p r i m e l i n e s

Trabectedin and Pegylated Liposomal Doxorubicin: New Treatment Option
for Relapsed Ovarian Cancer

On September 24, the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use rendered a positive opinion recommending marketing authorization for PharmaMar’s trabectedin (Yondelis^®) in combination with pegylated liposomal doxorubicin for the treatment of patients with relapsed platinum-sensitive ovarian cancer. In contrast, the US Food and Drug Administration (FDA) Oncology Drugs Advisory Committee, in July, nearly unanimously voted against approval on the grounds that the benefits do not outweigh the risks. In Europe, but not in the United States, trabectedin is also approved for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracylines and ifosfamide or who are unsuited to receive these agents.

On September 25, the FDA approved pralatrexate (Folotyn^®) for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL), a rare form of non-Hodgkin lymphoma (NHL) affecting about 9500 patients in the United States each year. The drug also received orphan drug status. Accelerated approval was based on evidence of durable responses in a phase II study, which allowed some patients to receive potentially curative allogeneic stem cell transplants, and this was considered reasonably likely to predict a clinical benefit. Of 109 evaluable patients, 27% had an objective response.

On September 4, ibritumomab tiuxetan (Zevalin^®) received a supplemental indication for use as part of first-line therapy for the treatment of patients with follicular NHL based on data from the FIT (First-line Indolent Trial) study. At 3.5 years of follow-up, results from FIT demonstrated that the addition of ibritumomab tiuxetan significantly improved median progression-free survival (PFS) in patients who achieved a complete response (CR) or partial response (PR) to first-line chemotherapy (38 months versus 18 months; P<.0001). Ibritumomab tiuxetan had been previously approved only for relapsed or refractory follicular NHL.

Approximately 15,000 oncologists gathered September 20-24 in Berlin, Germany, for the joint 15th Congress of the European CanCer Organisation and the 34th Congress of the European Society for Medical Oncology (ECCO/ESMO). Highlights of the meeting are summarized below, including several late breaking abstracts.

Several major developments were reported at ECCO/ESMO regarding the treatment of breast cancer. José Baselga, MD (Vall d'Hebron University Hospital, Barcelona, Spain) presented the results of the SOLTI-0701 trial (Abstract 3LBA). This was a randomized, placebo-controlled, phase IIb trial of sorafenib (Nexavar^®) plus capecitabine (Xeloda^®) in patients with locally advanced or metastatic HER2-negative breast cancer. In this study, the combination of sorafenib (400 mg bid) and capecitabine (1000 mg/m² bid for 14 of 21 days) was shown to significantly prolong PFS compared to capecitabine plus placebo (median 6.4 months versus 4.1 months; hazard ratio = 0.58; P = .0006). Combination therapy was tolerable with clinically manageable toxicities. This is the first study to show a significant clinical benefit with sorafenib in patients with advanced breast cancer when combined with chemotherapy; benefit was shown in first-line and second-line therapy. For more information on this study, please go to http://www.primeoncology.org/DCUBerlin to view the prIME Oncology interview with Dr Baselga.

Two landmark studies of denosumab in patients with bone metastases were reported at ECCO/ESMO. These double-blind, randomized, phase III studies demonstrated that inhibition of RANK ligand with denosumab can prevent skeletal complications due to bone metastases. In the first study, presented during the Presidential Session on Wednesday, September 23, by Alison Stopeck, MD, from the University of Arizona in the United States (Abstract 2LBA), denosumab was shown to significantly delay time to first and subsequent skeletal-related events (SREs; defined as a pathologic fracture, radiation or surgery to bone, or spinal cord compression) compared with zoledronic acid (Zometa^®) in breast cancer patients with bone metastases (HR0.77; 95% CI 0.66, 0.89; P = .001). Of note, the incidence of osteonecrosis of the jaw (ONJ), although low (1% to 2%), was similar in both arms, while renal toxicity was more frequent in the zolendronic acid arm (8.5%) than in denosumab arm (4.9%). For more information on this study, please go to http://www.primeoncology.org/DCUBerlin to view the prIME Oncology interview with Dr Robert Coleman.

