NEWS FROM THE EUROPEAN MULTIDISCIPLINARY CANCER CONGRESS (ECCO/ESMO/ESTRO)

On September 23-27, Stockholm, Sweden, hosted the European Multidisciplinary Cancer Congress (EMCC), jointly organized by the European CanCer Organization (ECCO), the European Society of Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO). Approximately 16,000 scientists, doctors, nurses, patients, caregivers, and industry representatives from 116 countries attended. The renaming and rebranding of this important oncology congress with the tagline Integrating basic & translational science, surgery, radiotherapy, medical oncology & care reflects the diverse perspectives of its member organizations. It is the only cancer congress in Europe to offer presentations of cutting-edge research across the entire field of oncology.

Targeting the Hedgehog Pathway: A Potential New Treatment Option for Advanced Basal Cell Carcinoma

The first-in-class small-molecule inhibitor of Hedgehog signaling, vismodegib, induced objective responses in 43% of patients with locally advanced basal cell carcinoma (BCC) and in 30% of patients with metastatic BCC (by independent review). Although most BCCs can be effectively treated with surgery, about 5% become locally advanced or metastatic, for which there are no effective treatment options. Disruption of the Hedgehog signaling pathway was found in approximately 90% of basal cell carcinomas, and its inhibition with vismodegib in a phase I study yielded a 55% response rate in 33 patients with advanced BCC. Based on this encouraging result, a multicenter pivotal phase II trial of vismodegib was initiated, which enrolled 104 patients with locally advanced and metastatic BCC who received oral vismodegib 150 mg daily until progression or withdrawal from the study. This study showed an impressive response rate and a median time to progression of 9.5 months. Vismodegib was relatively well tolerated; adverse events occurring in >30% of patients were muscle spasms, alopecia, taste disturbance, weight loss, and fatigue, and only 4 patients experienced serious adverse events considered related to vismodegib. Caroline Robert, MD, PhD (Institut Gustave Roussy, Paris, France), who discussed this abstract at EMCC, highlighted that vismodegib truly represents a breakthrough for the treatment of advanced BCC but wondered if long-term tolerance may be an issue.

Dirix L, et al. Eur J Cancer. 2011;47(Suppl 2): Abstract 1BA.

Radium-223 Chloride Improves Survival in CRPC Patients with Bone Metastases

Interim results of the randomized, phase III ALSYMPCA trial of the alpha particle–emitting drug radium-223 chloride (Alpharadin) in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases demonstrated a significant overall survival (OS) benefit. Radium-223 chloride is taken up by the bone, and it targets bone metastases with high-energy alpha particles of extremely short range (<100 μm or 2-10 cell diameters), thus limiting damage to healthy tissue. The phase III trial enrolled 922 patients who were randomized 2:1 to receive up to 6 injections of radium-223 (50 kBq/kg IV) or matching placebo every 4 weeks. The preplanned interim analysis showed a median OS of 14.0 months for radium-223 chloride and 11.2 months for placebo (P = .002; HR = 0.695). Based on these results, the Independent Data Monitoring Committee recommended the trial be stopped early and patients receiving placebo were able to crossover to radium-223 chloride. In his discussion, Wim Oyen, MD, PhD (Radboud University Nijmegen Medical Center, Nijmegen, Netherlands), highlighted that radium-223 chloride represents a very effective, well tolerated, and convenient treatment modality that has impact on survival. He pointed out that now we need to consider its best sequence or combination with other recently approved effective therapies for CRCP and further exploration in adjuvant setting for high-risk prostate cancer. Radium-223 chloride is currently fast-tracked for US Food and Drug Administration (FDA) approval in mid-2012.

Parker C, et al. Eur J Cancer. 2011;47(Suppl 2): Abstract 1LBA.

