Robert D. Mass

Addition of Bevacizumab to Bolus Fluorouracil and Leucovorin in First-Line Metastatic Colorectal Cancer: Results of a Randomized Phase II Trial

PURPOSE Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan. PATIENTS AND METHODS Patients had metastatic CRC and one of the following characteristics: age > or = 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin < or = 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed. RESULTS Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation. CONCLUSION Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.

Combined Analysis of Efficacy: The Addition of Bevacizumab to Fluorouracil/Leucovorin Improves Survival for Patients With Metastatic Colorectal Cancer

PURPOSE Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that inhibits tumor angiogenesis, has demonstrated survival benefit in patients with previously untreated metastatic colorectal cancer when combined with irinotecan/fluorouracil (FU)/leucovorin (LV; IFL). Three randomized clinical studies have evaluated bevacizumab in combination with FU/LV alone. A combined analysis of raw data from these studies was performed to better assess the efficacy of bevacizumab with FU/LV. PATIENTS AND METHODS The analysis used primary efficacy data from three independent studies, including 241 patients in a combined control group receiving either FU/LV or IFL and 249 patients receiving FU/LV/bevacizumab (5 mg/kg once every 2 weeks). The efficacy data included response rate, progression-free survival, and overall survival. RESULTS The median duration of survival was 17.9 months in the FU/LV/bevacizumab group, compared with 14.6 months in the combined control group, corresponding to a hazard ratio for death of 0.74 (P = .008). The median duration of progression-free survival was 8.8 months in the FU/LV/bevacizumab group, compared with 5.6 months in the combined control group, corresponding to a hazard ratio for disease progression of 0.63 (P < or = .0001). The addition of bevacizumab also improved the response rate (34.1% v 24.5%; P = .019). CONCLUSION The addition of bevacizumab to FU/LV provides a statistically significant and clinically relevant benefit to patients with previously untreated metastatic colorectal cancer.

Determination of HER2 Gene Amplification by Fluorescence In situ Hybridization and Concordance with the Clinical Trials Immunohistochemical Assay in Women with Metastatic Breast Cancer Evaluated for Treatment with Trastuzumab

SummaryPurpose. To evaluate the concordance between HER2 gene amplification, determined by fluorescence in situ hybridization (FISH), and HER2 protein overexpression assessed by an immunohistochemical (IHC) assay. The IHC protocol used was a research assay, known as the Clinical Trial Assay (CTA), developed to select women with metastatic breast cancer (MBC) for three pivotal clinical trials of trastuzumab therapy.Methods. A direct-labeled, dual-probe FISH assay was used to determine HER2 amplification in 623 fixed breast cancer tissue specimens. These specimens had been stored as paraffin-embedded sections for 2ᾢ5 years. All specimens had been analyzed for HER2 protein expression by the CTA. To assess the reproducibility of FISH results in archived material, we evaluated a separate group of 617 breast cancer tissue specimens at two di erent laboratories.Results. Informative FISH results were available for 529 (85%) of the 623 specimens. Overall concordance between FISH and IHC results was 82% (95% CI; 78ᾢ85%). Assay agreement between FISH results and specimens with immunostaining scores of 0, 1+, and 3+ were 97, 93 and 89%, respectively. However, only 24% of specimens with 2+ immunostaining scores had HER2 amplification by FISH; there was assay disagreement in 76% of specimens in this IHC subgroup. Interlaboratory FISH concordance was 92% (95% CI; 89ᾢ94%), indicating very good assay reproducibility in these archived specimens.Conclusion. HER2 status determined by CTA-IHC and FISH are significantly correlated; however, differences between these two assays can a ect patient selection for trastuzumab therapy.

Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107

PURPOSE In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. PATIENTS AND METHODS For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. RESULTS Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. CONCLUSION In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

Evaluation of HER-2/neu expression in prostatic adenocarcinoma: A request for a standardized, organ specific methodology

Some evidence suggests a role for HER‐2/neu overexpression in prostate carcinoma progression. Reported rates of HER‐2/neu overexpression in patients with prostate carcinoma vary greatly.

The Development of Avastin

Bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, USA) is a humanized monoclonal antibody that specifically targets and neutralizes vascular endothelial growth factor (VEGF-A), an essential endothelial cell mitogen and survival factor. As the first anti-angiogenic therapy developed and approved for human cancer, it represents the culmination of many years of biologic and human research in many laboratories and clinics around the world. This chapter will review (1) the development of bevacizumab beginning with the cloning of human VEGF which allowed for the generation of murine-derived, human-specific anti-VEGF monoclonal antibodies; (2) the process by which a single clone, A4.6.1, was identified and selected for clinical development; (3) the process of “humanizing” the murine antibody to form bevacizumab to enable human testing; (4) the clinical development program from phase I through phase III clini cal experiments; (5) the future areas for clinical evaluation of bevacizumab.respect to differential efficacy and adverse effect profiles.

erb-B2 as a Therapeutic Target

Trastuzumab is a humanized monoclonal antibody that targets the type 1 tyrosine kinase receptor erb-B2 and has demonstrated survival benefit when used in combination with chemotherapy in the treatment of metastatic, HER2 overexpressing breast cancer. This chapter reviews the history of the development of trastuzumab including the biology of HER signaling, the technical issues of antibody “humanization,” the diagnostic challenges in developing “targeted” therapeutic agents, and the clinical data that led to the approval of this agent for patients with HER2 overexpressing breast cancer.