primeLINES CLINICAL OPINION POLL

AUGUST 2010 Issue

FROM THE LITERATURE

Sorafenib for Gastric Cancer: Interesting Activity But What Is the Target?

Although many cytotoxic agents show activity in advanced gastric cancer, either as single agents or in combination, with response rates of approximately 20% to 40%, the overall benefit is still disappointing, and median survival is approximately 10 months. Thus, the development of targeted therapies is an important priority in the treatment of gastric cancer, and the proof of concept is significantly improved progression-free survival (PFS) and overall survival (OS) with the use of targeted therapy plus trastuzumab in patients with HER2-positive gastric cancer. Targeting other important pathways to inhibit tumor growth, eg, angiogenesis, has provided new important therapeutic options for cancers such as renal cell carcinoma and hepatocellular carcinoma. One such anti-angiogenic agent is sorafenib, a multitargeted tyrosine kinase inhibitor (TKI) that targets Raf, the vascular endothelial growth factor receptors (VEGFR1, 2, and 3), and the platelet-derived growth factor receptor-beta (PDGFR-β).

Eastern Cooperative Oncology Group study 5203 (E5203), a small phase II study involving 44 chemotherapy-naïve patients with metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction (~20% of patients had locally advanced disease), was designed to determine the efficacy and toxicity of sorafenib with docetaxel and cisplatin. The study demonstrated a 41% partial response rate, median PFS of 5.8 months, and median OS of 13.6 months (11.3 months for patients with metastatic disease). The authors concluded that this regimen has an encouraging efficacy profile and suggested that sorafenib may have a role in the treatment of advanced gastric cancer and warrants further study.

In the accompanying editorial, Lawrence Leichman critically reviewed the data from this study. He pointed out that the observed median PFS and OS were not particularly striking compared with studies combining 5-fluorouracil with a platinum agent or a taxane/platinum doublet. He also questioned the rationale for combining sorafenib with chemotherapy in gastric cancer and highlighted that the investigators in this trial appeared to be betting on a targeted agent without first defining the target. He addressed the idea that, in the era of personalized medicine, trials should be designed “smart” and all efforts should be made to include translational research.

J Clin Oncol. 2010;28(18):2947-2951.

J Clin Oncol. 2010;28(18):2937-2938.

Neoadjuvant Chemotherapy Not the Best Choice for Invasive Classical Lobular Breast Cancer

In the “Comments and Controversies” section of the August 1 issue of the Journal of Clinical Oncology, Arnie Purushotham and colleagues review evidence suggesting that endocrine therapy, rather than chemotherapy, may be the best neoadjuvant approach for patients with estrogen receptor (ER)–positive, HER2-negative, classical type invasive lobular breast cancer. These tumors are nearly always ER-positive (up to 93%) and rarely HER2-positive (11%). In contrast to invasive ductal carcinoma, these tumors exhibit a low rate of pathologic complete response to neoadjuvant chemotherapy and a correspondingly low rate of successful breast conserving surgery. The available evidence also suggests that neoadjuvant chemotherapy is associated with a higher rate of positive surgical margins in women with invasive lobular carcinoma. However, the majority of these data come from retrospective analyses. Unfortunately, none of the three large prospective studies of neoadjuvant endocrine therapy for breast cancer (P024 conducted by the Letrozole Neoadjuvant Breast Cancer Study Group, IMPACT [Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen], and PROACT [Pre-Operative “Arimidex” Compared to Tamoxifen]) analyzed histologic type–specific effectiveness of neoadjuvant therapy (ie, lobular vs ductal carcinoma). Thus, prospective data regarding this small subset of patients are sparse. Nevertheless, the authors argue that the available evidence consistently shows that lobular carcinoma is biologically distinct from ductal carcinoma of the breast. In light of all reviewed evidence, the authors argue that “in the era of tailored therapy for individual patients, we would no longer routinely recommend neoadjuvant chemotherapy in patients with ER-positive, HER2-negative, classical type invasive lobular carcinoma.”

