Fine-tuning the Best Use of Trastuzumab in Metastatic Breast Cancer

CHICAGO—The best use of trastuzumab in the setting of metastatic breast cancer remains an open question. Several presentations at the ASCO Annual Meeting here focused on this issue, including: Defining the optimal schedule for trastuzumab plus chemotherapy as first-line treatment. The combination of lapatinib plus trastuzumab for patients with HER2-positive disease that progresses on trastuzumab. A combination of novel agents that attacks both the HER2 and VEGF pathway as upfront treatment, with trastuzumab reserved for progression. HERTAX Trial A randomized, Phase II study suggests that combination therapy with trastuzumab/docetaxel followed by trastuzumab may be superior to the use of sequential trastuzumab followed by docetaxel at disease progression. The HERTAX (trastuzumab [HERceptin] given with docetaxel [TAXotere] versus sequential single-agent therapy with trastuzumab followed by docetaxel as first-line treatment for HER2-positive metastatic breast cancer) trial compared Arm A (combination therapy) with Arm B (sequential therapy) in 101 patients as first-line treatment for metastatic breast cancer, with progression-free survival as the primary endpoint. The small Phase II study was undertaken to explore the best sequence of trastuzumab plus docetaxel, since that combination has been established as superior to docetaxel alone in the metastatic setting, explained Caroline Seynaeve, MD, of the Dutch Breast Cancer Cooperative Group, who noted that the study was investigator-initiated, and that the pharmaceutical companies that provided some financial support had no involvement in the analyses, conclusions, and discussion of the implications of the findings. “The toxicity of the combination [trastuzumab and docetaxel] is mainly attributable to cytotoxic chemotherapy,” said Dr. Seynaeve, a medical oncologist at Erasmus University Medical Center. “The goal of palliative therapy is to improve quality of life and survival. The outcome of sequential monotherapy with trastuzumab followed by single-agent docetaxel has not been studied until this trial.” The adverse event profiles of the two treatment arms were similar, except for Grade 3 neurotoxicity, which was seen only in the combination arm: 8% vs 0%, respectively. Also, more neutropenic fever and two toxic deaths were reported in the combination arm. There was no difference in cardiotoxicity observed between the two arms. Progression-free survival was not significantly different between the two groups: median progression-free survival in Arm A was 9.4 vs 10.8 months in Arm B. However, a nonsignificant trend toward increased overall survival was seen with combination therapy: a median survival of 30.5 months with combination therapy vs 20.2 months with sequential therapy. Differences in treatments between the two arms may explain the findings, Dr. Seynaeve suggested. The duration of trastuzumab during the study was twice as long in the combination arm: median of 8.8 vs 4.1 months, respectively. Somewhat more patients in the combination arm used trastuzumab as post-study treatment: 35.8% vs 30.4%, respectively. Furthermore, more patients in the combination arm had no disease progression at database lock: 20.8% versus 4.4%, respectively. Dr. Seynaeve said that she and her colleagues think that an exploratory study of trastuzumab followed by the combination of trastuzumab/docetaxel is worthwhile—“perhaps holding the administration of chemotherapy and the resulting side effects until disease progression.” Addition of Another Arm In a separate interview, Ingrid Mayer, MD, Assistant Professor of Medicine at Vanderbilt-Ingram Cancer Center and Clinical Core Director of the Breast Cancer SPORE there, followed up on Dr. Seynaeve's suggestion of holding the combination for disease progression: “It would have been more informative if there had been another arm in this trial, with trastuzumab given upfront followed by the combination of docetaxel/trastuzumab at progression. Typically, in clinical practice the patient is started on trastuzumab and stays on trastuzumab at progression with the addition of chemotherapy.” Dr. Mayer said that although she agreed that chemotherapy should be considered upfront, trastuzumab alone as first-line therapy is still a valid strategy for patients who are asymptomatic and do not have a large burden of disease: “Trastuzumab as a single agent is much less toxic and there are no statistically significant differences in overall survival and progression-free survival between trastuzumab alone followed by chemotherapy and trastuzumab plus docetaxel.” The study's Discussant, Francisco J. Esteva, MD, Associate Professor of Breast Medical Oncology at the University of Texas M. D. Anderson Cancer Center, said that the HERTAX trial showed synergy between trastuzumab and docetaxel, with improved time to progression for the combination. “Although not statistically significant, the 10-month improvement of overall survival in the combination arm is of great interest,” he said. Lapatinib+Trastuzumab for Progression on Trastuzumab The next presentation at the same oral session explored the results of a Phase III trial comparing the combination of lapatinib plus trastuzumab versus lapatinib alone in heavily pretreated