Reports

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PRIORITY PRESS - 46th Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 4-8, 2010

The multicentre phase III PELICAN (Pegylated Liposomal Doxorubicin or Capecitabine as First Line Chemotherapy for Metastatic Breast Cancer) study has generated evidence for a rational selection of first-line therapy for metastatic breast cancer (MBC). The trial compared the anthracycline doxorubicin in its pegylated liposomal formulation (PLD) to the antimetabolite capecitabine, which is a prodrug enzymatically converted to its active form of 5-fluorouracil. Both agents are common therapies in MBC with proven efficacy. Consistent with previously published studies, the rates of efficacy were similar but differences in side effects were considered clinically relevant.

“Overall, the relative tolerability profile was better on the PLD, although the types of adverse events were not the same. In general, better tolerability for the first-line drug may increase choices for subsequent single-agent therapies, although the relative differences in the types of adverse events observed in this phase III study may still be meaningful for individualization of care,” reported Dr. Elke Jäger, chief physician, Hematology-Oncology, Medical Clinic II, Krankenhaus Nordwest, Frankfurt, Germany. “Clearly, the safety profile of these agents should be taken into consideration when selecting a first-line agent in advanced breast disease.”

PELICAN Findings

In this study, 210 women with MBC who had not received prior chemotherapy for their metastatic disease and who had no indication for trastuzumab were randomized to receive PLD 50 mg/m² intravenously every 28 days or capecitabine 1250 mg/m² administered orally b.i.d. for 14 days out of every 21-day cycle. The therapies were investigated for a variety of efficacy end points, including time to progression (TTP), time to treatment failure (TTF) and overall survival (OS), as well as safety measures, which included relative rates and severity of toxicity. No concomitant anti-cancer medications were allowed and patients with a history of anthracycline resistance were excluded.

The population enrolled in this study was typical of those with MBC who are candidates for single-agent chemotherapy. The median age was 62 and more than 90% (divided relatively evenly) were in ECOG performance status 0 or 1. More than 80% of the women were postmenopausal and more than half had metastases in both visceral and non-visceral sites.

There were no significant differences between PLD and capecitabine in any of the efficacy measures evaluated. Median OS was 22.4 months for PLD and 29.4 months for capecitabine (P=0.44). The median TTP was 6.2 and 7.1 months (P=0.31), respectively. The confirmed and unconfirmed overall objective response rates were similar (P=0.64 and P=0.86, respectively), as were complete or partial response rates and the proportion of patients achieving stable disease. Confirmed rates of progressive disease were 36.9% for PLD and 42.2% for capecitabine, which were also not statistically different.

Although the safety profiles were different, PLD was better tolerated when the two regimens were compared by serious adverse events (SAEs). This was reflected both in the number of SAEs (58 for PLD vs. 115 for capecitabine; P=0.015) and the percentage of patients with SAEs (30% vs. 48%, respectively; P=0.0073). No grade 3 or 4 event was more common on PLD than capecitabine. Conversely, grade 3 or 4 diarrhea (12% vs. 0%; P=0.0002) and grade 3 or 4 thromboembolic events (10% vs. 2%; P=0.0186) were significantly more common with the antimetabolite. However, two events were more common on PLD than capecitabine when considering all grades: leukopenia (25% vs. 16%; P=0.0025) and mucositis (57% vs. 29%; P<0.0001). The greater rate of vomiting of all grades on capecitabine relative to PLD approached statistical significance (29% vs. 17%; P=0.07). There was no difference in the rates of cardiac events either by all grades (9% in both groups) or grade 3 or 4 events (2% for PLD vs. 0% for capecitabine).

It is notable that more than one-third of patients had prior exposure to anthracyclines, which was permitted if the cumulative prior exposure did not exceed 360 mg/m2 of doxorubicin or its equivalents (e.g. 600 mg/m² of epirubicin). There was no difference in the median TTP for patients receiving PLD when stratified by prior anthracycline exposure. However, patients randomized to capecitabine fared better if they had not had previous exposure to an anthracycline (TTP of 9.0 months) than if they had (TTP of 4.8 months; P=0.02 vs. no previous exposure).

Formulation, Previous Drug Exposure

The absence of any influence from prior exposure to anthracyclines on the efficacy and safety, including the cardiac safety, of PLD provides additional validation of the mechanism of formulating this drug with pegylation and liposomal encapsulation. The liposomes prevent the drug from entering normal tissues with tight capillary junctions, such as the heart and gastrointestinal tract, while encouraging more deposition in tumours that are characterized by leaky vessels. The pegylation stabilizes the liposomes, thereby increasing the resident time of the drug in the blood, boosting efficacy and minimizing toxicity risk. PLD has been increasingly adopted for use in cancers where anthracyclines have been active because of this safety advantage, particularly a low relative risk of both SAEs, such as cardiotoxicity, and side effects that adversely affect quality of life, such as diarrhea and nausea and vomiting.

The low relative risk of SAEs with PLD relative to capecitabine in this randomized trial is useful information because one of the advantages of capecitabine relative to many of the other options, including conventional anthracyclines, has been a favourable tolerability profile. In a separate study that collated data from three studies with capecitabine in MBC, the conclusion was that capecitabine remains highly active as a first-line therapy even among those with prior exposure to anthracyclines and taxanes. The data were collected from a single-institution study with 225 patients, a multicentre phase II study with 161 patients and a German observational study that included 542 patients on capecitabine monotherapy.

“In these three studies, up to 48% of patients had prior exposure to an anthracycline and 25% had prior exposure to a taxane, but the median TTF was similar for those who had not received these therapies previously when compared to those who had,” reported Dr. Friederike Siedentopf, Centre for Breast Disease, DRK-Kliniken, Berlin, Germany. These median rates, similar to those reported by Dr. Jäger in the PLD trial, were 8.9 months and 8.3 months for prior and no prior chemotherapy, respectively, which did not differ significantly. In the context of evidence that PLD and capecitabine have similar efficacy as single-agent, first-line therapy in MBC, the safety advantage of PLD is important, but the safety differences are also relevant to treatment selection. Dr. Jäger indicated that PLD is particularly attractive for avoiding grade 3 and 4 side effects, but comorbidities in patients may ultimately affect treatment choice. For example, the higher rate of mucositis on PLD relative to capecitabine, although not significantly different at the grade 3 or 4 level (8% vs. 3%), may be relevant to patients particularly anxious to avoid this adverse event. However, it is not just the immediate risks but the burden of SAEs on the course of disease that must be considered.

“One of the important issues of choice for first-line single-agent chemotherapy in MBC is how these treatment options will affect ability to provide subsequent therapies to extend survival,” Dr. Jäger observed. On this basis, she indicated that PLD might be an appropriate choice in many individuals.

Summary

A phase III comparison trial of two commonly used single agents for the treatment of MBC has demonstrated that PLD and capecitabine offer similar activity and outcomes but that the anthracycline in the pegylated liposomal formulation is better tolerated. In particular, it produced significantly fewer grade 3 and 4 diarrhea and thromboembolic events with no relative increase in other types of grade 3 or 4 events. The differences in the side-effect profiles generated by this randomized trial provide guidance for first-line therapy selection.