J Clin Oncol. 2010;28(22):3552-3554.

Charting the Metastatic Behavior of Breast Cancer Subtypes

Gene expression profiling of early breast cancer has identified 6 distinct “intrinsic” subtypes described as luminal A, luminal B, luminal/HER2-positive, HER2-enriched, basal-like, and triple-negative (TN) nonbasal. The luminal subtypes are all hormone receptor–positive, and the others are hormone receptor–negative. The basal-like and TN tumors express neither hormone receptors nor HER2. These 6 subtypes are all biologically distinct and associated with a differential risk for disease recurrence in the adjuvant setting, but less is known about their metastatic behavior. In this study, the authors characterized tumors from 3726 eligible patients with a median follow-up of 14.8 years according to intrinsic subtype and then examined sites of metastasis (brain, liver, lung, bone, distant nodal, pleural/peritoneal, or other) and survival outcomes. Competing risk methods were used to analyze the cumulative risk of metastasis to various sites, and the association between subtype and site(s) of metastasis was analyzed using multivariate logistic regression models.

As might be expected, these breast cancer subtypes were associated with distinct patterns of metastatic spread with notable differences in survival after metastatic disease recurrence. Compared with luminal A tumors, luminal/HER2-positive and HER2-enriched tumors were associated with a significantly higher incidence of brain, liver, and lung metastases. Basal-like tumors had a higher incidence of brain, lung, and distant nodal metastases but a significantly lower incidence of liver and bone metastases, whereas TN nonbasal tumors demonstrated a similar pattern but with fewer liver metastases. Notable survival differences were also observed. Median OS from diagnosis of distant metastasis was 2.2 years for luminal A, 1.6 years for luminal B, 1.3 years for luminal/HER2-positive, 0.7 years for HER2-enriched, 0.5 years for basal-like tumors, and 0.9 years for TN nonbasal. The authors concluded that a better understanding of these patterns of metastatic spread may influence adjuvant therapy and surveillance decisions.

J Clin Oncol. 2010;28(20):3271-3277.

Can Oral Bisphosphonates Really Reduce the Risk of Breast Cancer in Healthy Women?

That is the question posed by Michael Gnant in his editorial based on 2 reports in the August 1 issue of the Journal of Clinical Oncology. The 2 observational studies reported in the June issue add yet another dimension to the growing body of evidence that bisphosphonates, as a class, have potent anticancer activity.

Rowan Chlebowski and colleagues reported the results of a multivariate analysis of longitudinal data from the Women’s Health Initiative Observational Study (WHI-OS), which included a total of 154,768 postmenopausal women. Their analysis compared a group of 2816 women receiving bisphosphonates (90% oral alendronate) for the treatment of osteoporosis versus 151,952 women not receiving bisphosphonates. At a mean follow-up of nearly 8 years, bisphosphonate users had a 32% lower incidence of invasive breast cancer compared with non-users (hazard ratio [HR] = 0.68; P>.01), and the risk reduction was similar for both ER-positive and ER-negative invasive cancers. Interestingly, bisphosphonate users had a higher incidence of ductal carcinoma in situ (HR = 1.58; P = .02).

Gad Rennert and colleagues reported similar results from an analysis of the ongoing Breast Cancer in Northern Israel Study (BCINIS) involving 4039 postmenopausal women. As in the previous study, the authors controlled for a wide range of prognostic factors, and in this study they also analyzed the data by duration of bisphosphonate use (87% oral alendronate). The conclusion was that use of bisphosphonates for >1 year was associated with a statistically significant 28% relative reduction in the risk of developing breast cancer (HR = 0.72) and that bisphosphonate users tended to develop tumors with a more favorable prognosis. These results are further supported by a third study reported earlier this year by Newcomb et al (Br J Cancer. 2010;102(5):799-802.) showing a 33% relative reduction in the risk of breast cancer among bisphosphonate users.

