Lapatinib May Offer “No-Chemo” Option in Metastatic Breast Cancer

June 17, 2008

Several studies exploring the use of lapatinib (Tykerb, GlaxoSmithKline) in metastatic breast cancer have suggested that it offers an alternative to chemotherapy in this setting, both as monotherapy and in combination with other targeted therapies.

One study explored the use of lapatinib alone, whereas others investigated combinations with trastuzumab (Herceptin, Genentech/Roche), with bevacizumab (Avastin, Genentech/Roche), and with the investigational agent pazopanib (under development by GlaxoSmithKline).

The studies, presented here at the American Society of Clinical Oncology 44th Annual Meeting, open up “an exciting potential new paradigm for patients with HER2+ breast cancer,” one of the investigators commented. However, discussant Francisco Esteva, MD, PhD, from the MD Anderson Cancer Center, in Houston, Texas, cautioned that “biological therapy without chemotherapy for metastatic breast cancer is an interesting area of investigation, but it is not ready for prime time.”

There are 2 reasons for this, Dr. Esteva continued. The efficacy of these targeted agents is higher when they are combined with chemotherapy, and the toxicity of these agents in combination needs to be explored further. Hence, for the time being, the preferred front-line choice for metastatic breast cancer remains trastuzumab with chemotherapy, and the evidence suggests that continuation of trastuzumab is the best option for patients who progress.

However, Dr. Esteva said that combining drugs that have different targets is a promising option, and he congratulated the manufacturers for their research efforts and collaboration.

All of the studies were exploring new uses for lapatinib. The drug is approved in the United States for a very narrow indication: in combination with capecitabine (Xeloda, Roche) for advanced metastatic HER2+ breast cancer in women who have received previous chemotherapy, including an anthracycline, a taxane, and trastuzumab. A similar approval in Europe is pending.

Phase 3 Study of Combination Lapatinib and Trastuzumab

The largest of the new trials presented was a phase 3 study of lapatinib monotherapy compared with a combination of lapatinib and trastuzumab (designated EGF104900).

Both of these drugs target HER2+ breast cancer, but trastuzumab (a monoclonal antibody) is a large-protein molecule that targets the part of the HER2 protein on the outside of the cell; lapatinib (an oral drug) is a smaller molecule that enters the cell and blocks the function of this and other proteins intracellularly. “Effectively attacking HER2 from multiple angles is an exciting and innovative approach,” said lead research Joyce O’Shaughnessy, MD, from the Baylor-Sammons Cancer Center, in Dallas, Texas.

The trial involved 269 patients with HER2+ breast cancer who had documented progression on trastuzumab in the metastatic setting. The combination of lapatinib plus trastuzumab showed a significant increase in progression-free survival, compared with lapatinib alone (12 weeks vs 8.1 weeks). This translates into a 27% reduction in the risk for disease progression (hazard ratio [HR], 0.73; P = .008).

The overall clinical-benefit rate (the response rate and the rate of durable stable disease) for the combination was double that for monotherapy (24.7% vs 12.4%; P = .01). There was a trend toward improved overall survival, Dr. O’Shaughnessy reported. There were 69 deaths in patients taking the combination and 56 deaths in patients taking monotherapy, with mean overall survival of 39 weeks for combination therapy and 51 weeks for monotherapy; the unadjusted HR was 0.75, (P = .106), and the adjusted HR was 71 (P = .095), which translates into a 29% reduction in the risk for death, she said.

Adverse events were similar in both groups, but grade 1/2 diarrhea was more frequent with the combination (53% for combination vs 41% for monotherapy; P = .03). Cardiovascular toxicity was seen in both groups. Two patients on the combination and 1 patient on lapatinib alone experienced symptomatic decreases in left ventricular ejection fraction (LVEF), but 2 of these 3 patients later recovered. In addition, 1 patient on the combination died from a pulmonary thromboembolism with progressive malignant pleural effusions.

This is the first study to demonstrate synergy between lapatinib and trastuzumab in a phase 3 setting, Dr. O’Shaughnessy commented. It showed improved clinical outcome in patients progressing on trastuzumab without a substantial change in the adverse-effect profile; hence, this combination “may provide a chemotherapy-free option” for women with metastatic HER2+ breast cancer, she concluded. When asked by a fellow clinician whether she would consider using this combination in place of the approved lapatinib-plus-capecitabine option, she answered that she would use this new combination “as a later-line therapy,” and would offer it to patients who didn’t want to take any more chemotherapy.

More data on the role of combined HER2+ therapy in combination with chemotherapy will be available soon from the ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) study, she said. ALTTO is being conducted in less-heavily pretreated patients with early-stage disease, she noted.

Lapatinib Plus VEGF-Targeting Agents

Another approach combined lapatinib, which acts on the HER2+ pathway, with agents that target the vascular endothelial growth factor (VEGF) pathway: the monoclonal antibody bevacizumab, which was recently approved for use in metastatic breast cancer, and the investigational oral agent pazopanib.