A similar study reported by David Henry, MD, from Pennsylvania Hospital in the United States (Abstract 20LBA) compared denosumab with zoledronic acid in patients with solid tumors other than breast or prostate (mainly non-small cell lung cancer) or with multiple myeloma. This study showed that denosumab was noninferior to zoledronic acid in terms of delaying the first on-study SRE.

Jean-Yves Douillard, MD (University of Nantes, France), presented the results of the PRIME trial (Abstract 10LBA) during the Presidential Session on Thursday, September 24. This was a study of panitumumab (Vectibix^®), a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), in combination with FOLFOX4 vs FOLFOX4 alone as first-line therapy for metastatic colorectal cancer (mCRC). Based on evidence that EGFR-directed therapies are not effective against tumors that harbor KRAS mutations, this trial was amended to allow blinded centralized testing of all tumors for KRAS mutational status and to assess the efficacy of panitumumab in KRAS wild-type and mutant populations. As expected, addition of panitumumab (6 mg/kg every 2 weeks) to FOLFOX4 improved PFS only in patients with wild-type KRAS (median 9.6 months versus 8.0 months; P = .023), whereas PFS for combination therapy was inferior to PFS for FOLFOX4 alone in the subset of patients with mutant KRAS (median 7.3 months versus 8.8 months). This study confirms the hypothesis that KRAS mutational status predicts clinical benefit from treatment with an anti-EGFR mAb.

A very similar randomized phase III study of panitumumab plus FOLFIRI vs FOLFIRI alone as second-line therapy for mCRC (Abstract 14LBA) was reported by Marc Peeters, MD, PhD (University Hospital Ghent, Belgium). This trial also demonstrated a statistically significant PFS benefit in the KRAS wild-type population (5.9 months vs 3.9 months; P = .004). However, an improvement in overall survival (OS) of 2 months (14.5 months vs 12.5 months) was not statistically significant. In the subset of patients with mutant KRAS, no difference in PFS, OS, or response rate was observed in the panitumumab plus FOLFIRI arm in comparison with the FOLFIRI-alone arm.

Update of IES Trial (Abstract O-5010): Charles Coombes, MD, PhD (Imperial College London, United Kingdom), reported the updated results of the Intergroup Exemestane Study (IES). In this study, 4724 postmenopausal women with ER-positive/unknown completely resected breast cancer received 2-3 years of tamoxifen followed by either tamoxifen or exemestane (Aromasin^®) to completion of 5 years of adjuvant therapy. The initial analysis at a median follow up of 56 months showed a significant survival benefit (HR = 0.83; P = .05) for patients receiving exemestane. The updated analysis at a median follow up of 91 months showed that the DFS (HR 0.82; P = .0009) and OS benefit (HR 0.86; P = .04) were maintained.

First Findings of Adjuvant XELOXA Trial for Colorectal Cancer (Abstract 5LBA): Hans Joachim Schmoll, MD, PhD (University of Halle, Germany), presented the first efficacy results of the NO16968/XELOXA study. Adjuvant therapy with capecitabine (Xeloda^®) and oxaliplatin (XELOX regimen) was superior to IV bolus 5FU/LV (Mayo or Roswell Park regimen) in terms of 3-year and 4-year disease-free survival (DFS) in patients with stage III colon cancer (71.0% vs 67.0%; 68.4% vs 62.3%, respectively). Overall survival was not reported as the data are immature.

Farletuzumab for Ovarian Cancer (Abstract O-8000): Deborah Armstrong, MD (John Hopkins University, United States), reported preliminary results of a phase II study investigating the efficacy and safety of farletuzumab, a novel humanized mAb directed against folate receptor alpha, in patients with platinum-sensitive relapsed ovarian cancer. Patients were treated with farletuzumab either alone or in combination with a platinum/taxane regimen. The combination demonstrated an impressive 73.5% objective RECIST response rate, and median PFS was 10.3 months.