Although these data are strikingly consistent, Dr Gnant cautioned that because of the potential that these results could be confounded by a wide range of interrelated risk factors, in the absence of data from prospectively randomized trials, these results should be “viewed as hypothesis generating and not practice changing at this time.” However, based on these data, he suggested that it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy, in addition to its bone-protecting effects, when evaluating treatment options in women with postmenopausal osteoporosis, especially considering that bisphosphonates are generally well tolerated. Further translational research is needed to understand the underlying anticancer mechanisms by which targeting the bone microenvironment with a bisphosphonate could affect early stages in the development of invasive breast cancer.

J Clin Oncol. 2010;28)22):3582-3590.

J Clin Oncol. 2010;28(22):3577-3581.

J Clin Oncol. 2010;28(22):3548-3551.

Clinical Relevance of Trastuzumab-Related Cardiotoxicity

The incorporation of trastuzumab into adjuvant chemotherapy regimens for patients with HER2-positive early breast cancer has been a major clinical advance that has changed the course of disease for these patients. Long-term assessments of trastuzumab-related cardiotoxicity in patients receiving adjuvant chemotherapy with an anthracycline-based regimen have been reported from the HERceptin Adjuvant (HERA) trial and a combined independent review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and the North Central Cancer Treatment Group (NCCTG) N9831 clinical trials. Both reports showed an overall low incidence of cardiac events, consisting mainly of a significant (≥10%) decrease in left ventricular ejection fraction (LVEF), and the majority of events were completely or partially reversible. The report by Procter et al showed that in the HERA trial, at a median follow-up of 3.6 years, the incidence of significant LVEF decrease was 3.6% with trastuzumab versus 0.6% without, and congestive heart failure occurred in 1.9% of trastuzumab-treated patients compared to 0.1% in the control group. Complete or partial recovery occurred in 59 of 73 patients (81%) with a cardiac event, and no cardiac deaths were attributed to trastuzumab. Similarly, Russell et al reported that in the NSABP B31 and NCCTG N9831 trials, trastuzumab-treated patients had a 2.0% incidence of symptomatic heart failure events compared to 0.45% in the chemotherapy-alone arm at a median follow-up of 2 years, and 86% had a complete or partial recovery. Patrick Morris and Cliff Hudis commented in the accompanying editorial that these reports are reassuring and suggest that long-term cardiotoxicity associated with the use of trastuzumab following anthracycline-based chemotherapy is relatively infrequent and associated with a favorable outcome. Therefore, patients with normal baseline LVEF can be safely treated with these regimens. However, they highlighted that confirmation of the equivalent efficacy of a non-anthracycline regimen will be important as will the development of biomarkers to predict cardiotoxicity.

J Clin Oncol. 2010;28(21):3422-3428.

J Clin Oncol. 2010;28(21):3416-3421.

J Clin Oncol. 2010;28(21):3407-3410.

Exploring the Role of Gefitinib in Locally Advanced Head and Neck Cancer

Overexpression of the epidermal growth factor receptor (EGFR), often due to gene amplification, occurs frequently in squamous cell carcinoma of the head and neck (SCCHN), and cetuximab, an anti-EGFR monoclonal antibody, has been shown to improve OS when combined with radiotherapy in patients with locally advanced SCCHN. In a phase II study recently reported by Ezra Cohen and colleagues, gefitinib, a small-molecule inhibitor of EGFR, was added to concurrent chemoradiotherapy (CCRT) and thereafter as maintenance therapy. The authors noted that gefitinib had demonstrated radiosensitizing effects in preclinical models, and they hypothesized that gefitinib would be a less toxic radiation sensitizer than paclitaxel. This study was undertaken to test the feasibility of combining gefitinib with CCRT and to determine if gefitinib could decrease failure rates. The primary endpoint was complete response (CR) rate after CCRT, but the study also looked at PFS and OS and whether EGFR gene copy number correlated with clinical outcome.