patients with HER2-positive metastatic breast cancer whose disease progressed on trastuzumab immediately before study entry. The hypothesis was that more complete HER2 blockade, using two drugs that act on different parts of the HER2 pathway, would improve outcomes, and indeed, the combination was found to be superior. Joyce O'Shaugnessy, MD, Co-Director of Breast Cancer Research and Director of Chemoprevention Research at US Oncology, Inc., reported that the combination achieved significant improvement in progression-free survival and doubled the clinical benefit (i.e., complete response, partial response, and stable disease) compared with lapatinib alone. “Lapatinib plus trastuzumab was effective for HER2-positive metastatic breast cancer progressing on or after trastuzumab. This is the first Phase III study to confirm that more complete blockade of HER2 improves outcome,” she said. “Based on these results, it may be possible to offer patients who progress on trastuzumab a chemotherapy-free alternative.” Following her presentation, Dr. O'Shaugnessy responded to an audience question about where this non-chemotherapy doublet would fit in the course of disease. “Capecitabine and lapatinib are used earlier in the course of metastatic disease. I would use lapatinib plus trastuzumab as a later line of therapy for patients who want a chemotherapy-free option,” she stated. Efficacy and safety data were reported on 299 patients. The most common adverse event was diarrhea, occurring in 60% of the combination arm and 48% of the lapatinib-monotherapy arm. Cardiac events were similar in the two groups, occurring in eight and five patients, respectively. Most of these events resolved; one cardiac event was a fatal pulmonary embolus in the combination arm. Median overall survival was 51 weeks for the combination group and 39 weeks for patients receiving monotherapy with lapatinib. The combination achieved a 29% reduction in risk of death, and clinical benefit was doubled in the combination arm: approximately 25% vs 12%, respectively. The six-month progression-free survival rate was 28% for the combination vs 13% for lapatinib monotherapy. Multivariate analysis identified the following predictors of progression-free survival for lapatinib plus trastuzumab (versus lapatinib alone): Eastern Cooperative Oncology Group performance status, liver metastases, and the number of sites of metastases. Time from the last trastuzumab treatment did not influence progression-free survival, Dr. O'Shaugnessy said. Take-Home Message The take-home message, Dr. Mayer said, is that using a non-chemotherapy strategy for HER2 blockade has clinical activity. “HER2-positive disease is so driven by HER2 that you don't need chemotherapy to get an effect. The study also provides proof of concept that both drugs are synergistic against these tumors,” she continued. Dr. Mayer questioned, however, whether the four-week difference in progression-free survival (12 vs 8 weeks) was clinically relevant. “This combination is active in these heavily pretreated patients, and it should be explored earlier in metastatic disease and in the adjuvant setting, as is being done in the ALTTO trial,” she said. The large ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, conducted jointly by the Intergroup in the US and the Breast International Group in Europe and globally, is enrolling thousands of patients to explore different combinations of one year of adjuvant therapy for early breast cancer, including lapatinib plus trastuzumab. The four arms of the study will be: chemotherapy followed by trastuzumab. chemotherapy followed by lapatinib. chemotherapy plus trastuzumab followed by lapatinib. chemotherapy plus trastuzumab plus lapatinib followed by trastuzumab and lapatinib. “This trial will inform us whether both drugs should be used together as adjuvant therapy for HER2 breast cancer,” Dr. Mayer said. Preliminary Data for Novel Combination A short, 12-week, preliminary Phase II study, presented by trastuzumab pioneer Dennis Slamon, MD, Professor and Chief of the Division of Hematology/Oncology at David Geffen School of Medicine at UCLA, showed promising activity using less than full doses of two oral multikinase inhibitors that block different pathways involved in the downstream effects of HER2 compared with lapatinib alone in HER2-positive metastatic breast cancer. Pazopanib is directed against the VEGF receptor and trastuzumab against the HER2 receptor. Patients with advanced or metastatic HER2-positive breast cancer were randomized to the combination of pazopanib plus lapatinib or lapatinib alone. After 12 weeks, patients with aggressive or stable disease were taken off therapy and put on trastuzumab. Dr. Slamon had no long-term final safety data to report at the meeting. The study was only 12 weeks long as a safety measure, so that patients who had disease progression could be given trastuzumab, which has established benefit in this population. “This is the first Phase II study of this pure oral regimen,” Dr. Slamon said, noting that more study is needed to determine the safety and efficacy of this combination. The primary endpoint was 12-week progression, and progression-free survival favored the combination arm: 84% vs 63%, respectively. Scans were performed in 114 patients, and a significant