The Rapid Reporter: American Society of Clinical Oncology

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â–º Navigating Multiple Pathways: Evolving Strategies and Future Directions in Targeted Therapies

Manuel Hidalgo, MD, PhD, Associate Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD chaired an Amgen-sponsored, continuing medical education—certified, satellite symposium at ASCO. The symposium was designed to provide the clinical community with updated information on advances in targeted agents and the rapidly evolving understanding of molecular biology and cellular pathways in cancer.

The first presentation was a discussion of the clinical evidence for targeting epidermal growth factor receptor (EGFR), led by Louis M. Weiner, MD, Chairman, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

EGFR is a transmembrane glycoprotein that is constitutively expressed in normal epithelial tissues and a variety of solid tumors. It is a member of the ErbB receptor tyrosine kinase family, which consists of four family members, EGFR (ErbB1), ErbB2 (Her2), ErbB3, and ErbB4. Ligand binding to the EGFR induces a conformational change, causing the ErbB family receptors to homodimerize or heterodimerize with each other, resulting in transautophosphorylation, with subsequent initiation of intracellular proliferation and survival signaling pathways. In malignant cells that express EGFR, inappropriate activation of the receptor occurs, which leads to uncontrolled cellular growth. Constitutive signaling in these tumors may be the result of EGFR overexpression, increased production of ligands, heterodimerization with other ErbB receptors, transactivation of heterologous signaling networks, activating mutations, and/or loss of negative regulatory mechanisms for receptor signaling. EGFR activation mediates several tumor-promoting processes, including cell proliferation, inhibition of apoptosis, angiogenesis, enhanced survival, and metastatic tumor spread. In preclinical studies, inhibition of EGFR signaling results in antitumor activity in multiple xenograftmodels of human disease.

Lee S. Rosen, MD, President and Founder, Premier Oncology, California, Santa Monica, CA (affiliated with the John Wayne Cancer Institute and St. John’s Health Center, Santa Monica, CA) led a discussion about multi-targeted tyrosine kinase inhibitors. Dr. Rosen and colleagues are actively pursuing the next generation of targeted therapies that attack tumor cells and tumor stroma. They apply this approach in an extensive research and clinical development program. Current areas of focus are growth regulation, angiogenesis, apoptosis, bone metabolism and metastases, muscle metabolism and cachexia, tissue protection and repair, and hematopoiesis.

Three pathways involved in growth regulation were reviewed: 1) the epidermal growth factor (EGF) pathway, 2) the hepatocyte growth factor (HGF) pathway, and 3) the insulin-like growth factor—1/2 (IGF-1/2) pathway. HGF signaling, through its receptor, the tyrosine kinase c-Met, appears to play an important pathologic role in many types of human cancers. Signaling through the HGF pathway mediates a large number of normal activities in cells of epithelial origin—including proliferation, survival, migration, and invasion. Many of these cellular functions play important roles in cancer-cell dysregulation, tumorigenesis, and tumor metastasis. The ligands IGF-1 and IGF-2 exert pleiotropic effects on cellular behavior via signaling through cell surface receptors. IGF-1 signaling via the type-1 insulinlike growth factor receptor (IGF-1R) influences cellular proliferation, survival, and differentiation. Most human cancers express IGF-1R, and the inhibition of IGF-1R signaling may represent a promising anticancer strategy.

Two pathways relating to angiogenesis were discussed—the angiopoietin—1/2 pathway and the vascular endothelial growth factor (VEGF) pathway. The angiopoietin family— angiopoietin (Ang)-1, Ang-2, Ang-3, and Ang- 4—and their corresponding receptors (Tie-1 and Tie-2)—play an important role in angiogenic as well as lymphangiogenic processes. VEGF receptor–1 (VEGFR-1) and VEGFR-2 are major regulators of angiogenesis. VEGFR-3 is involved in lymphangiogenesis and cancer metastasis via the lymphatic system.

Apoptosis is an evolutionarily conserved process of programmed cell death. Dysregulation of this process contributes to many diseases, including cancer. Apo2L/TRAIL is a member of the tumor necrosis superfamily of cytokines that selectively induces apoptosis in cancer cells. Apo2L/TRAIL binds specifically to distinct cell-surface receptors which are expressed on a wide range of human tumors.