New Promising Drug for Melanoma (Abstract 6BA): Paul Chapman, MD (Memorial Sloan Kettering Cancer Center, United States), at the Presidential Session on Thursday, September 24, reported the results of a phase I study of PLX4032 in patients with advanced melanoma. This promising new agent inhibits the oncogenic V600E mutant BRAF kinase that is present in ~60% of melanomas. The maximum tolerated dose (MTD) was 960 mg twice daily, and among 22 patients with recurrent metastatic disease and BRAF mutations who received oral PLX4032 at the MTD (expansion cohort), 14 patients (64%) have had a PR. Responses have been seen in subcutaneous, lung, bone, and visceral sites. Due to these positive data, the results of larger phase II studies are eagerly awaited.

Triple-negative breast cancer (TNBC), which does not express either hormone receptors or human epidermal growth factor receptor 2 (HER2), as defined by immunohistochemistry, represents ~15% of human breast cancers. These tumors are typically basal-like and are associated with a poor prognosis (frequent occurrence of visceral metastases and short overall survival with best available chemotherapy). Unfortunately, improvements in therapy for this subset of patients have been minimal.
Vascular endothelial growth factor (VEGF) has been indicated as the major angiogenic factor in cancer, with numerous studies showing reduced survival for patients with high levels of VEGF in the primary tumor.

The authors of this study sought to compare intratumoral VEGF expression and survival in operable TNBC with non-TNBC. A retrospective analysis of 679 consecutive patients with primary breast cancer identified 87 patients with TNBC (13%) and showed that TNBC was associated with significantly higher VEGF expression (mean of 8.2 pg/µg DNA compared with 2.7 pg/µg DNA in non-TNBC; P<.001). Additionally, the authors demonstrated that the patients with TNBC in this retrospective cohort had significantly shorter RFS and OS compared with non-TNBC patients, consistent with the published literature.

These results provide support for the hypothesis that increased intratumoral VEGF expression may contribute to the poor prognosis of TNBC and also provides a strong biologic rationale for investigating antiangiogenic agents in this subset of patients. Ongoing phase III clinical trials will determine whether blockade of angiogenesis in addition to chemotherapy improves outcomes in TNBC.

At the opposite end of the spectrum from TNBC are those tumors that express hormone receptors and also overexpress HER2. Approximately half of all HER2-positive breast cancers express hormone receptors (HRs). Traditionally, these tumors have been treated with anti-HER2 therapy (ie, trastuzumab) plus chemotherapy due to their clinically aggressive nature. HER2 overexpression is an independent adverse prognostic factor for breast cancer regardless of hormonal status, and HER2 overexpression has been shown in preclinical models to confer resistance to hormonal therapy. However, until recently, the question of whether these patients might benefit from combined treatment with anti-HER2 and hormonal therapy had not been addressed. This approach could potentially offer some patients a more tolerable alternative to trastuzumab plus chemotherapy. In an editorial in the Journal of Clinical Oncology, Cortes and Baselga discuss the implications of two large randomized, placebo-controlled, phase III studies designed to answer this question. These studies combined anti-HER2 therapy with an aromatase inhibitor (AI) in patients with advanced hormone receptor–positive/HER2-positive breast cancer.

The TAnDEM study reported by Kaufman et al compared anastrozole plus trastuzumab with anastrozole plus placebo in 207 postmenopausal women (J Clin Oncol. 2009 September 28. [Epub ahead of print].) The second study, known as EGF30008, reported by Johnston et al compared letrozole plus lapatinib with letrozole plus placebo in a large cohort of 1286 patients with HR-positive breast cancer, of whom 219 were also HER2-positive (J Clin Oncol. 2009 September 28. [Epub ahead of print].). Both studies showed a significant improvement in PFS, objective response rate, and clinical benefit rate in the combination arm compared with the AI alone in HR-positive and HER2-positive patients. Median PFS was in the range of 5 months to 8 months with objective response rates of 20% to 30%. These benefits did not translate into significant improvement in OS. However, in the TAnDEM study with more mature data, a trend toward improved OS was shown despite a large amount of cross-over to the trastuzumab arm at disease progression. Taken together, these studies showed that combining anti-HER2 therapy with hormonal therapy (an AI) provided clinical benefit in this patient population and underscored the importance of anti-HER2 therapy as the foundation for treatment of HER2-positive breast cancer.

