Promising Novel Approaches for Metastatic HER2-Overexpressing Breast Cancer Progressing on Trastuzumab: (1) Pertuzumab+Trastuzumab Active after Failed Sequential Therapy; (2) Adding Lapatinib & Continuing Trastuzumab Better than Lapatinib Alone, Reinforcing Trastuzumab Use Beyond Progression; (3) Trastuzumab+Ridaforolimus Effective in Heavily Pretreated Patients; (4) T-DM1 Shrinks Tumors after Multiple Previous Treatments

The backbone of treatment for women with metastatic HER2-overexpressing breast tumors is trastuzumab. But what should be done for women with advanced breast cancer who experience disease progression while on trastuzumab? In the past, doctors tended to discontinue that medication and try other treatments. But an increasing number of studies show that continuing trastuzumab therapy while adding other drugs—some old and some new—offers better disease control. In one study reported at the CTRC-AACR San Antonio Breast Cancer Symposium, a one-two punch from pertuzumab and trastuzumab was found to be effective in patients who progressed on sequential treatment with each monoclonal antibody alone. Another showed that maintaining trastuzumab therapy while adding lapatinib provides greater disease control than lapatinib treatment alone. A third showed that the combination of trastuzumab and the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus has antitumor activity in heavily pretreated trastuzumab-resistant HER-positive metastatic breast cancer patients. Also, researchers found that single-agent trastuzumab-DM1 is effective in heavily pretreated women who received more than two years of prior HER2-directed therapy. Pertuzumab+Trastuzumab Active after Failed Sequential Therapy SABCS Abstract 5114 and 5088 The combination of pertuzumab and trastuzumab shows efficacy in patients with HER2-positive metastatic breast cancer whose disease has progressed on sequential treatment with each monoclonal antibody alone, researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium. Overexpression of the HER2 gene is found in 20% to 30% of breast tumors, noted Jose Baselga, MD, Chairman of the Medical Oncology Service and Director of the Division of Medical Oncology, Hematology, and Radiation Oncology at the Vall d'Hebron University Hospital in Barcelona. Two humanized monoclonal antibodies, trastuzumab and pertuzumab, have thus been developed, targeting different epitopes of HER2, he said. Trastuzumab binds to the juxta-membrane eptiope, inhibiting ligand-independent HER2 signaling. Pertuzumab represents the first in a new class of investigational agents known as HER-dimerization inhibitors. It is designed to bind to the HER2 receptor and inhibits the ability of HER2 to interact with other HER family members (HER1/EGFR, HER2, HER3, and HER4). In the first two cohorts of the current Phase II trial (article now available online ahead of print in the Journal of Clinical Oncology), the combination of pertuzumab plus trastuzumab was highly effective is patients who had disease progression on trastuzumab. The results were so promising, Dr. Baselga said, that he and his co-researchers amended the protocol to allow recruitment of a third cohort of patients who are receiving pertuzumab as monotherapy. Combo Therapy Best At the meeting, Dr. Baselga reported on the third cohort of 29 patients with HER2-positive metastatic breast cancer who were administered pertuzumab monotherapy after progressing on trastuzumab plus chemotherapy. Of those, one patient did not progress and remains on pertuzumab monotherapy. Another 12 patients discontinued treatment, and 16 patients with documented progressive disease on pertuzumab monotherapy were also administered trastuzumab. Trastuzumab was given as either a 4 mg/kg loading dose followed by 2 mg/kg weekly or an 8 mg/kg loading dose followed by 6 mg/kg every three weeks. Pertuzumab was given an 840 mg loading dose, followed by 420 mg every three weeks. Of the 19 patients on pertuzumab monotherapy, one (3.4%) had a partial response and two (6.9%) had stable disease for eight or more cycles, leading to an objective response rate of 3.4% and a clinical benefit rate of 10.3%, Dr. Baselga reported. Of the 16 patients who received the monoclonal antibody doublet, 14 have achieved the overall best response endpoint of eight cycles of assessment, he said. Three (21.4%) achieved a partial response and three (21.4%) had stable disease for eight or more cycles, for a clinical benefit rate of 43.8%. Eight (57.1%) patients experienced progressive disease. “In total, three patients remain on combination therapy. One had not reached the overall best response endpoint at eight cycles and showed stable disease at last tumor assessment. One patient died of hepatorenal failure due to progressive disease before an efficacy assessment was carried out,” Dr. Baselga said. Safety Profile The most frequent adverse events were diarrhea (48% of patients on monotherapy and 31% of patients on combination therapy) and nausea (34% of patients in monotherapy and 31% of patients on combination therapy). Three patients showed a Grade 2 drop in left ventricular ejection fraction (LVEF)—two during pertuzumab monotherapy and one during combination therapy. All the LVEF decreases were asymptomatic. Cardiac Safety Trial Also at the meeting, researchers reported results of a retrospective analysis showing that the cardiac safety profile of pertuzumab appears to be similar to that of trastuzumab. The analysis involved 569 patients who received pertuzumab: 302 as a single agent, 175 in combination with cytotoxic chemotherapy, and 92 in combination with trastuzumab or erlotinib. Overall, 5.7% of patients experienced a significant drop in LVEF. Of these, four (0.7%) patients developed symptomatic heart failure.JOSE BASELGA, MD: “The clinical benefit rate in patients on combination therapy is very impressive. The doublet is very active without significant toxicity.”The rate of asymptomatic LVEF decrease was similar regardless of whether pertuzumab was given as monotherapy or in combination with chemotherapy or trastuzumab or erlotinib, reported Thomas M. Suter, MD, Associate Professor of Medicine at the Swiss Cardiovascular Center of the University of Berne. “In carefully selected patients, the combination of pertuzumab and trastuzumab does not appear to increase the rate of cardiac events,” he said. Funding for the poster study was provided by Genentech. Phase III Trial Underway Dr. Baselga said that the combination of trastuzumab, pertuzumab, and docetaxel is now being evaluated as first-line treatment of metastatic breast cancer patients in the Phase III CLEOPATRA (Clinical Evaluation Of Pertuzumab and Trastuzumab) trial, Dr. Baselga said. The primary objective of the study, which is now recruiting patients, is to compare progression-free survival rates in patients randomized in a one-to-one fashion to either trastuzumab plus docetaxel and placebo or trastuzumab plus docetaxel and pertuzumab. Secondary objectives include the comparison of overall survival rates, objective response rates, and the duration of response between the two arms, and to evaluate safety and quality of life. The investigators will also evaluate biomarkers and correlate them with clinical outcomes. Key eligibility criteria include age 18 years or older; confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease; formalin-fixed and paraffin-embedded tissue for central testing; overexpression of HER2; baseline LVEF of at least 50%, and an Eastern Cooperative Oncology Group performance status of 0/1. If this study is successful, this combination of trastuzumab plus pertuzumab and chemotherapy has the potential to become a new standard of care in HER2-positive metastatic breast cancer, Dr. Baselga said. Additionally, a large randomized Phase II trial is investigating trastuzumab, pertuzumab, and capecitabine in patients who have disease progression after first-line trastuzumab therapy, he said. Discussion Asked for her opinion, Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL, called the clinical benefit rate in patients on the combination therapy “very impressive” and said that it was promising that the doublet is very active without significant toxicity.” Adding Lapatinib & Continuing Trastuzumab Better than Lapatinib Alone, Reinforcing Trastuzumab Use Beyond Progression SABCS Abstract 61 In women with metastatic HER2-overexpressing breast tumors that progress on trastuzumab, maintaining trastuzumab therapy while adding lapatinib provides greater disease control than lapatinib treatment alone, researchers report. “We observed a 26% reduction in the risk of death among women on the combination therapy,” said Kimberly L. Blackwell, MD, Director of the Clinical Trials Program in Breast Cancer at Duke University Medical Center. “The updated intention-to-treat overall survival data indicated that there was a 4.5-month improvement in overall survival in favor of early randomization to combination