A total of 69 patients with stage III or IV locally advanced SCCHN received 2 cycles of carboplatin/paclitaxel induction chemotherapy followed by CCRT with fluorouracil, hydroxyurea, and twice daily radiotherapy (FHX) plus gefitinib (250 mg/day) followed by continued gefitinib for up to 2 years. The CR rate after CCRT was 88%. At a median follow-up of 3.5 years, the 4-year PFS rate was 72% and the 4-year OS rate was 74%. Moreover, the 4-year disease-specific survival rate was 89%. However, among 31 patients with available tissue, high EGFR gene copy number was a poor prognostic feature in this study, associated with worse OS (P = .02), suggesting that addition of gefitinib may not overcome resistance to treatment mediated by EGFR overexpression. The authors concluded that addition of gefitinib to FHX is feasible, and that the observed CR and OS rates compared favorably with prior experience.

J Clin Oncol. 2010;28(20):3336-3343.

Emerging Options for the Treatment of Relapsed, Platinum-Sensitive, Ovarian Cancer

Ovarian cancer ranks fifth among causes of cancer-related deaths in US women, and approximately 70% of patients will have advanced disease at diagnosis. Although it is highly sensitive to initial platinum-based chemotherapy, with response rates in the range of 70% to 80%, the majority of patients will relapse. Patients who respond well to initial chemotherapy and develop a recurrence more than 6 months after first-line treatment are more likely to be platinum-sensitive and to respond to retreatment with a platinum and taxane containing combination. The recently published phase III CALYPSO study showed that the combination of pegylated liposomal doxorubicin (PLD) plus carboplatin significantly improved PFS with less toxicity compared with paclitaxel plus carboplatin (J Clin Oncol. 2010;28(20):3323-3329.). In another phase III study, trabectedin, a novel cytotoxic drug that interferes with nucleotide excision repair, in combination with PLD, also demonstrated promising activity in platinum-sensitive, relapsed, ovarian cancer (J Clin Oncol. 2010;28(19):3107-3114). The most recent addition to the novel agents being investigated in relapsed ovarian cancer is farletuzumab (MORAb-003), a humanized monoclonal antibody against folate receptor alpha, which is overexpressed in ~90% of ovarian cancers and is rarely expressed on normal tissue.

In a review article in Community Oncology, Deborah Armstrong discussed the potential of farletuzumab in the treatment of relapsed ovarian cancer. Much of the excitement about this novel agent is based on data from a phase II study presented at the 2010 Annual Oncology Meeting in Chicago investigating the activity of farletuzumab as a single agent and in combination with platinum/taxane chemotherapy in patients with platinum-sensitive ovarian cancer at first relapse. The outcomes of the combination in this study were striking in several respects. First, among 44 evaluable patients, this regimen normalized CA125 in 89% and produced an objective response by RECIST in 70% of patients. Second, in 21% of treated patients, the duration of second remission was equal to or longer than their first remission, which is rare in this disease. Based on these encouraging results, 2 important studies of farletuzumab are ongoing. The FAR-131 study is a multicenter, double-blind, randomized, phase III trial that will test whether treatment with farletuzumab following standard platinum-based chemotherapy can improve PFS and OS in patients with platinum-sensitive relapsed disease. This study plans to enroll approximately 900 patients worldwide who will first receive 6 cycles of carboplatin plus either paclitaxel or docetaxel every 3 weeks. Patients will then be randomized to 1 of 2 doses of farletuzumab (1.25 mg/kg or 2.5 mg/kg weekly) or placebo. In addition, a placebo-controlled phase II study is currently investigating the benefit of adding farletuzumab following paclitaxel in patients with platinum resistant/refractory ovarian cancer (J Clin Oncol. 2010;28(15S): Abstract TPS255.). Pending the results of these ongoing studies, treatment for advanced ovarian cancer will likely include targeted agents in the near future.

Community Oncology. 2010;7(2 Suppl 1):1-4.

J Clin Oncol. 2010;28(15S): Abstract 5001.