Sustained Survival Benefit of Aflibercept in Subgroups of Metastatic Colorectal Cancer Patients

Addition of aflibercept (a VEGF-trap) to FOLFIRI significantly improved OS and PFS in patients with metastatic colorectal cancer (CRC) previously treated with oxaliplatin, and these benefits were consistent across patient subgroups, including patients who previously received bevacizumab. The results of the randomized, phase III VELOUR trial, first reported at the ESMO World Congress on Gastrointestinal Cancer meeting earlier this year (abstract O-0024), showed that addition of aflibercept to chemotherapy significantly improved OS (13.5 months versus 12.1 months; P = .003) and progression-free survival (6.9 months versus 4.7 months; P<.001) compared with chemotherapy alone. Interaction between treatment and patient subgroups regarding efficacy outcome was tested in prespecified subgroup analyses, which were presented at EMCC. Interestingly, the subgroup analyses showed survival benefits associated with aflibercept to be consistent irrespective of patients' performance status, prior bevacizumab exposure, age, gender, geographic region, prior hypertension, number of metastatic sites, or primary cancer location. Patients with isolated liver metastasis appeared to derive more benefits from aflibercept than those with no liver metastasis or those with disease not confined to the liver (P = .090 and P = .008 for interaction, respectively). The authors concluded that prespecified subgroup analyses confirmed the robustness of the efficacy results. In his discussion, David Kerr, MD (University of Oxford, Oxford Radcliffe Hospitals Trust, Oxford, United Kingdom), said that introduction of aflibercept changed the landscape of mCRC and we now have a new agent to consider for those patients who progress following front-line treatment with FOLFOX +/- bevacizumab.

Tabernero J, et al. Eur J Cancer. 2011;47(Suppl 2): Abstract 6LBA.

Trastuzumab-DM1 is Superior to Standard Therapy for HER2-Positive Metastatic Breast Cancer

Trastuzumab-guided chemotherapy with trastuzumab-DM1 significantly improved PFS compared with standard first-line therapy of trastuzumab plus docetaxel in patients with metastatic HER2-positive breast cancer. The results of a randomized, multicenter, open-label phase II trial demonstrated that patients treated with trastuzumab-DM1 had a median PFS of 14.2 months versus 9.2 months for patients receiving standard regimen of trastuzumab plus docetaxel (HR = 0.59; P = .035). Although the objective response rate was similar between treatment groups, trastuzumab-DM1 was associated with more durable responses. In addition, trastuzumab-DM1 was also better tolerated, and patients stayed on therapy twice as long. Consistent with previous reports, grade ≥3 adverse events were reported less frequently in the trastuzumab-DM1 arm (46.4% versus 89.4%). The beauty of this antibody-drug conjugate is that the cytotoxic agent (emtansine, often referred to as a derivative of maytansine) is attached to trastuzumab via a stable linker and is released only after trastuzumab has been internalized by a HER2-positive cell. Intracellular delivery of the cytotoxic agent DM1 explains why there were fewer side effects experienced by patients who received trastuzumab-DM1 than by those assigned to the chemotherapy-containing control arm. In her discussion, Martine Piccart-Gebhart, MD, PhD (Jules Bordet Institute, Brussels, Belgium), agreed that these are important and exciting results, but she cautioned that validation from a large phase III trial is needed.

Hurvitz S, et al. Eur J Cancer. 2011;47(Suppl 1): Abstract 5001.

