p r i m e l i n e s

This newsletter is dedicated to a number of very interesting and some practice-changing presentations from the 45th Annual Meeting of the American Society for Clinical Oncology (ASCO) held May 29 – June 2, 2009 in Orlando, Florida. The theme of this year’s Annual Meeting was “Personalizing Cancer Care’’ and was reflected in many of the educational and scientific sessions.

Two investigational drugs (BSI-201 and olaparib) targeting a DNA repair enzyme known as PARP (poly [ADP-ribose] polymerase) showed encouraging activity against triple-negative and/or BRCA1/BRCA2-deficient breast cancer in 2 separate phase II trials.

Abstract 3: In the plenary session, Joyce O’Shaughnessy, MD, of Baylor-Sammons Cancer Center in Dallas, Texas, presented the interim results of a randomized multicenter phase II study of the PARP inhibitor BSI-201 that is being developed by BiPar Sciences, now a wholly-owned subsidiary of sanofi-aventis. This study has a target accrual of 120 patients with triple-negative breast cancer, and the interim analysis showed that the combination of BSI-201 plus gemcitabine/carboplatin (G/C) significantly improved both progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone. This study was designed based on in vitro evidence of synergy between BSI-201 and chemotherapy, indicating that PARP-1 inhibitors can sensitize tumor cells to DNA damaging agents. Gemcitabine (1000 mg/m²) and carboplatin (AUC = 2) were given on days 1 and 8, and BSI-201 was given IV at a dose of 5.6 mg/kg on days 1, 4, 8, and 11 every 21 days. Based on analysis of the first 86 randomized patients, BSI-201 plus G/C significantly improved the objective response rate (48% vs 16%, P = .002) and significantly prolonged both PFS (median 6.9 months vs 3.3 months, HR = 0.342, P<.0001) and OS (median 9.2 months vs 5.7 months, HR = 0.348, P = .0005) compared to treatment with G/C alone. Importantly, the safety profile was similar in both treatment arms. Given these encouraging results, a phase III trial has already been initiated and should begin enrollment in late June 2009.

Abstract CRA501: A phase II study with another PARP inhibitor, olaparib, was presented at the Clinical Science Symposium by Andrew Tutt, MD, PhD, of Guy’s Hospital, London. In this study an orally active PARP inhibitor, olaparib, was administered as single-agent therapy in patients with confirmed BRCA1/BRCA2 mutations and recurrent, chemotherapy-refractory breast cancer. Olaparib (AZD2281; KU-0059436) is being developed by AstraZeneca. A previous phase I study in BRCA-deficient ovarian cancer had established a maximum tolerated dose of 400 mg BID. In this single-arm, proof-of-concept, phase II study in BRCA-deficient breast cancer, 54 patients, who had received a median of 3 prior lines of chemotherapy, were treated with continuous oral olaparib, either at 400 mg BID (n = 27) or at 100 mg BID (n = 27), a dose previously shown to effectively inhibit PARP. The most common adverse events consisted of grade 1 to 3 fatigue, nausea, and vomiting. Among patients treated at 400 mg BID, 11 (41%) had an objective response (1 CR and 10 PR), and median PFS was 5.7 months. Among patients treated at 100 mg BID, only 6 (22%) patients had a partial response, and median PFS was 3.8 months. The investigators concluded that olaparib was well tolerated and active at 400 mg BID in patients with heavily pretreated, chemotherapy-refractory, BRCA-deficient breast cancer. Based on this positive proof of concept, further studies are planned.

Benefit of Bevacizumab for Metastatic Breast Cancer Confirmed in a Third Phase III Trial

