtuzumab (7). Most patients had Rai stages III or IV and had undergone at least two prior chemotherapeutic regimens. Eleven of 29 patients (38%) attained a partial response (PR), 1 patient (4%) had a CR, and 12 patients (41%) had


stable disease. Complete morphologic remission within the bone marrow was observed in 9 of 25 assessable patients. The median duration of response was 12 months for the treatment responders.

  • Toxicities include infusion reactions (common), and moderate hematologic toxicity with opportunistic infection as the primary treatment-related adverse event (serious).

Gemtuzumab Ozogamicin (Mylotarg)

  • Gemtuzumab is a humanized MAB conjugated to calicheamicin that targets CD33, a marker found on the surface of leukemic blasts and immature normal cells of myelomonocytic lineage but not on normal hematopoietic stem cells.
  • It is indicated for the treatment of patients with CD33+acute myeloid leukemia (AML) in first relapse who are 60 years or older and who are not considered candidates for other chemotherapeutic regimens.
  • Controlled trials do not demonstrate an improvement in disease-related symptoms or increased survival compared with other treatment options Product Info Mylotarg, 2001 (8).
  • Overall response rate is 30% in phase II studies (n= 142), with median overall survival of 5.9 months (9).
  • Grade 3 or 4 toxicities are neutropenia (97%), thrombocytopenia (99%), hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), and infections (28%).
  • An 84% CR rate was reported in a phase II study of gemtuzumab ozogamicin in combination with cytarabine and daunorubicin in patients younger than 60 years with de novoAML (10).

Cetuximab (Erbitux)

  • Cetuximab (Erbitux) is a chimeric anti–epidermal growth factor receptor (EGFR) MAB.
  • It is indicated in metastatic colorectal cancer in combination with irinotecan in patients refractory to irinotecan.
  • In a multicenter, randomized, controlled clinical trial conducted in 329 patients randomized to either cetuximab plus irinotecan (n= 218) or cetuximab monotherapy (n = 111), there was evidence of durable responses in the combination arm without evidence of an effect on survival (OR 23% versus 12%; TTP 4.1 versus 1.5 months).
  • Toxicities include acneform rash (90%), asthenia/malaise (50%), and fever (33%).

Bevacizumab (Avastin)

  • Bevacizumab (Avastin) is a humanized MAB directed against vascular endothelial growth factor (VEGF).
  • It is indicated in combination with intravenous 5-fluorouracil-based chemotherapy as a therapy for patients with first-line metastatic cancer of the colon or rectum.
  • In a large, placebo-controlled, randomized study, the median survival of patients treated with bevacizumab plus the IFL (5-FU/leucovorin/irinotecan) chemotherapeutic regimen (n= 403) was 20.3 months versus 15.6 months in the IFL chemotherapeutic regimen alone arm (n = 412; p = 0.00003) (11).
  • Toxicities include asthenia, pain, hypertension, diarrhea, and leukopenia (common), and gastrointestinal (GI) perforations, wound healing complications, hemorrhage, hypertensive crises, nephrotic syndrome, and congestive heart failure (severe).


Small molecules can be used to target specific pathways that are active in cancer cells so as to alter their ability to grow. Some of these drugs may be active as single agents, whereas others may be best used in combination with other therapies (see Table 43.2).

TABLE 43.2. U.S. Food and Drug Administration (FDA)-approved Small Molecule Targeted Therapy for Cancer Treatment

Generic name

Trade name


FDA indication

CML, chronic myeloid leukemia; PDGF, platelet-derived growth factor; GIST, gastrointestinal stromal tumors; EGFR, epidermal growth factor receptor; MM, multiple myeloma.
Recombinant DNA-derived cytotoxic protein composed of the amino acid sequences for diphtheria toxin fragments A and B followed by the sequences for interleukin so that it binds to CD25. It is produced in an Escherichia coli expression system.