Receptor activator of nuclear factor B ligand— also called RANK ligand (RANKL)—is an essential mediator of osteoclast formation, function, and survival that is expressed by osteoblasts and stromal cells. RANKL is a member of the tumor necrosis factor (TNF) ligand family, which is essential for this process. RANKL binds to RANK, a receptor on the cell surface of osteoclasts and osteoclast precursors, to stimulate proliferation and differentiation of cells to form the osteoclast phenotype and inhibit apoptosis. In metastatic disease, RANKL is thought to contribute to a vicious cycle of bone destruction and tumor growth.

Myostatin—a member of the transforming growth factor β (TGF-β) superfamily of secreted proteins—has been found to be overexpressed in muscle-wasting conditions such as cancer cachexia, disuse atrophy, and AIDSrelated muscle-wasting syndrome. Targeting the myostatin pathway may potentially provide a way to treat a variety of disorders in which an increase in, or maintenance of, lean body mass is desirable.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. It binds to the tyrosine kinase FGF receptor FGFR2IIIb (KGFR), which is predominantly expressed in epithelial cells of multiple tissues, including the gastrointestinal tract and skin. The triggering of the KGFR on epithelial cells stimulates cell proliferation, differentiation, migration, and up-regulation of DNA repair and survival mechanisms. The potential role of KGF in the amelioration of mucosal ulceration and injury induced by anticancer cytotoxic therapies is an area of ongoing research.

Finally, three hematopoietic pathways were discussed—the granulocyte—colony-stimulating factor (G-CSF) pathway, the erythropoietin (EPO) pathway, and the thrombopoietin (TPO) pathway. Hematopoiesis is driven by endogenously produced proteins known as colony stimulating factors (CSFs). G-CSF is a lineage-restricted hematopoietic growth factor that stimulates the proliferation and maturation of certain hematopoietic progenitors, and is a powerful mobilizer of bone marrow–derived stem cells. Most of the activity of G-CSF is restricted to the single lineage of neutrophils. The EPO receptor (EPOR) is a member of the cytokine receptor family. The binding of EPO to EPOR promotes the phosphorylation of other pathways, including mitogen-activated protein (MAP) kinase, STAT5, and phosphatidylinositol- 3 (PI3) kinase. It is these pathways that are involved in the proliferation, survival, and differentiation of erythroid precursors to generate erythrocytes. TPO is an essential factor for megakaryopoiesis and thrombopoiesis. TPO is relatively lineage-specific, working both alone and in synergy with early-acting cytokines to support megakaryocyte colony formation, and acting at a late stage of development to increase megakaryocyte size, polyploidization, and expression of differentiation markers.

â–º Two Studies Evaluate Efficacy and Safety of Lapatinib (Tykerb) in Advanced Breast Cancer

At this year’s American Society of Clinical Oncology annual meeting in Chicago, Illinois, Angelo Di Leo, MD, Sandro Pitigliani Medical Oncology Unit, Prato, Italy, disclosed the results of a multinational Phase III study evaluating the efficacy and safety of lapatinib (Tykerb) plus paclitaxel (Taxotere) compared with paclitaxel alone in patients with advanced breast cancer.

Enrolled patients (n=580) had incurable Stage IIIb, IIIc, or IV breast cancer at first diagnosis or relapse, and were randomized to receive paclitaxel 175 mg/m2 every 3 weeks plus either lapatinib 1500 mg po qd or placebo. Blinded efficacy and safety data from 579 patients were reported— 293 in the lapatinib arm and 286 in the placebo arm. Of the 579 patients, 87% presented with Stage IV disease, 55% received prior adjuvant chemotherapy or antihormonal therapy, and 0% received previous trastuzumab. Fifty-two patients (19%) in the lapatinib group were HER2-positive, compared with 39 (15%) in the placebo group.

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Complete or partial response was observed in 35.1% of patients in the lapatinib group, compared with 25.3% in the placebo group ( = 0.008). Median duration of response was 6.5 months and 6.2 months in the two groups, respectively.

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However, when the investigators stratified the data based on HER2 status, there was a notable difference in outcome. Among HER2- positive patients, median time to progression was 8.1 months in the lapatinib group, compared with 5.8 months in the placebo group ( = 0.011). Among HER2-negative patients, median time to progression was 5.8 months and 5.3 months in the two groups, respectively ( = 0.747). Similarly, median event-free survival among HER2-positive patients was 7.9 months in the lapatinib group versus 5.2 months in the placebo group ( = 0.007), compared with 5.5 months and 5.3 months, respectively, among HER2-negative patients ( = 0.458).