Abstract 1005: Results from the RIBBON-1 trial have confirmed, once again, the benefit of adding bevacizumab (B, Avastin^®) to standard first-line chemotherapy in patients with HER2-negative locally-recurrent or metastatic breast cancer. The results of this important study were presented by Nicholas Roberts, MD, of US Oncology. In this randomized placebo-controlled phase III study, 1237 chemotherapy-naïve patients were treated with standard chemotherapy plus placebo or B (15 mg/kg q 3 weeks). Investigators could choose to use either capecitabine (Xeloda^®) (2000 mg/m² x 14 days), a taxane (either nab-paclitaxel [Abraxane^®] [260 mg/m² q 3 weeks] or docetaxel [Taxotere^®] [75 or 100 mg/m² q 3 weeks]), or an anthracycline-based regimen (q 3 weeks). The capecitabine cohort (Cape) and the pooled taxane or anthracycline (T + A) cohort were independently powered and analyzed in parallel. At a median follow-up of 15.6 months (Cape cohort) and 19.2 months (T + A cohort), the addition of B significantly improved PFS by 31% (P = .0002) in the Cape cohort and by 36% (P<.0001) in the T + A cohort compared with placebo. In patients with measurable disease at baseline, B significantly improved the objective response rate compared with placebo (35.4% vs 23.6% in the Cape cohort and 51.3% vs 37.9% in the T + A cohort). In both cohorts, median OS was longer in patients who received B (29 months vs 21 months for Cape and 25 months vs 24 months for T + A) but did not reach statistical significance in either cohort due to the limited number of events. Further follow up is needed. Safety was comparable to that observed in previous trials with B.

The discussant of this abstract, Kathy Miller, MD, of Indiana University, put the results of the RIBBON-1 trial into perspective. She indicated that these results have extended and confirmed the benefit of B combined with standard first-line chemotherapy in metastatic HER2-negative breast cancer, which has been previously demonstrated in the E2100 and AVADO trials. All 3 of these studies have shown that B improves response rate and PFS, but none have demonstrated an OS benefit. She also pointed out that the RIBBON-1 trial is really 2 trials combined and suggested that the Cape and T+A cohorts should not be compared.

CYP2D6 Inhibitors: To Be or Not to Be Important for Breast Cancer Recurrence?

Two large epidemiologic studies were conducted to investigate whether drugs that inhibit the activity of CYP2D6 could potentially affect the therapeutic effectiveness of adjuvant tamoxifen (TAM) in women with early breast cancer. TAM is metabolized to its active form—endoxifen—in the liver by the cytochrome P450 isoenzyme CYP2D6. It has been shown that women receiving TAM who are poor metabolizers due to loss of enzyme function have lower levels of endoxifen and are at higher risk of breast cancer recurrence. Concomitant medications that inhibit the activity of CYP2D6 could potentially slow that metabolism and reduce plasma concentrations of the active form of TAM. This is of potential concern because of the large number of drugs that can inhibit CYP2D6, including many antidepressants, such as selective serotonin reuptake inhibitor antidepressants fluoxetine and paroxetine, which many women take to prevent hot flashes while receiving TAM.

Abstract CRA508: The first study, presented by Ronald Aubert, MD, PhD, was conducted by Medco Health Solutions and investigators at Indiana University School of Medicine. They analyzed an integrated research database of medical and pharmacy claims data for 10.7 million US health plan members and identified women with breast cancer new to TAM therapy in a 30-month period from 2003 to 2005. They then compared the risk of breast cancer recurrence as a function of concurrent use of potent and moderate inhibitors of CYP2D6. Importantly, however, they only included in their analysis patients with at least 2 years of follow-up data who were documented to have been adherent to treatment (medication possession ratio >70%) over that time period. A total of 1298 women were identified who met these criteria, of whom 945 received TAM alone and 353 received TAM concomitant with a CYP2D6 inhibitor. The median duration of concomitant use of a CYP2D6 inhibitor was 255 days. The study groups were well matched with respect to age (52 years and 53 years, respectively) and therapeutic interventions (mastectomy, lumpectomy, and radiation therapy were performed in a similar percentage of patients in each group). Patients receiving TAM plus a CYP2D6 inhibitor had a 2-year breast cancer recurrence rate of 13.9% compared with 7.5% in patients receiving TAM alone (HR = 1.92; P<.001). These findings support the presence of a clinically significant drug interaction between TAM and known CYP2D6 inhibitors, which resulted in nearly a 2-fold higher risk of recurrence over a 2-year period.

Abstract CRA509: Another very similar observational study reached the opposite conclusion. This study, presented by Vincent Dezentje, MD, of Leiden University Medical Center, was conducted in The Netherlands using data from PHARMO, a pharmacy database, PALGA, a nationwide pathology database, and the Dutch Medical Register. A total of 1990 patients with breast cancer who were treated with adjuvant TAM between 1994 and 2006 were included in the analysis. This study looked at event-free interval and attempted to correlate it with both concomitant use of CYP2D6 inhibitors and adherence to therapy. A Cox proportional hazards model with a time-dependent definition for exposure to CYP2D6 inhibitors was used. Contrary to the previous study, this analysis found no association between concomitant CYP2D6 inhibitor use and breast cancer recurrence. However, the investigators did find that poor adherence to TAM therapy was associated with reduced event-free interval. Poor compliance in this cohort of patients may have confounded the analysis of concomitant use of a CYP2D6 inhibitor.

