Lapatinib New Option for Metastatic HER2+ Breast Ca

June 1, 2006

Lapatinib (Tykerb), an oral small-molecule reversible dual inhibitor of HER1 (EGFR) and HER2 tyrosine kinases, is emerging as a promising option for HER2-positive breast cancer patients, investigators of phase II and III trials reported at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO). Clinical evidence suggests that lapatinib, unlike trastuzumab (Herceptin), can cross the blood-brain barrier to treat brain metastases, which develop in about one-third of HER2-positive breast cancer patients.

ASCO — Lapatinib (Tykerb), an oral small-molecule reversible dual inhibitor of HER1 (EGFR) and HER2 tyrosine kinases, is emerging as a promising option for HER2-positive breast cancer patients, investigators of phase II and III trials reported at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO). Clinical evidence suggests that lapatinib, unlike trastuzumab (Herceptin), can cross the blood-brain barrier to treat brain metastases, which develop in about one-third of HER2-positive breast cancer patients.

Lapatinib and trastuzumab activity may be complementary, researchers said, and there is potential for synergy, as lapatinib blocks the intracellular portion of HER1 and HER2 homodimers and heterodimers, while trastuzumab blocks the extracellular portion of HER2.

In a scientific special session, Charles E. Geyer, Jr., MD, of Allegheny General Hospital, Pittsburgh, presented results of a phase III international multicenter trial showing substantial improvement in time to progression (TTP) with the oral combination of lapatinib plus capecitabine (Xeloda) and fewer brain metastases vs capecitabine alone in HER2-positive women with locally advanced or metastatic trastuzumab-refractory disease.

Dr. Geyer said there is preclinical evidence that dual blockade of signaling may be more effective than single-agent inhibition provided by agents such as trastuzumab. An important rationale for combining lapatinib and capecitabine, he explained, is that "inhibition of HER1 has been seen in preclinical studies to possibly potentiate one of the major metabolites of capecitabine, 5'-DFUR. This has been shown with gefitinib [Iressa] and with a dual inhibitor that is closely related to lapatinib."

The study included 321 capecitabine-naive women with advanced HER2-positive breast cancer refractory to an anthracycline or taxane in the adjuvant or metastatic setting and to trastuzumab in the metastatic setting. All eligible patients had measurable disease by RECIST and normal left ventricular ejection fraction (LVEF). Disease status was assessed every two cycles at 6-week intervals for the first 6 months and then every 12 weeks until progression. Patients were randomized to combination therapy (lapatinib 1,250 mg/m2 daily continuously plus capecitabine 1,000 mg/m2/bid on days 1 to 14 every 3 weeks) or capecitabine alone at 1,250 mg/m2/bid daily on days 1 to 14 every 3 weeks.

'Clinically Meaningful' Results

After an independent radiographic review committee determined that 114 of 321 patients had met progression criteria of the protocol, a planned interim analysis was performed by an independent statistician and then reviewed by an Independent Data Monitoring Committee (IDMC). On March 20, 2006, the IDMC recommended accrual be discontinued, citing demonstration of "a clinically meaningful statistically significant advantage in the primary endpoint TTP in the combination vs the capecitabine-alone group," according to Dr. Geyer. TTP was 36.9 weeks with combination therapy vs 19.7 weeks with capecitabine alone (HR 0.51, 95% CI 0.35 to 0.74, P = .00016).

There was a similar advantage in progression-free survival (PFS); median PFS was 36.9 weeks in the combination group vs 17.9 weeks with capecitabine alone (HR 0.48, P = .000045). The overall response rate was higher with lapatinib/capecitabine, at 22.5% vs 14.3% for capecitabine alone, but did not reach statistical significance. In addition, Dr. Geyer reported, fewer women treated with lapatinib/capecitabine developed central nervous system (CNS) relapses, compared with women who received capecitabine alone (4 vs 11 patients, respectively).

Events requiring drug discontinuation occurred in 14% of the combination patients vs 11% of the capecitabine-alone group, Dr. Geyer reported. More women on the combination arm had diarrhea (58% vs 39% with capecitabine alone), although the increase was largely due to increased reports of grade 1 diarrhea. The combination also resulted in slightly higher rates of hand-foot syndrome (43% vs 34%) and rash (about 35% vs 30%). In the combination arm, he said, four patients had treatment-related cardiac events with "modest declines" in LVEF; all recovered normal LVEF.

Survival data are not mature; there were 29 deaths in both arms at interim analysis. "Survival may not be an endpoint that we can use in future follow-up because of crossover that was provided, but it will continue to be monitored," Dr. Geyer commented.

Treating Brain Mets

At a clinical science symposium on HER2-directed therapy, Nancy U. Lin, MD, of the Dana-Farber Cancer Institute, presented a phase II multicenter trial of lapatinib to treat brain metastases in patients with HER2-positive breast cancer, nearly all of whom had received prior chemoradiotherapy (abstract 503). Eligible patients had at least one CNS lesion at least 10 mm in its longest dimension and prior therapy with trastuzumab, alone or in combination with chemotherapy. Women who had received prior therapy with an EGFR inhibitor or a HER2 inhibitor other than trastuzumab were excluded.

The primary endpoint was objective response rate (ORR) in the CNS by modified RECIST criteria. In addition, Dr. Lin said, "because of the expectation that some patients would have relatively small lesions, for partial response and progressive disease we required an absolute change of at least 5 mm." Lapatinib was given in 4-week cycles at a starting dose of 750 mg orally twice daily, with this higher dose chosen because of the potential of better CNS penetration. Patients received a median of three cycles of therapy (range, 1 to 13).

Overall, 2 of 39 patients responded to therapy (both had prior radiation), for an ORR of 5.1% (95% CI 1% to 17%). The results did not meet the study's statistical criteria of at least four ORRs required to reject the null hypothesis, "although we did observe evidence of clinical activity," Dr. Lin said. Four of 16 patients with measurable non-CNS disease had a partial response in sites outside of the CNS. Median TTP for all patients was approximately 3 months.

Encouragingly, Dr. Lin said, by investigator assessment, 23 patients were free of CNS progression for 2 months, 8 were progression free for 4 months, and 4 were progression free for 6 months.

In terms of volumetric changes in CNS lesions, four patients had decreases of 30%, and six had decreases between 10% and 30%. Unfortunately, she noted, "the optimal method by which to assess clinical benefit in the CNS is unclear," in that the degree of volume change that correlates with clinically meaningful outcomes is not well defined. Median overall survival, calculated from the time of study entry, was about 6.6 months.

Quality-of-life data were inconclusive because only 19 of the 39 patients had complete data, though "most patients reported stable symptoms at 8 weeks," she said. The most common grade 3 adverse events were diarrhea (21% of patients), fatigue (15%), and rash (5%). Notably, she added, "we observed no cases of grade 3 or 4 LVEF dysfunction on study; four patients developed LVEF less than 50%, but only one of these patients developed a 10% or higher change from baseline."

Dr. Geyer's study was funded by GlaxoSmithKline, the developer of lapatinib. Dr. Lin's study was sponsored by the NCI through an Avon-NCI Partners for Progress Award.