Everolimus Reverses Endocrine Therapy Resistance in Advanced Breast Cancer

The addition of everolimus to exemestane dramatically prolonged PFS in postmenopausal women with advanced ER-positive breast cancer who had failed other hormonal therapies, including letrozole or anastrozole. These results are from the randomized, placebo-controlled, phase III BOLERO-2 trial that enrolled 724 patients in 24 countries. Based on central review, median PFS was improved by nearly 7 months (10.6 months versus 4.1 months; HR = 0.36; P = 3.3 x 10^-15). The objective response rate was also significantly improved in the combination arm (9.5% versus 0.4%; P<.0001). The trial was halted after an interim analysis in February showed overwhelming efficacy. Overall survival data were immature after 83 deaths, with comparable rates of death in everolimus and placebo arms (10.6% vs 13.0%). The combination of everolimus and exemestane was associated with an increased incidence of stomatitis, anemia, dyspnea, hyperglycemia, fatigue, and pneumonitis compared with exemestane alone, but was generally well tolerated. Professor José Baselga from the Massachusetts General Hospital and Harvard Medical School, who presented the trial, said "these results are impressive and, potentially, could represent a new therapeutic option for women with advanced postmenopausal breast cancer who have previously been treated with hormonal therapy." In his discussion, Fabrice André, MD, PhD (Institut Gustave Roussy, Villejuif, France), shared the enthusiasm about the trial results and stated that results of the BOLERO-2 trial are robust and clinically relevant and "in the range of the most important advances in medical oncology."

Baselga J, et al. Eur J Cancer. 2011;47(Suppl 2): Abstract 9LBA.

FROM THE LITERATURE

Eribulin Active in Prostate Cancer

In a phase II study of 108 patients with metastatic CRPC, eribulin mesylate demonstrated ≥50% PSA response in 22.4% and 8.5% of taxane-naïve and taxane-pretreated patients, respectively, and it showed a favorable safety profile. Given the important role of docetaxel in the treatment of metastatic CRPC, novel agents in this class continue to be explored. Eribulin mesylate is a synthetic analog of halichondrin B, a natural product derived from a deep sea sponge, with a unique binding site on β-tubulin; it has demonstrated preclinical activity against prostate cancer and cancer cells that are resistant to taxanes due to β-tubulin mutations. Eribulin was recently approved for heavily pretreated patients with metastatic breast cancer based on survival benefit in this patient population. In this study, eribulin was given as single-agent therapy (1.4 mg/m² IV day 1, 8 every 3 weeks) without prednisone and steroid premedication. The most common grade 3/4 adverse event associated with eribulin therapy was neutropenia (30.5%), although febrile neutropenia was seen in only 3.7%. Peripheral neuropathy was rare (13.9%), with grade 3 in only 2.8%, and no grade 4. The authors also reported an objective response by RECIST in 15.2% of taxane-naïve patients with measurable disease. They concluded that the observed antitumor activity and favorable safety profile of eribulin warrants further studies in comparison with currently employed agents, particularly in patients with CRPC who have poorer performance status or comorbidities.

Ann Oncol. 2011 Sep 7. [Epub ahead of print].

Sizing Up Mutant BRAF as a Potential Target in Non-Small Cell Lung Cancer

The authors of this report examined a retrospective series of 1046 non-small cell lung cancers (NSCLCs) (739 adenocarcinomas and 307 squamous cell carcinomas) and found BRAF mutations in 5% of adenocarcinomas, the majority of which were V600E mutations. Excitement over the potential of BRAF as a molecular target in oncology was sparked by recent reports of high response rates in BRAF-mutant melanoma treated with vemurafenib, a small molecule inhibitor that specifically targets the BRAF V600E mutation. The study reported here sought to determine the frequency and prognostic significance of BRAF mutations in NSCLC. Although the frequency of BRAF mutations was low (4.9% in adenocarcinoma and 0.3% in squamous cell carcinoma), 57% of those mutations were V600E. The authors also showed that V600E mutations were associated with aggressive histology and micropapillary features in 80% of patients and were significantly associated with shorter disease-free and overall survival rates. These mutations were also found predominantly in female nonsmokers. Non V600E mutations were found more commonly in smokers and were not associated with prognosis. These findings might have important implications with regard to the selection of NSCLC patients carrying BRAF mutations for clinical trials.

J Clin Oncol. 2011;29(26):3574-3579.