Based on the conflicting data from these two studies, we still do not have a definitive answer about the impact of CYP2D6 inhibition in patients receiving TAM for breast cancer. However, until more conclusive data are available, caution was advised when prescribing moderate or potent CYP2D6 inhibitors to patients taking TAM.

Abstract 1: For many years, women with ovarian cancer who achieve a complete response to platinum-based chemotherapy have been routinely monitored for recurrence using the serum tumor marker CA125. This practice is based on evidence that CA125 often rises several months before patients develop clinical signs or symptoms of relapse. However, the long awaited results of the MRC OV05/EORTC 55955 trial, presented in the Plenary Session by Gordon Rustin, MD, of the Mount Vernon Cancer Center in the United Kingdom, do not support using serum CA125 levels to determine when patients should begin treatment for recurrence. Women with ovarian cancer in clinical complete remission after first-line platinum-based chemotherapy and a normal serum level of CA125 were registered, and CA125 was measured every 3 months. Patients and investigators were blinded to the test results. If serum CA125 levels exceeded twice the upper limit of normal, patients were randomized to either immediate treatment or to continued blinded CA125 measurements with treatment commencing only when clinical or symptomatic recurrence occurred. Patients in both arms were treated according to standard local practice, and the primary outcome measure was OS.

A total of 1442 patients were registered from 59 sites in 10 countries between 1996 and 2005. Median age at registration was 61 years, and 81% were FIGO stage III/IV. Randomization closed on March 31, 2008 with 527 patients randomized (264 to immediate treatment and 263 to delayed treatment). Baseline characteristics were well balanced between arms. Among patients randomized to immediate treatment, second-line chemotherapy started a median of 5 months earlier. However, at a median follow-up of 49 months from randomization and a total of 351 deaths, there was no evidence of a difference in OS between the immediate treatment and delayed treatment arms (HR = 1.01; P = .91).

Based on these results, which constitute level 1 evidence, the authors concluded that there is no value in the routine measurement of CA125 in the follow-up of patients with ovarian cancer. Nevertheless, it remains to be seen how this will be accepted in the community by oncologists and their patients.

Carboplatin plus paclitaxel is standard first-line therapy for ovarian cancer, while single-agent pegylated liposomal doxorubicin (PLD, Caelyx^®/DOXIL^®) is commonly prescribed for platinum-resistant ovarian cancer. Taxanes are associated with peripheral neuropathy that can adversely affect quality of life (QoL) early in the course of advanced ovarian cancer. Two large randomized cooperative group studies investigated the efficacy and safety of PLD combined with carboplatin in women with advanced ovarian cancer in newly diagnosed and platinum-sensitive ovarian cancer. This novel regimen could provide women with a new treatment option of equivalent efficacy with more acceptable toxicity.

Abstract LBA5508: The first of these 2 studies was the Multicentre Italian Trials in Ovarian Cancer (MITO-2) randomized phase III trial in patients with newly diagnosed ovarian cancer, presented by Sandro Pignata, MD, of the National Tumor Institute in Napoli. This trial randomized 820 patients (410 to each arm) with FIGO stage IC to stage IV disease between 2003 and 2007. Patients were randomized to receive either standard carboplatin (AUC 5) plus paclitaxel (175 mg/m² on day 1 q 21 days) (C+P) or carboplatin (AUC 5) plus PLD (30 mg/m² on day 1 q 21 days) (C+PLD) for up to 6 cycles. The primary endpoint was PFS. The median age was 57 years, and the majority of patients had FIGO stage III (60%) or IV (22%) disease at study entry. Greater than 80% of patients in both arms completed all 6 cycles. Among 290 patients evaluable by RECIST (≥1 target lesion), the objective response rate was 59% with C+P and 57% with C+PLD (P = .70). Among 182 patients with nontarget lesions only, complete response was 33% with C+P and 29% with C+PLD (P = .64). Although these regimens appear comparable in terms of response rate, the required number of events necessary to perform the primary analysis of PFS has not been reached. As of May 4, 2009, at a median follow-up of 35 months, 531 of the required 632 progression events have occurred. However, it is clear from the currently available data that these regimens each have a unique safety profile. The standard C+P regimen was associated with significantly more diarrhea, alopecia, and neurotoxicity compared with C+PLD, whereas C+PLD was associated with significantly more skin toxicity, stomatitis, and hematologic toxicity (particularly thrombocytopenia and anemia), which resulted in more treatment delays compared with C+P.

