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.

Targeting VEGF-A to treat cancer and age-related macular degeneration.

Inhibiting angiogenesis is a promising strategy to treat cancer and several other disorders, including intraocular neovascular syndromes. The identification of vascular endothelial growth factor (VEGF)-A as a major regulator of normal and pathological angiogenesis has enabled significant progress toward effective treatments for such disorders. Several VEGF inhibitors have been recently approved by the U.S. Food and Drug Administration for the treatment of cancer and the neovascular form of age-related macular degeneration. This review summarizes the basic biology of VEGF-A and illustrates the clinical progress in targeting this molecule.

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.

PURPOSE: 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 25 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 different 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; 7885%). 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; 8994%), 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.

Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab.

BACKGROUND: We evaluated the influence of HER2 gene amplification, as determined by fluorescence in situ hybridization (FISH), on clinical outcomes (objective response rates, time to disease progression, and overall survival time) in women with metastatic breast cancer treated with trastuzumab in 3 clinical trials. Breast cancer tissue specimens were evaluated using a direct labeled, dual-probe FISH assay. MATERIALS AND METHODS: Specimens with a HER2:CEP17 ratio of > or = 2:0 were considered positive for gene amplification. All specimens had previously demonstrated overexpression of HER2 protein at the 2+ or 3+ level by immunohistochemistry using the Clinical Trials Assay. Response rate, time to disease progression, and survival times were then compared between the FISH-positive and FISH-negative cohorts in each of the 3 clinical trials. RESULTS: Informative FISH results were obtained in 765 (96%) of the 799 patients enrolled in the 3 clinical trials. Overall, 596 (78%) were FISH-positive and 169 (22%) were FISH-negative. The proportion of FISH-positive patients was comparable in all 3 trials. Clinical benefit from trastuzumab therapy appeared to be restricted to patients with FISH-positive metastatic breast cancer. In each clinical trial, the cohort of FISH-positive patients had higher overall response rates and longer durations of survival compared with FISH-negative patients. CONCLUSION: These data indicate that assessment of HER2 amplification by FISH is the preferred method to select patients for trastuzumab therapy.

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.

Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease.

The purpose of this study was to evaluate the feasibility, efficacy, safety, and pharmacokinetics of trastuzumab plus cisplatin and gemcitabine in patients with Her2-overexpressing stages IIIB or IV non-small cell lung cancer (NSCLC) and to study the relationship between results from the two methods for determining levels of Her2 overexpression. Chemonaive patients were eligible if they had stages IIIB or IV NSCLC with either a Her2 score of at least 1+ by immunohistochemical (IHC) analysis or a serum Her2 shed antigen level of at least 15 ng/ml by enzyme-linked immunosorbent assay (ELISA). Treatment consisted of cisplatin 75 mg/m(2) day one plus gemcitabine 1250 mg/m(2) days one and eight plus trastuzumab 4 mg/kg day one and 2 mg/kg weekly thereafter on a 21-day cycle for six cycles followed by weekly maintenance trastuzumab therapy. Of the 21 patients enrolled, 8 (38%) patients had a partial response. The 1-year survival rate was 62% (13/21). Median time to progression was 36 weeks. Pharmacokinetic studies revealed no interaction between trastuzumab and gemcitabine plus cisplatin. In patients screened for this study, Her2 expression was zero in 283/360 (79%); 1+ in 32/360 (9%); 2+ in 27/360 (8%); and 3+ in 18/360 patients (5%). Serum Her2 shed antigen was >15 ng/ml in 27/ 288 (9%) patients. Of patients who had both Her2 assays, 24% (4/17) with ELISA scores >15 ng/ml had IHC scores of 3+, compared with only 2% (3/145) of the patients <15 ng/ml and 4% (7/162) of all patients. The addition of trastuzumab to cisplatin and gemcitabine was well tolerated, but further study will be required to determine whether this combination is superior to chemotherapy alone. This may be demonstrated if only those patients with Her2, having a score of IHC 3+ were eligible. Since IHC 3+ is rare in NSCLC, performing IHC in only those patients with serum Her2 shed antigen >15 ng/ml would greatly increase the efficiency of IHC screening though at the cost of excluding nearly half the patients with Her2 scores of 3+ on IHC analysis. Thus, if sequential screening consisting of serum ELISA followed by IHC analysis is implemented, it may make a trastuzumab trial feasible but should ultimately be supplanted by another screening system if trastuzumab is shown to be beneficial to some patients with IHC Her2 scores of 3+.

The HER receptor family: a rich target for therapeutic development.

PURPOSE: The key role of the HER family of receptors in cancer has been widely acknowledged. HER receptor activation occurs via ligand binding or nonligand-dependent receptor dimerization, initiating signals that promote tumorigenesis via cell proliferation, survival, migration, adhesion, and differentiation. Therapeutic strategies designed to target and inhibit HER activation that are in clinical development are reviewed, including examples of both small-molecule tyrosine kinase inhibitors and monoclonal antibodies. MATERIALS AND METHODS: A literature review. RESULTS: Tarceva is a potent, highly selective, reversible inhibitor of HER1/epidermal growth factor receptor tyrosine kinase with inhibitory activity against various in vitro and in vivo models of solid human tumors. Phase II trials in refractory non-small-cell lung, head-and-neck, and ovarian cancer have demonstrated clinical activity, including objective responses and prolonged, stable disease. Four Phase III trials are ongoing evaluating primarily the effect on survival of Tarceva in combination with chemotherapy. 2C4 is a humanized anti-HER2 monoclonal antibody that binds to a broad, extracellular epitope, resulting in steric inhibition of HER-receptor complex formation that involves HER2. 2C4 has shown significant activity in xenograft models of prostate, lung, and breast cancer. 2C4's activity, unlike Herceptin's, is not dependent on HER2 amplification. This antibody is in early clinical development. CONCLUSION: The strategy of targeting the HER system has been further validated by early experience with Tarceva and 2C4. The optimal clinical benefit of these agents will likely involve combinations of biologic agents, with or without traditional chemotherapy, and will be guided by critical predictive diagnostic information.