The results for lapatinib plus bevacizumab were reported by Hope Rugo, MD, from the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. This was a small phase 2 single-group study, conducted in 32 patients who had received a median of 5 previous metastatic breast cancer therapies (range, 0–15); 28 of these 32 patients had received treatment with trastuzumab.

The combination resulted in a 34.4% clinical-benefit rate (defined as complete response plus partial response plus stable disease at 24 weeks or more), and 62.5% of patients were progression free at week 12.

The most common adverse events were diarrhea (81%), rash (66%), nausea (56%), fatigue (56%), and vomiting (46%). There were 2 grade 2 asymptomatic LVEF decreases, 1 grade 3 gastrointestinal hemorrhage, and 1 grade 3 hypertensive event.

Blocking both the HER2 and the VEGF pathways led to “anticancer activity for even heavily pretreated patients with metastatic breast cancer that could potentially advance the treatment of this high-risk disease,” Dr. Rugo said in a statement.

The study of lapatinib plus pazopanib was reported by Dennis Slamon, MD, from UCLA’s Johnsson Comprehensive Cancer Center, in Los Angeles, California. He noted that both drugs were taken orally once daily, and suggested that they might “provide a potential future treatment option for HER2+ breast cancer.”

This study involved 141 patients and compared the combination with lapatinib monotherapy. Dr. Slamon noted that, for ethical reasons, all patients were assessed at 12 weeks, because “trastuzumab is available and should be used in these patients.”

The results confirmed the efficacy of lapatinib monotherapy, Dr. Slamon commented, and showed a trend toward better outcomes with the combination. At 12 weeks, 36.2% of patients taking the combination and 38.9% taking the monotherapy experienced disease progression (P = .37). The response rate was 44.9% with the combination and 28.8% with the monotherapy according to investigator assessment, and 36.2% vs 22.2%, respectively, according to independent assessment.

In discussing this trial, Dr. Esteva noted that some of the data on some of these patients were missing, so these results must be considered preliminary.

Adverse effects seen more commonly with the combination than with monotherapy were as follows: diarrhea (67% vs 58%), rash (28% vs 29%), liver enzyme increases (aspartate aminotransferase [AST], 32% vs 16%; alanine aminotransferase [ALT], 30% vs 16%), and hypertension (26% vs 4%). There was 1 death in the combination groups due to dyspnea and 1 death in the monotherapy group due to hepatic failure. In addition, 3 patients in the combination group had LVEF decreases that were asymptomatic and 1 patient had an LEVF decrease that was symptomatic.

Lapatinib Monotherapy

The above trials with a lapatinib monotherapy group confirm the drug’s efficacy in metastatic breast cancer, according to a statement from GlaxoSmithKline.

Final results were also presented from the trial of lapatinib monotherapy in HER2+ inflammatory breast cancer, the largest prospective trial ever conducted in this form of the disease. Earlier results from this study were presented at cancer meetings in 2007 and 2006, as reported by Medscape Oncology at the time.

The trial was conducted in 126 patients with HER2+ inflammatory breast cancer refractory to anthracyclines and taxanes. The final analysis found that lapatinib (1500 mg daily) was clinically active, with a 38.9% response rate overall, and a 36% response rate in refractory patients previously treated with trastuzumab. The median duration of response was 20.9 weeks, and overall progression-free survival was 14.6 weeks.

Diarrhea was the most common adverse event, occurring in approximately 60% of patients; the most common serious adverse events were dyspnea (6%), pleural effusion (4%), and pyrexia (2%). Thirteen patients had fatal serious adverse events, of which 5 were considered to be possibly related to the treatment.

“We are very excited to see these results; they provide the promise of future options for these patients,” commented lead investigator Bella Kaufman, MD, from the Chaim Sheba Medical Center, in Tel Hashomer, Israel. “Inflammatory breast cancer is one of the most misunderstood and aggressive forms of breast cancer. In fact, often the disease is so advanced in many patients by the time of diagnosis that there are few effective therapies available.”

Dr. Esteva reported consultancy for Genetech and GlaxoSmithKline [GSK]). Dr. O’Shaughnessy reported acting as a consultant to GSK. Dr. Slamon and coauthors reported consultancy for GSK, BioOncology, and Genentech, and receiving honoraria from GSK. Dr. Rugo and coauthors reported various financial dealings with GSK, consultancy and honoraria with Roche, and honoraria and research grants from several other companies. Dr. Kaufman and coauthors reported various ties with GSK, consultancy for Novartis and Pfizer, and research grants from Novartis and Roche.

American Society of Clinical Oncology (ASCO) 44th Annual Meeting: Abstracts 1015 and 1016, presented June 1, 2008; abstract 636, presented June 2, 2008; and abstract 1042, presented June 3, 2008.

Reviewed by Ramaz Mitaishvili, MD

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