Based on these results, the authors concluded that C+PLD appears to have similar activity and a different safety profile compared with C+P as first-line therapy for ovarian cancer, but final conclusions must await results of the primary efficacy analysis.

Abstract LBA 5509: The second study, known as CALYPSO, presented by Eric Pujade-Lauraine, MD, PhD, of University Hospital Hotel-Dieu, Paris, was conducted by the Gynecologic Cancer InterGroup (GCIG), an international consortium of investigators, and evaluated the use of PLD in patients with relapsed platinum-sensitive ovarian cancer. The rationale for this study was based on evidence that PLD is superior to topotecan in relapsed platinum-sensitive ovarian cancer. This study compared standard carboplatin (AUC 5) plus paclitaxel (175 mg/m² on day 1 q 21 days) (C+P) with carboplatin (AUC 5) plus PLD (30 mg/m² on day 1 q 28 days) (C+PLD) for ≥6 cycles. Patients with recurrent disease >6 months after completing first-line or second-line platinum-based therapy (including a taxane) were eligible. As in MITO-2, the primary endpoint was PFS, and QoL was also evaluated. CALYPSO, which enrolled 976 patients between 2005 and 2007, is the largest study ever conducted in this patient population, and it has reached its primary endpoint. Greater than 85% of patients had FIGO stage III or IV disease, and >80% had received only 1 prior line of chemotherapy.

The analysis of PFS showed that C+PLD was significantly superior to C+P in this setting. At a median follow-up of 22 months, 85% of patients have progressed, and median PFS was 11.3 months with C+PLD versus 9.4 months with C+P (HR = 0.82; P = .005). Although C+PLD was associated with more frequent hand-foot syndrome, mucositis, nausea/vomiting, and thrombocytopenia compared with C+P, it was associated with significant less neurotoxicity and alopecia and less long-lasting neuropathy, which adversely affected QoL and led to more early treatment discontinuations in the C+P arm. Therefore, the authors concluded that the C+PLD regimen has a superior therapeutic index and provides an evidence-based alternative to C+P in patients with platinum-sensitive recurrent ovarian cancer.

Pazopanib: Expanding the Arsenal of Targeted Therapies for Renal Cell Carcinoma

Abstract 5021: Sunitinib, an oral multitargeted tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), has become established as the standard of care for first-line treatment of metastatic renal cell carcinoma (RCC). Pazopanib is an oral multikinase angiogenesis inhibitor that has also demonstrated promising activity in patients with advanced RCC. Cora Sternberg, MD, of San Camillo and Forlanini Hospital in Rome, presented data from a randomized phase III placebo-controlled study of pazopanib in 233 treatment-naïve and 202 cytokine-pretreated patients with advanced clear cell RCC. Patients were randomized 2:1 to pazopanib (800 mg/day; n = 290) or placebo (n = 145). The primary endpoint was PFS, and secondary endpoints included OS, response rate, and safety. Pazopanib significantly prolonged PFS in the overall study population (9.2 months vs 4.2 months, P<.001), in treatment-naive patients (11.1 months vs 2.8 months, P<.001), and in cytokine-pretreated patients (7.4 months vs 4.2 months, P<.001). The objective response rate was 30% with pazopanib versus 3% with placebo, and median duration of response was 58.7 weeks. Pazopanib was well tolerated; most adverse events were grade 1 or 2. The most common adverse events in pazopanib-treated patients were diarrhea, hypertension, hair color change, nausea, anorexia, and vomiting.

Based on the promising single-agent activity of pazopanib demonstrated in this trial, a large randomized international head-to-head comparative trial of pazopanib versus sunitinib has been initiated and will involve approximately 300 centers in the United States, Canada, Europe, Japan, and China. Defining appropriate patient profiles for use of the available multitargeted TKIs is of critical importance and thoughtful evaluation of efficacy and adverse event profiles will be necessary when choosing among treatment options.