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The presently available data indicate a median survival of 24 months in patients treated with lapatinib plus paclitaxel versus 19 months in those receiving paclitaxel alone ( = 0.160), but the data are not yet fully mature.

Grade 3 rash was observed in 4% of patients treated with the combination of lapatinib plus paclitaxel, compared with 0% of those who received paclitaxel alone. Grade 3 diarrhea was seen in 15% and 1% of patients in the two groups, respectively.

Data from this trial of lapatinib plus paclitaxel versus paclitaxel alone as first-line treatment in patients with newly diagnosed metastatic breast cancer provide the first evidence that in the HER2-positive subgroup, the combination significantly improves progression-free survival compared with the chemotherapy alone.

Dr. Di Leo concluded by stating, “In HER2- negative or untested breast cancer, there was no significant difference in time to progression, event-free survival, or overall survival between patients treated with a combination of lapatinib and paclitaxel compared with those who received paclitaxel alone.”

“In a predefined central analysis of HER2-positive tumors, the combination of lapatinib plus paclitaxel was significantly superior to paclitaxel alone in terms of overall response rate, time to progression, and event-free survival.”

“The addition of lapatinib to paclitaxel resulted in an increase in diarrhea and rash. There were more serious adverse event— related deaths in the combination group than in the monotherapy group—2.7% vs. 0.6%. Possible reasons for the discrepancy could be a lack of experience in managing diarrhea or a pharmacokinetic interaction between lapatinib and paclitaxel.”,br>

“These results have the potential to directly impact clinical practice and may benefit patients in the first-line treatment setting.”

“Confirmation of these positive efficacy results in HER2-positive patients is underway in randomized trials. Two trials—EGF104535 and EGF105764—are testing weekly paclitaxel combined with lapatinib in patients with HER2-positive advanced breast cancer. A pooled analysis of data from the first 208 patients enrolled did not raise any safety concerns.”

In a related oral presentation, Nancy U. Lin, MD, Dana Farber Cancer Institute, Boston, Massachusetts, presented the results of a Phase II study evaluating lapatinib for brain metastases in patients with HER2-positive breast cancer following trastuzumab-based systemic therapy and cranial radiotherapy (RT).

Eligible patients had HER2-positive breast cancer, prior trastuzumab therapy and cranial RT, and radiographic evidence of progressive brain metastases with at least one measurable brain lesion. Enrolled patients received lapatinib 750 mg po bid. As of May 4, 2007, 241 patients have been accrued, of whom 21 are still receiving lapatinib monotherapy and 52 have entered optional extension arms evaluating combination therapy with lapatinib plus capecitabine.

Results from an independent radiology review showed that 19 patients (7%) treated with lapatinib monotherapy experienced a partial response, defined by a ≥50% volumetric reduction in brain lesions with no progression of tumor outside the brain, no increase in corticosteroid requirement, or worsening of neurological symptoms. Forty-six patients (19%) experienced a ≥20% volumetric reduction in brain lesions.

An additional 102 patients (42%) achieved stable disease for at least 8 weeks based on protocol-defined composite response criteria. Twenty-two percent of all patients had no disease progression within the first 6 months on lapatinib monotherapy. Lapatinib 750 mg bid was generally well tolerated.

This study confirms the single-agent efficacy of lapatinib in patients with recurrent brain metastases from HER2-positive breast cancer. Dr. Lin concluded by stating that although overall lapatinib activity was modest and the target response rate was not reached, some patients derived durable volumetric reductions in brain-tumor burden, with improvement or stabilization of CNS symptoms.

Dr. Lin added, “There is a significant need for effective alternatives to prevent and treat brain metastases arising from breast cancer, as there are no currently approved systemic treatments for these patients. These data suggest that Tykerb may cross a compromised blood brain barrier, and suggest CNS activity for Tykerb.”

Lapatinib is a first-in-class, oral small-molecule inhibitor of the HER2 tyrosine kinase receptor. Stimulation of HER2 is associated with cell proliferation and with multiple processes involved in tumor progression and metastases. Overexpression of the HER2 tyrosine kinase receptor has been reported in a variety of human tumors and is associated with poor prognosis and reduced overall survival.