Report Prepared Matt Stenger, MS

Axitinib is a second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 that exhibits increased potency in VEGFR inhibition and reduced off-target effects compared with first-generation inhibitors. The phase 3 AXIS trial recently compared axitinib with the VEGFR inhibitor sorafenib in the second-line treatment of advanced renal cell carcinoma (RCC). The trial is the first phase 3 trial to directly compare antiangiogenesis agents in this setting.¹

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Axitinib is a second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 that exhibits increased potency in VEGFR inhibition and reduced off-target effects compared with first-generation inhibitors. The phase 3 AXIS trial recently compared axitinib with the VEGFR inhibitor sorafenib in the second-line treatment of advanced renal cell carcinoma (RCC). The trial is the first phase 3 trial to directly compare antiangiogenesis agents in this setting.¹

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Axitinib is a second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 that exhibits increased potency in VEGFR inhibition and reduced off-target effects compared with first-generation inhibitors. The phase 3 AXIS trial recently compared axitinib with the VEGFR inhibitor sorafenib in the second-line treatment of advanced renal cell carcinoma (RCC). The trial is the first phase 3 trial to directly compare antiangiogenesis agents in this setting.¹

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Ruxolitinib, a JAK 1/JAK 2 kinase inhibitor, was recently approved by the Food and Drug Administration for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. JAK kinases mediate signaling of cytokines and growth factors that are involved in hematopoiesis and immune function. JAK signaling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, STAT activation, and localization of STATs to the nucleus, which results in the modulation of gene expression. Myelofibrosis is associated with aberrant JAK signaling. Ruxolitinib acts to attenuate downstream signaling by inhibiting JAK 1 and JAK 2 kinases, which results in reduced plasma cytokine levels and the induction of antiproliferative and proapoptotic effects...

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Ruxolitinib, a JAK 1/JAK 2 kinase inhibitor, was recently approved by the Food and Drug Administration for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. JAK kinases mediate signaling of cytokines and growth factors that are involved in hematopoiesis and immune function. JAK signaling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, STAT activation, and localization of STATs to the nucleus, which results in the modulation of gene expression. Myelofibrosis is associated with aberrant JAK signaling. Ruxolitinib acts to attenuate downstream signaling by inhibiting JAK 1 and JAK 2 kinases, which results in reduced plasma cytokine levels and the induction of antiproliferative and proapoptotic effects...

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Ruxolitinib, a JAK 1/JAK 2 kinase inhibitor, was recently approved by the Food and Drug Administration for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. JAK kinases mediate signaling of cytokines and growth factors that are involved in hematopoiesis and immune function. JAK signaling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, STAT activation, and localization of STATs to the nucleus, which results in the modulation of gene expression. Myelofibrosis is associated with aberrant JAK signaling. Ruxolitinib acts to attenuate downstream signaling by inhibiting JAK 1 and JAK 2 kinases, which results in reduced plasma cytokine levels and the induction of antiproliferative and proapoptotic effects...

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Aflibercept is a recombinant human fusion protein that acts as a decoy receptor to prevent vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF) from interacting with their native receptors, thereby inhibiting angiogenesis (Figure 1). Currently, the humanized monoclonal antibody bevacizumab, which binds to VEGF-A, is the only agent targeting the VEGF pathway that is approved for use in colorectal cancer (CRC). It is used in combination with FOLFOX (5- fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, and irinotecan). Findings from the recent multinational phase III EFC10262-VELOUR trial have shown that aflibercept is effective in prolonging survival when it is used in combination with FOLFIRI in the second-line treatment of metastatic CRC (mCRC).1

*For a PDF of the full article and accompanying Commentary, click on the links to the left of this introduction.

Aflibercept is a recombinant human fusion protein that acts as a decoy receptor to prevent vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF) from interacting with their native receptors, thereby inhibiting angiogenesis (Figure 1). Currently, the humanized monoclonal antibody bevacizumab, which binds to VEGF-A, is the only agent targeting the VEGF pathway that is approved for use in colorectal cancer (CRC). It is used in combination with FOLFOX (5- fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, and irinotecan). Findings from the recent multinational phase III EFC10262-VELOUR trial have shown that aflibercept is effective in prolonging survival when it is used in combination with FOLFIRI in the second-line treatment of metastatic CRC (mCRC).1

*For a PDF of the full article and accompanying Commentary, click on the links to the left of this introduction.

Aflibercept is a recombinant human fusion protein that acts as a decoy receptor to prevent vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF) from interacting with their native receptors, thereby inhibiting angiogenesis (Figure 1). Currently, the humanized monoclonal antibody bevacizumab, which binds to VEGF-A, is the only agent targeting the VEGF pathway that is approved for use in colorectal cancer (CRC). It is used in combination with FOLFOX (5- fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, and irinotecan). Findings from the recent multinational phase III EFC10262-VELOUR trial have shown that aflibercept is effective in prolonging survival when it is used in combination with FOLFIRI in the second-line treatment of metastatic CRC (mCRC).1

*For a PDF of the full article and accompanying Commentary, click on the links to the left of this introduction.

Vemurafenib, an oral inhibitor of some mutated forms of the BRAF serine threonine kinase, was recently approved for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA- approved test. It is not recommended for use in patients with wild-type BRAF melanoma. The clinical trial supporting approval of vemurafenib (PLX4032) was performed in treatment-naïve patients with the V600E mutation as detected by the Cobas 4800 BRAF V600 Mutation Test. About 40%-60% of cutaneous melanomas have BRAF mutations that result in constitutive activation of downstream signaling through the MAPK pathway; about 90% of those carry the V600E mutation.

*For a PDF of the full article, click on the link to the left of this introduction.

Vemurafenib, an oral inhibitor of some mutated forms of the BRAF serine threonine kinase, was recently approved for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA- approved test. It is not recommended for use in patients with wild-type BRAF melanoma. The clinical trial supporting approval of vemurafenib (PLX4032) was performed in treatment-naïve patients with the V600E mutation as detected by the Cobas 4800 BRAF V600 Mutation Test. About 40%-60% of cutaneous melanomas have BRAF mutations that result in constitutive activation of downstream signaling through the MAPK pathway; about 90% of those carry the V600E mutation.

*For a PDF of the full article, click on the link to the left of this introduction.

Vemurafenib, an oral inhibitor of some mutated forms of the BRAF serine threonine kinase, was recently approved for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA- approved test. It is not recommended for use in patients with wild-type BRAF melanoma. The clinical trial supporting approval of vemurafenib (PLX4032) was performed in treatment-naïve patients with the V600E mutation as detected by the Cobas 4800 BRAF V600 Mutation Test. About 40%-60% of cutaneous melanomas have BRAF mutations that result in constitutive activation of downstream signaling through the MAPK pathway; about 90% of those carry the V600E mutation.

*For a PDF of the full article, click on the link to the left of this introduction.

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

 *For a PDF of the full article, click in the link to the left of this introduction.

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

 *For a PDF of the full article, click in the link to the left of this introduction.

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

 *For a PDF of the full article, click in the link to the left of this introduction.

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.