Maximum benefit of platinum-based induction chemotherapy for non-small cell lung cancer (NSCLC) occurs with 4 to 6 cycles of therapy. Various strategies are being explored to extend that benefit. One approach that has been widely debated is administration of “maintenance” therapy to patients who have not progressed after 4 cycles of first-line chemotherapy. In the Lung Cancer Oral Session, 3 important studies investigating the role of maintenance therapy were presented.

Pemetrexed (Alimta^®) is a multitargeted antifolate with activity in the treatment of NSCLC, and it is approved for second-line treatment of NSCLC following standard platinum-based chemotherapy. However, that approval was recently limited to patients with non-squamous cell carcinoma based on evidence from randomized phase III trials indicating that the activity of pemetrexed is inferior to other chemotherapy agents in patients with squamous cell histology. Pemetrexed is also well tolerated with a low incidence of hematologic toxicity. Consequently, there has been considerable interest in the role of pemetrexed as maintenance therapy for patients who achieve a response to first-line platinum-based chemotherapy.

Abstract CRA8000: Chandra Belani, MD, of Penn State Hershey Cancer Institute in Pennsylvania, presented the results of a randomized phase III placebo-controlled trial investigating pemetrexed as maintenance therapy in patients with advanced stage IIIB/IV NSCLC who had not progressed after 4 cycles of standard platinum-based chemotherapy. A total of 663 patients were randomized 2:1 to receive pemetrexed (500 mg/m², day 1) plus best supportive care (BSC) or placebo plus BSC every 21 days until disease progression. Patients also received vitamin B₁₂, folic acid, and dexamethasone. The analysis of PFS and OS demonstrated a statistically significant benefit in favor of pemetrexed, which was primarily observed in the subset of patients with non-squamous cell histology. In the intent-to-treat (ITT) population, median PFS was 4.0 months with pemetrexed+BSC versus 2.0 months with placebo+BSC (HR = 0.6; P<.0001), and in the non-squamous cell subset median PFS was 4.4 months versus 1.8 months (HR = 0.47; P<.001). Overall survival was also significantly improved with pemetrexed both in the ITT population (P = .012) and non-squamous cell subset (P = .002). Drug-related grade 3/4 adverse events were infrequent (16% of patients treated with pemetrexed) and consisted mainly of fatigue (5%) and neutropenia (3%). This study clearly showed that pemetrexed is well tolerated and improves treatment outcomes compared with BSC in patients who respond to initial chemotherapy. It also provided further validation that the activity of pemetrexed is predicted by non-squamous cell histology. Therefore, the authors concluded that this should be the new treatment paradigm for non-squamous cell NSCLC that is stable or responding after 4 cycles of induction chemotherapy.

Abstracts 8001 and 8002: Erlotinib (Tarceva^®) is a small-molecule epidermal growth factor receptor (EGFR) TKI that has demonstrated prolonged survival versus placebo as second/third-line therapy in advanced NSCLC. Two similar studies have investigated whether the addition of erlotinib as maintenance therapy can improve clinical outcomes. The SATURN study investigated single-agent erlotinib, whereas the ATLAS study investigated the combination of bevacizumab plus erlotinib compared with bevacizumab alone. Both studies demonstrated a significant improvement in PFS when erlotinib was used as maintenance therapy. In the SATURN trial, erlotinib compared with placebo, significantly improved PFS by 29% in all patients (HR = 0.71; P<.0001) and by 31% in EGFR IHC+ patients (HR = 0.69; P<.0001) In the ATLAS trial the median PFS after randomization was 4.8 months for bevacizumab plus erlotinib versus 3.8 months for bevacizumab plus placebo (HR = 0.72; P = .0012). The benefit of erlotinib was independent of tumor histology. However, in both studies this was also associated with an increase in toxicity. Again, these studies raise the question whether maintenance therapy provides any real benefit compared to treating patients with erlotinib at disease progression. Moreover, neither of these studies has yet shown an OS benefit; the survival data are not yet mature.

Cappuzzo F, et al. J Clin Oncol. 2009;27(15S): Abstract 8001.
Miller VA, et al. J Clin Oncol. 2009;27(18S): Abstract 8002.