C kit, PDGF

Philadelphia chromosome + CML c-Kit + GIST




Locally advanced or metastatic nonsmall cell lung cancer after failure of both platinum-based and docetaxel chemotherapies



Proteosome inhibitor

For patients with MM who have failed two prior regimens

Denileukin diftitoxa



Persistent or recurrent CD 25+ cutaneous T-cell lymphoma



Imatinib Mesylate (Gleevec)

  • Imatinib mesylate (Gleevec) is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It is also an inhibitor of the receptor tyrosine kinase for platelet-derived growth factor (PDGF) and c-kit.
  • It is indicated as first-line therapy in newly diagnosed patients with Philadelphia chromosome positive (Ph+) CML and Ph+ CML in blast, accelerated, or in chronic phase, after failure with interferon-αtherapy, and in unresectable gastrointestinal stromal tumors (GIST).
  • Its indication for CLL is based on superiority to interferon-α plus cytarabine in both tolerability and efficacy (12). See Chapter 11 for details on use.
  • In GIST, imatinib mesylate is associated with a confirmed PR of greater than 50% (13).
  • Toxicities include fluid retention, muscle cramps, nausea, vomiting, and diarrhea (common), and liver toxicity and myelosuppression (serious).

Gefitinib (Iressa)

  • Gefitinib (Iressa) inhibits the intracellular phosphorylation of several tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the EGFR.
  • It is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non–small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. See Chapter 2 for details regarding use.
  • A clinical trial evaluated the effectiveness of two doses of gefitinib (n= 221; 142 evaluable) (14):
  • The patients had advanced non–small cell lung cancer with progressive disease (PD) after two earlier chemotherapeutic regimens including a platinum drug and docetaxel.
  • Twelve percent of the patients receiving a 250-mg daily dose (n= 102) experienced a partial radiographic response, which was better than the response (9%) for those receiving the 500-mg dose (n = 114).
  • There is a greater probability of clinical response from patients with somatic EGFR mutations in the (adenosine 5'-triphosphate) ATP-binding pocket of the tyrosine kinase domain than from those patients without these mutations (15,16). These activating mutations occur more often in nonsmokers, women, and those with adenocarcinoma.



  • Other large clinical trials combining gefitinib with chemotherapy did not show any clinical benefit from the addition of gefitinib (17).

Bortezomib (Velcade)

  • Bortezomib (Velcade) is a reversible 26S proteasome inhibitor.
  • It is indicated for patients with multiple myeloma (MM) who have failed to respond to at least two earlier therapies and who have progressed on their last therapy.
  • In a single-arm phase II trial of 202 heavily pretreated refractory and relapsed patients with MM, 35% achieved an OR rate (median duration 12 months) (18).
  • Bortezomib is being evaluated in combination with gemcitabine, docetaxel, and irinotecan in patients with solid tumors.
  • Toxicities include fatigue, malaise, fever, constipation, and anorexia (common), and diarrhea, nausea, vomiting, anemia, thrombocytopenia, and peripheral neuropathy (serious).

Denileukin Diftitox (Ontak)

  • Denileukin Diftitox (Ontak) is an interleukin-2 receptor-specific fusion protein consisting of diphtheria toxin fragments A and B fused to interleukin-2.
  • It is indicated for persistent or recurrent CD 25+cutaneous T-cell lymphoma.
  • An OR rate of 30% [10% CR or clinical complete response (CCR), 20% PR] was achieved in a phase III study (n= 71) of patients with Ib-III cutaneous T-cell lymphoma, either mycosis fungoides or Sezary syndrome (19).
  • Toxicities include diarrhea, nausea, dyspnea, and flulike symptoms (common), and fever, hypotension, infections, and vascular leak syndrome (serious).

There is continuing research with a variety of different agents, including antibodies, small molecules, and vaccines. It is likely that these targeted therapies will offer some more therapeutic options that may be better tolerated than therapy with traditional cytotoxic agents.


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