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Lapatinib Shows Promise for Women with Difficult-to-treat Breast Cancers

According to Charles E. Geyer, MD, “Lapatinib provides a clinically meaningful and statistically significant prolongation of median time to progression when added to capecitabine for women with ErbB2-positive refractory breast cancer.” Dr. Geyer, of Allegheny General Hospital, addressed attendees during his presentation at the Scientific Special Session, “Lapatinib in Trastuzumab Resistant Breast Cancer,” on Saturday morning.

The primary objective of this phase III, open-label, international study was to evaluate and compare time to progression among women with refractory locally advanced or metastatic breast cancer treated with lapatinib and capecitabine compared with capecitabine alone.

Eligible women had ErbB2-positive locally advanced or metastatic breast cancer and had received prior anthracycline, taxane, and trastuzumab therapy. Women were randomly assigned to receive oral lapatinib 1,250 mg once daily continuously with oral capecitabine 2,000 mg/m2/day on days 1 to 14 or capecitabine 2,500 mg/m2/day on days 1 to 14. Cycles were repeated every 3 weeks. The first planned interim analysis included 114 time to progression events. Response was defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Although the study was open-label, evaluation was blinded by referring imaging and photographic assessments to an Independent Review Committee; the analysis was performed on an intention-to-treat basis.

At the time of the data lock, evaluations were available for 321 women, 160 in the lapatinib/capecitabine group and 161 in the monotherapy group. The two treatment groups were well balanced for both demographic and prognostic features. Median time to progression was 36.9 weeks for women in the combination arm compared with 19.7 weeks for women in the capecitabine monotherapy arm (hazard ratio [HR] 0.51, 95% CI = 0.35-0.74, p = 0.00016). Median progression-free survival was 36.9 weeks for those receiving combination therapy compared with 17.9 weeks for those in the capecitabine monotherapy arm (HR 0.48, 95% CI = 0.33-0.70, p = 0.000045).

The overall response rate for the combination therapy group was 22.5% compared with 14.3% for the monotherapy group (p = 0.113). Relapse within the central nervous system showed a correspondingly positive trend in favor of the combination (11 events in the capecitabine monotherapy group compared with 4 events in the lapatinib/capecitabine group). Survival data are not yet mature, with 29 deaths in each arm.

Events requiring discontinuation of therapy occurred in 22 patients in the lapatinib/capecitabine group (14%) compared with 16 in the capecitabine group (11%). The overall pattern of adverse events was similar. Diarrhea was more common on the combination arm (58%) compared with capecitabine alone (39%), as were hand-foot syndrome (43% vs. 34%) and rash (34.5% vs. 30%). Among women in the combination therapy arm, more than 20% had a relative decrease in left ventricular ejection fraction (LVEF) compared with less than 1% of women receiving capecitabine monotherapy; all recovered normal LVEF.

Dr. Geyer concluded by emphasizing that lapatinib provides a clinically meaningful, statistically significant prolongation in median time to progression when added to capecitabine for women with ErbB2-positive breast cancer who have been pretreated with chemotherapy and trastuzumab. Enrollment was halted following unanimous recommendation of the Independent Data Monitoring Committee based upon acceptable tolerability and superior efficacy of the combination regimen.

In other news about lapatinib, Neil L. Spector, MD, of GlaxoSmithKline, reported results of an ongoing multicenter study of lapatinib monotherapy for women with relapsed or refractory inflammatory breast cancer (Abstract 502).

In this study, women with relapsed or refractory inflammatory breast cancer were randomly assigned to Group A (overexpression of ErbB2) or Group B (ErbB2 not overexpressed) following analysis of a fresh tumor biopsy at a central reference laboratory. Patients received 1500 mg of lapatinib once daily. Response was assessed according to RECIST criteria. As RECIST criteria do not adequately address the skin involvement observed in inflammatory breast cancer, a special evaluation of skin response was documented by digital photography.
According to updated results, 69% of patients in Group A had a clinical response (complete or partial) to lapatinib documented by RECIST, extent of skin disease, or both. Among responders, all tumors overexpressed ErbB2 (2/3+ IHC or FISH+); all also had increased p-ErbB2 (2/3+), coexpression of IGF-IR, and expression of activated p-ErbB3. PTEN status did not affect response to lapatinib. Treatment with lapatinib was well tolerated. Ninety percent of the adverse events were grade 1 or 2; 57 events were gastrointestinal-related, and 23 were skin rashes; only 10 events were grade 3 or 4, and included diarrhea, anorexia, headache, anemia, and thrombocytopenia.

Dr. Spector concluded that lapatinib monotherapy is clinically active for women with inflammatory breast cancer who have been heavily pretreated.

Dr. Nancy Lin of the Dana-Farber Cancer Institute reported results from a study of women with HER-2-positive breast cancer and new or progressive brain metastases (with at least one measurable lesion [Abstract 503]). Women received oral lapatinib 750 mg twice daily. Tumor response was assessed by magnetic resonance imaging (MRI) every 8 weeks. Fluorodeoxyglucose positron emission tomography (FDG-PET) scans were performed at baseline and repeated at weeks 1 and 8. The primary endpoint was objective response (complete or partial) in the brain according to RECIST criteria. Secondary endpoints included safety, quality of life, and PET-scan changes, as well as objective response rate in non-central nervous system (CNS) sites, time to progression, and overall survival. According to the statistical criteria for the study, four or more objective responses were required to reject the null hypothesis.

Thirty-nine women were enrolled in the trial (median age 52; range, 31 to 76). CNS disease developed in all patients during treatment with trastuzumab, and 38 had disease progression after radiotherapy. Two women achieved a partial response according to RECIST criteria. Four of the 16 women with measurable non-CNS disease achieved partial response. Median time to treatment failure was 3.2 months (95% CI; 2.04-3.68); median overall survival was 6.57 months.

Toxicity data—available for all of the women enrolled—indicate that the most common grade 3 adverse events were diarrhea (21%), fatigue (15%), and rash (5%). Analysis of quality of life was difficult because of the limited instruments available, and Dr. Lin noted that improved methods are needed for capturing neurologic and quality-of-life outcomes.

Dr. Lin concluded that lapatinib is well tolerated in this population. Although the study failed to demonstrate the hypothesized level of activity as assessed by RECIST, there is sufficient evidence of clinical effect—albeit preliminary—to suggest that lapatinib can penetrate the blood-brain barrier. Investigators remain cautiously optimistic about the potential for lapatinib to play a role in HER-2-positive brain metastases. Further investigation of lapatinib in HER-2-positive CNS disease is warranted and ongoing.




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