Nasser Hanna, MD, of Indiana University discussed these studies and gave his perspective with regard to the potential benefits of maintenance therapy. He indicated that the key clinical question is whether up-front maintenance therapy with either pemetrexed or erlotinib improves survival or QoL compared with delaying treatment with these agents until after patients progress (ie, in the second-line setting). In addition, it is important to consider whether patients are being overtreated and exposed to unnecessary added toxicity. Although maintenance pemetrexed was relatively well tolerated and did show a significant survival benefit compared with placebo, this study did not address whether maintenance pemetrexed provides a survival benefit compared with second-line pemetrexed after disease progression. In fact, he pointed out that patients in the placebo arm of this study who later received second-line pemetrexed survived as long as patients who received maintenance pemetrexed. The same question also applies to the SATURN and ATLAS studies and is particularly relevant to the combination of bevacizumab plus erlotinib, which resulted in substantial added toxicity. Moreover, neither of these studies showed an OS benefit. Therefore, unless maintenance therapy reduces disease symptoms or otherwise improves QoL, Dr Hanna suggested that it may be reasonable to delay further treatment until disease progression occurs, thereby affording the patient at least a brief holiday from treatment-related toxicity.

Abstract 4000: The QUASAR study, presented by David Kerr, MD, of Oxford University, was conducted to validate a quantitative multigene RT-PCR assay for prediction of recurrence and benefit of treatment with 5-fluorouracil/leucovorin (5FU/LV) in patients with stage II colon cancer. The goal is to develop new tools to improve risk assessment and guide treatment decisions. Genes were selected based on data from 4 development studies that enrolled a total of 1851 patients who were treated with either surgery alone or surgery plus 5FU/LV. Combined analysis of the 4 development studies identified 48 genes associated with recurrence risk, and 66 genes predictive of 5FU/LV benefit. Multivariate analysis in the context of stage, grade, nodes examined, and microsatellite instability (MSI) status identified 18 genes (7 prognostic genes, 6 predictive genes, and 5 reference genes) that were then used to develop 2 algorithms that would produce either a prognostic recurrence score (RS) or a predictive treatment score (TS).

In the QUASAR study, which enrolled 1490 patients with stage II colon cancer and available tissue blocks, RT-PCR was successful in 1436 eligible patients. Recurrence-free interval (RFI), disease-free survival (DFS), and OS were analyzed, and clinical outcomes were compared with the prognostic RS and predictive TS. In the primary analysis of patients following surgery, the prognostic RS accurately predicted recurrence risk (P = .004), DFS (P = .01), and OS (P = .04), and it retained prognostic significance in a multivariate analysis (P = .008). With respect to treatment outcomes, the benefit of treatment with 5FU/LV was statistically significant (P<.001); however, TS was not validated as a predictor of 5FU/LV benefit (interaction P = .19). Therefore, this study successfully validated the RS as a predictor of individualized recurrence risk following surgery, but the TS could not be validated as a predictor of treatment outcome. Nevertheless, the RS should provide important prognostic information to oncologists and help them determine which patients with stage II disease are at highest risk of recurrence following surgery and should receive further treatment with 5FU/LV. This information is extremely important for decision making since 75% to 80% of patients with stage II colon cancers are cured with surgery alone.

Gastric cancer is a leading cause of cancer mortality, particularly in Asia. Unfortunately, management of advanced-stage gastric cancer has improved relatively little, and there remains no standard therapy. In particular, no targeted therapies have thus far been successfully incorporated into treatment. However, there is mounting evidence that HER2 overexpression plays an important role in gastric cancer, more so in intestinal-type adenocarcinomas, and HER2 overexpression has been correlated with poor outcomes and more aggressive disease. Up to 35% of intestinal, but only about 6% of diffuse-type gastric cancers, overexpress HER2.