However, as Cortes and Baselga point out in their editorial, these two studies provide prospective and definitive evidence that HER2-positive tumors are, indeed, less responsive to hormonal therapy. The authors question whether this approach should be used as an alternative to taxane-based chemotherapy plus anti-HER2 therapy, which is currently the standard first-line therapy for patients with HER2-positive metastatic breast cancer. The clinical benefit of trastuzumab or lapatinib in combination with taxane-based chemotherapy appears to be superior to that observed in the studies described above with response rates of ~60% and median time to progression in the range of 9 months to 12 months. Although this question cannot be answered with the available data, the combination of an AI with anti-HER2 therapy may represent another effective treatment option that could be considered for patients who cannot tolerate chemotherapy or for those with less aggressive disease. With further research in the field of HER2-positive breast cancer, it may be possible to identify the molecular hallmarks of patients who could derive the most benefit from this treatment approach.

Defining the Prognosis of Small, Node-Negative, HER2-Positive Breast Cancers

Trastuzumab has become an integral component of adjuvant therapy for HER2-positive early breast cancer. However, there are very limited data available on the prognosis of patients with HER2-positive T1a/b N0 M0 breast cancer, and since the effect of trastuzumab in this subset of patients has not been evaluated in clinical trials, its use in these patients remains controversial. Therefore, the authors set out to review the available literature to determine the prognosis of patients with small tumors (0.6-1.0 cm) and node-negative disease that also overexpresses HER2.

Based on their critical review of data from 7 adjuvant trials including patients with T1a/b N0 tumors, the authors concluded that HER2-positive breast cancer represents ~10% of patients with small primary tumors and node-negative disease at diagnosis; within this subgroup, patients with HER2-positive tumors are at significantly higher risk of recurrence regardless of hormone receptor status. In some studies, HER2 overexpression was also an independent prognostic factor for poor OS. Benefit of trastuzumab therapy was reported in retrospective analysis in patients with subcentimeter, high-risk, HER2-positive tumors.
Based on these findings, the authors concluded that anti-HER2 therapy should be considered in this group of patients. However, prospective studies and randomized clinical trials are urgently needed to clearly assess the prognostic impact of HER2 overexpression in this patient population and to clarify if this group of patients will benefit from standard 1-year trastuzumab therapy or if a less intense schedule will be appropriate.

Acute myeloid leukemia (AML) is a heterogeneous hematologic cancer with a wide range of outcomes. Current therapies can cure approximately 40% of young patients, but outcomes are worse in patients over the age of 60 years, who constitute the majority of cases of AML.

For over 20 years, standard therapy for AML has consisted of induction therapy with an anthracycline, usually daunorubicin, at a dose of 45 mg/m²/day for 3 days combined with cytarabine for 7 days. This is typically followed by post-remission consolidation therapy with high-dose cytarabine or allogeneic or autologous stem cell transplantation to eradicate any residual disease. Efforts to improve OS by adding other drugs during induction therapy or increasing the dose of cytarabine have failed, and most efforts to improve clinical outcomes have focused on better consolidation regimens.

In the September 24 issue of the New England Journal of Medicine, two phase III randomized studies were reported that have altered the perception on induction therapy with the conventional dose of daunorubicin. According to the editorial by Dombret and Gardin, these studies may have established a new standard of care for selected patients with AML. Patients were randomized to 3 once-daily doses of daunorubicin at either the conventional dose (45 mg/m²) or a high dose (90 mg/m²) combined with 7 daily doses of cytarabine. In both studies, the high-dose regimen significantly increased the complete remission (CR) rate compared to the standard regimen, without increasing acute toxicity or early deaths, delaying hematologic recovery, or diminishing eligibility for subsequent consolidation therapy.