Safety and Efficacy of Sorafenib Plus TACE Paves the Way for SPACE

A single-center, phase II study showed that sorafenib (400 mg twice daily) in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) in patients with advanced, unresectable hepatocellular carcinoma (HCC) appears to be safe and well tolerated. The rationale for this combination is based on the observation that TACE, although quite effective for local tumor control in patients with unresectable HCC, results in upregulation of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGFR), which increases tumor angiogenesis and may contribute to the high rate of tumor recurrence following TACE. Coadministration of sorafenib may block these proangiogenic signals and help to prevent local recurrence and distant metastasis. The toxicities observed in the phase II study reported by Pawlik et al were consistent with the known safety profile of sorafenib (primarily fatigue, anorexia, liver enzyme elevation, and rash). Moreover, the disease control rate was 95% by RECIST, and 58% of patients had an objective response by European Association for the Study of the Liver (EASL) response criteria. These results provide support for two ongoing, randomized, placebo-controlled trials of this combination. The SPACE (Sorafenib or Placebo in Combination With TACE) trial and Eastern Cooperative Oncology Group (ECOG) trial 1208 are investigating whether addition of sorafenib to conventional TACE or DEB-TACE can improve time to tumor progression or progression-free survival in patients with advanced, unresectable HCC. The SPACE trial incorporates continuous dosing, whereas the ECOG 1208 trial uses an interrupted schedule of sorafenib.

In an accompanying editorial, Ghassan Abou-Alfa, MD (Memorial Sloan-Kettering Cancer Center, New York, New York), suggests that the combination of local therapy with TACE and systemic therapy with sorafenib in advanced HCC may be a "good marriage," but it should remain investigational. However, the Pawlik study is an important prelude to the ongoing randomized studies that would hopefully define some controversial issues, such as definition of efficacy and response assessment. He also highlighted complexity of HCC and a need to refine continuously the therapeutic strategies based on a better understanding of the biology of HCC.

J Clin Oncol. 2011;29(30):3960-3967.

J Clin Oncol. 2011;29(30):3949-3952. (Editorial)

ADDITIONAL PUBLICATIONS WORTH READING

• ASCO Endorses Cancer Care Ontario (CCO) Practice Guidelines on Adjuvant Ovarian Ablation . Based on these guidelines the key recommendations for Ovarian Ablation (OA) in premenopausal women with early-stage invasive breast cancer are: (1) OA is not recommended either as an addition to systemic therapy or as an alternative to systemic therapy; (2) OA should be considered only for women who will not receive systemic therapy (eg, those patients who cannot tolerate, or who refuse, systemic therapy); (3) when LHRH agonists are considered, monthly injection was the modality suggested by CCO, but the ASCO ad hoc ovarian ablation guideline review panel suggests that treatment every 3 months may also be efficacious on the basis of emerging data; and (4) complete ovarian suppression may not be achieved with LHRH agonists. J Clin Oncol. 2011;29(29):3939-3942.
• Better Systemic Therapies Needed for Unresectable Malignant Mesothelioma. This review summarizes current treatment options for advanced mesothelioma and the need for developing more personalized therapy based on validated prognostic and predictive biomarkers. The current standard of care is pemetrexed and cisplatin, but survival outcomes are suboptimal, and no standard second-line therapy has emerged. To date, the development of effective targeted agents has been disappointing. Lung Cancer. 2011;73(3):256-263.
• Personalized Medicine for Non-Small Cell Lung Cancer. Tremendous progress has been made in recent years toward identifying and exploiting key targets for the treatment of NSCLC, including EGFR and ALK. Four key areas of knowledge that are essential to the development of targeted therapy for NSCLC are discussed in this review: knowing the target, identifying a biomarker, establishing relevant clinical endpoints, and understanding the potential mechanisms of resistance. Nat Rev Clin Oncol. 2011 Aug 23. [Epub ahead of print].

UPCOMING prIME EVENTS

OTHER prIME ACTIVITIES