Abstract LBA4509: The ToGA study, presented by Eric Van Cutsem, MD, PhD, is the first randomized, prospective, multicenter, phase III trial to investigate the efficacy and safety of trastuzumab (Herceptin^®) in HER2-positive gastric cancer. Out of 3807 patients with gastroesophageal and gastric adenocarcinoma (locally advanced, recurrent, or metastatic) who were screened, 22% were found to be HER2-positive, and 594 patients were randomized to receive chemotherapy (5FU or capecitabine plus cisplatin q 3 weeks for 6 cycles) plus trastuzumab (8 mg/kg loading followed by 6 mg/kg q 3 weeks until progression) (n = 294) or chemotherapy alone for 6 cycles (n = 290). Treatment arms were well balanced for baseline characteristics, and approximately 75% of patients had intestinal-type adenocarcinoma. Importantly, the addition of trastuzumab to chemotherapy significantly improved OS compared to chemotherapy alone (13.8 months vs 11.1 months; HR = 0.74; P = .0046) and significantly improved all secondary endpoints, including objective response rate (47.3% vs 34.5%; P = .0017). Moreover, the addition of trastuzumab to chemotherapy did not result in a clinically significant increase in toxicity. There was no difference in symptomatic congestive heart failure between treatment arms, although asymptomatic left ventricular ejection fraction decreases were reported in 4.6% of patients in the trastuzumab arm compared with 1.1% in the chemotherapy alone arm. Therefore, trastuzumab plus standard chemotherapy is a well tolerated and effective new treatment option for HER2-positive gastric cancer. This study has important implications for the treatment of gastric cancer, and particularly in Asia where there is a higher incidence of the intestinal type gastric cancer.

Biliary tract cancers are uncommon but are associated with a very poor prognosis (5-year survival rate of 5% to 10%). Most patients present with inoperable disease, and to date there is no established standard of care for the treatment of advanced metastatic disease. An improvement in PFS with the combination of gemcitabine plus cisplatin (Gem+Cis) compared with gemcitabine (Gem, Gemzar^®) alone was recently reported based on the results of a randomized phase II trial (ABC-01) in 86 patients.

Abstract 4503: Based on those encouraging results, the UK ABC-02 trial, presented by Juan Valle, MD, of Christie Hospital in Manchester, United Kingdom, was initiated to expand the results of the earlier phase II trial and to assess OS as the primary endpoint. Between 2005 and 2008, 324 patients with histologically/cytologically-confirmed advanced biliary cancer were enrolled in ABC-02, and the combined analysis of 410 patients (Gem+Cis = 206; Gem = 204) treated on ABC-01 and ABC-02 was presented. At a median follow-up of 6.1 months and 263 deaths, median OS was significantly improved in the Gem+Cis arm compared with Gem alone (11.7 months vs 8.3 months; HR = 0.70; P = .002). Median PFS was also improved with Gem+Cis (8.4 months vs 6.5 months; HR = 0.72; P = .003). Toxicity was similar between treatment arms (approximately 65% of patients in both arms had at least 1 grade ≥3 adverse event), although there was a slight excess of neutropenia in the Gem+Cis arm. Given the clear survival benefit of Gem+Cis without clinically significant added toxicity, the authors concluded that this regimen should be the new international standard of care for advanced metastatic biliary tract cancer and should be the platform for further clinical investigation. It is noteworthy that this is the first trial to ever show a survival benefit in advanced biliary tract cancer.

Abstract LBA4: The benefit of combining bevacizumab with oxaliplatin plus 5FU/LV (FOLFOX) is well established in patients with metastatic (stage IV) colon cancer, and there is currently great interest in exploring whether this regimen can improve DFS in the adjuvant setting in patients with stage II or stage III colon cancer. National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-08, presented by Norman Wolmark, MD, of Allegheny General Hospital in Pittsburgh, is the first of several studies investigating the potential role of bevacizumab in the adjuvant setting. This large multicenter trial enrolled more than 2600 patients between 2004 and 2006, and patients were randomized to receive either a modified FOLFOX regimen for 6 months (mFOLFOX6) or mFOLFOX6+bevacizumab (5 mg/kg q 2 weeks for 1 year). Although this combination was relatively well tolerated, at a median follow-up of 3 years (the prespecified analysis), there was no statistically significant improvement in DFS among patients receiving mFOLFOX6+bevacizumab (HR = 0.89; P = .15). There was, however, a transient statistically significant DFS benefit at 1 year (HR = 0.6; P = .0004) in the bevacizumab+mFOLFOX6 arm, suggesting that bevacizumab provides benefit only for as long as it is administered. Dr Wolmark suggested that longer duration of adjuvant therapy with bevacizumab may provide greater benefit. The results of the ongoing AVANT BO17920 study, which has a similar design, are eagerly awaited.

OTHER PRIME ACTIVITIES
	These independent medical education activities feature Expert Interviews focusing on important data from the recent oncology literature, with topics spanning Breast Cancer, GIST, and CML. Go to the Virtual Journal Club
	European Gynecologic Oncology Congress 26-27 June, 2009 \| Dublin, Ireland