increase in target lesion response was seen in the combination arm. Data were still missing on a number of patients at the time of Dr. Slamon's presentation. A preliminary review of short-term safety data showed that Grade 3 or 4 diarrhea occurred in 5% of the combination arm vs 9% of the monotherapy arm. All four patients who had a greater than 20% decrease in left ventricular ejection fraction were in the combination arm; three of these patients had been previously treated with anthracyclines; all cases resolved upon discontinuation. Transient elevations in transaminases were seen in the combination arm, all of which resolved when treatment stopped. “Further analysis of these data are ongoing. The safety profile of this combination needs to be determined, especially in anthracycline-pretreated patients. The cardiac signal is worrying,” Dr. Slamon said. Putting the Data Together Dr. Esteva noted that a goal of front-line treatment of HER2-positive metastatic breast cancer is to overcome resistance to trastuzumab, and that the preliminary study by Slamon et al suggests that the combination of small molecule tyrosine kinase inhibitors may be able to be used as front-line therapy for this purpose. “But a significant number of patients were missing in the 12-week analysis. When unknown patients were censored, then progression-free survival was improved. Efficacy data were missing on 20 percent or more patients, and we need these data to assess the combination,” Dr. Esteva commented. “The use of non-chemotherapy-containing regimens is an appealing concept for metastatic breast cancer. Toxicity is increased with chemotherapy, but the therapeutic efficacy of combined biologic therapy must be the same as chemotherapy or better in order to be the preferred therapy. For now, the combination of trastuzumab plus chemotherapy is the preferred option for front-line treatment of HER2-positive metastatic breast cancer.” Proof of Concept Dr. Mayer commented that the study by Slamon et al provides proof of concept that combined HER2 and angiogenesis blockade is potentially better than just HER2 blockade. “This is the right question to ask—that is, whether blocking these two targets is more clinically relevant in HER2-positive disease. This makes sense, because HER2 tumors have increased levels of VEGF,” she continued. “Pazopanib and lapatinib affect different pathways that cross talk.” Dr. Mayer said that the combination of bevacizumab (a monoclonal antibody directed against VEGF) plus trastuzumab (a monoclonal antibody directed against HER2), was found to be safe and active in Phase I and II trials. An ongoing cooperative group Phase III trial (CTSU/ECOG 1105) is evaluating the first-line combination of chemotherapy and trastuzumab with or without bevacizumab. Urologic Cancer Increases Risk for Colorectal Cancer Previous diagnosis of urologic cancer increases the risk of subsequent colorectal cancer and vice versa, according to a study published in Archives of Internal Medicine (2008;168:1003–1009). Audrey H. Calderwood, MD, of the Department of Medicine in the Section of Gastroenterology at the University of Chicago Medical Center, led the retrospective cohort analysis of the Surveillance Epidemiology and End Results public database from 1973 to 2000 assessing the association between the cancers. Included in the study were 186,972 patients with a urologic cancer (52,449 with renal parenchymal cancer; 6,403 with renal pelvis cancer; 3,744 with ureteral cancer; and 124,376 with bladder cancer) and 375,597 patients with colorectal cancer (251,946 with colon cancer and 105,651 with rectal cancer). Overall, patients with cancer of the upper urinary tract had a significant increase in risk of subsequent colorectal cancer as compared with the general population. A total of 2,789 patients with urologic cancer subsequently developed colorectal cancer (incident rate of 272.2 per 100,000 person-years). Patients who received the diagnosis of renal pelvis cancer before the age of 50 were approximately five times more likely to develop colorectal cancer, and patients diagnosed with ureteral cancer before the age of 60 had a more than two-fold increased risk for subsequent colorectal cancer. A total of 3,026 colorectal cancer patients were subsequently diagnosed with urologic cancer. Although patients diagnosed with colorectal cancer before age 50 had a two-fold increase in their risk for any subsequent urologic cancers compared with the general population, the relative risk by age of diagnosis differed among the different types of urologic cancer: Patients with colorectal cancer who received a diagnosis before the age of 50 had a 2.29-fold increase in subsequent renal parenchymal cancer, a 6.20-fold increase in subsequent renal pelvis cancer, a 6.37-fold increase in subsequent ureteral cancer, and a 1.66-fold increase in subsequent bladder cancer. The findings show that some patients with specific urologic cancers are at a higher risk for subsequent invasive colorectal cancer and may benefit from earlier screening and more frequent surveillance colonoscopic examinations, and patients with a primary diagnosis of colorectal cancer, especially those of a younger age, should be considered at increased risk for specific urologic cancers as well, the authors concluded.