The Eastern Cooperative Oncology Group study reported by Fernandez et al (N Engl J Med 2009;361(13):1249-1259.), enrolled 657 patients under 60 years of age who had either primary or therapy-related AML and were eligible for autologous or allogeneic stem-cell transplantation, according to their disease risk. A CR rate of 71% was demonstrated in the high-dose group compared to only 57% in the standard-dose group (P<.001). This study also demonstrated a significant survival benefit associated with the high-dose regimen (median, 23.7 months versus 15.7 months; P = .003).

A European study reported by Lowenberg et al (N Engl J Med 2009;361(13):1235-1248.) enrolled 813 patients ≥60 years of age with secondary AML or a high-risk myelodysplastic syndrome. A significant improvement in the CR rate was achieved in the high-dose group (64% versus 54%; P = .002) but no difference in OS was reported. However, those patients younger than 65 years who received high-dose daunorubicin had higher rates of CR (73% versus 51%), event-free survival (29% versus 14%), and OS (38% versus 23%) in comparison to those who received the conventional dose.

Dombret and Gardin emphasize that, in both studies, the benefit of high-dose daunorubicin was restricted to younger patients and those with favorable cytogenetics. Nevertheless, this regimen offers significant benefit in select patients. The current challenge involves improving the selection of patients who should be offered intensive therapy and the development of new approaches to improve survival in older patients.

Sentinel lymph node (SLN) status is the most important prognostic factor for OS in patients with stage I or stage II melanoma and SN biopsy is an established staging tool. However, this procedure is invasive and is generally carried out under general anesthesia following surgical resection of the primary tumor. Ultrasound has been increasingly incorporated and accepted in Europe and Australia as a follow-up tool for patients with melanoma. In a study performed in The Netherlands, it was shown that ultrasound can accurately identify which lymph node is the SN before excision by the surgeon.

Therefore, the authors of this study sought to investigate the sensitivity and specificity of ultrasound-guided fine-needle aspiration cytology (FNAC) in the detection of melanoma metastases to the SN, prior to SLN biopsy, to determine if FNAC can be used as an alternative.

This study involved 400 consecutive patients with stage I/II primary melanoma who underwent lymphoscintigraphy and then received an ultrasound examination. If ultrasound detected any suspicious pattern, FNAC was performed prior to the SLN biopsy. Ultrasound-guided FNAC identified 51 of 79 (65%) SLN metastases and demonstrated a specificity of 99% (317 of 321) with a 93% positive predictive value and a 92% negative predictive value. Notably, the detection rate improved with higher tumor stage and with larger tumor size. Eighty-six percent of SLN metastases >1 mm were detected by ultrasound-guided FNAC, but less than half of SLN tumors ≤1.0 mm were detected. Overall survival rates were 92% for patients with negative US-guided FNAC results and 51% for those with positive SN results.

Based on these results, the authors concluded that ultrasound-guided FNAC of SLNs is a highly accurate diagnostic procedure that could be used instead of SLN biopsy in most, if not all patients with stage I/II melanoma. Further multicenter trials are needed to determine the reproducibility of these results.

UPCOMING LIVE EVENTS

Expert Practice in Breast Cancer Management for Surgeons 7 November 2009 \| Athens, Greece	Expert Practice in Gynecologic Malignancies 14 November 2009 \| Munich, Germany	Expert Practice in Lung Cancer 14 November 2009 \| Nice, France

Expert Practice in Breast Cancer 28 November 2009 \| Nice, France	Variations on Central Themes in Breast Oncology 11 December 2009 \| San Antonio, Texas	Hematologic Malignancies Demystified: The Series A Critical Appraisal of Data from 2009 and ASH

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Expert Perspectives on Clinical Practice: Daily Clinical Updates from the Joint ECCO 15—34th ESMO Multidisciplinary Congress 2009	Expert Perspectives in Non-Small Cell Lung Cancer: Advances and Updates in Adjuvant Therapy for Resectable NSCLC