therapy over lapatinib alone. This is highly statistically significant,” she said during her oral presentation at the CTRC-AACR San Antonio Breast Cancer Symposium. Dual Hit to HER2 The addition of lapatinib to trastuzumab therapy provides a dual hit to the HER2 receptor that is overexpressed in these women, Dr. Blackwell said. Trastuzumab is a humanized monoclonal antibody against HER2, while lapatinib is an oral small-molecule epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor. Dual targeting of the HER2 receptor is believed to disrupt downstream signaling pathways and, in turn, interfere with cancer cell proliferation and cell survival, she said.KIMBERLY L. BLACKWELL, MD: “To put this into clinical perspective, the 4.5 month improvement in this population of heavily pretreated HER2-positive patients is similar to that seen with other biological agents and chemotherapy in first-line therapy without the side effects seen with traditional chemotherapy.”“In breast cancer, the targeting of [HER2] overexpression has led to many clinical benefits. Because [they attack the HER2 receptor differently], it was very appealing to combine these two agents without using a chemotherapy backbone.” At the San Antonio meeting, Dr. Blackwell updated the survival data of the EGF104900 study, a randomized clinical trial of patients with HER2-positve breast cancer who have recently had disease progression on trastuzumab. Documented Progression with Anthracyclines, Taxanes, & Trastuzumab The study involved 296 metastatic breast cancer patients with documented HER2-positive tumors and documented progression on anthracycline, taxane, and trastuzumab regimens. The participants’ last treatment regimen had to have included trastuzumab. The patients were a median age 51 and had good performance status; they had a median of four to five chemotherapy regimens prior to entering the trial. The women were randomized to oral lapatinib (1,500 mg per day) or oral lapatinib (1,000 mg per day) plus intravenous trastuzumab (2–4 mg/kg weekly). Patients were allowed to cross over to combination therapy if they had disease progression on single-agent lapatinib. A total of 77 (52%) of the 148 patients assigned to lapatinib monotherapy eventually did receive combination therapy—about half of them before the eight-week staging assessment. “The median number of trastuzumab regimens for advanced breast cancer was three different regimens in each arm,” Dr. Blackwell said. Half of the patients had estrogen receptor-negative tumors. “Three-fourths of the patients had known visceral disease, and unlike many of the studies that were done with HER2-targeted agents in the early days, we allowed for known brain metastases, and these were equally matched in the two arms.” Specifically, 20 of the 148 women in the monotherapy arm and 16 of the 148 women in the combination arm had brain metastases. Study Results The median survival time of the women taking lapatinib and trastuzumab was 14 months compared with 9.5 months for lapatinib alone, Dr. Blackwell reported. After one year of treatment, 41% of women who were treated with lapatinib monotherapy were alive vs 56% of the women treated with lapatinib. “The absolute survival difference remained at 10% at six months in favor of the combination therapy. This means that 15 more women out of 100 are alive at a year because they received combination therapy,” Dr. Blackwell said. “The survival benefit was seen in spite of the fact that over half the patients crossed over to receive dual blockade.” She said that after updating cardiac and safety events, the combination treatment did not appear to signal any unexpected concerns: “There has only been one cardiac-related death. That occurred in the combination arm and it was attributable to a fatal pulmonary embolism,” she said. The only Grade 3–4 adverse event that occurred in 5% or more of the patients was diarrhea, occurring in 8% of patients in the combination arm and 7% of those in the lapatinib arm. ‘Amazing That No Significant Safety Signal’ “As a clinician, I think it's amazing there was not a significant safety signal. And considering the heavily pretreated nature of these patients, the fact that we really did not see an increase in side effects with the combination of agents is remarkable,” Dr. Blackwell said. “To put this into clinical perspective, the 4.5 month improvement in this population of heavily pretreated HER2-positive patients is similar to that seen with other biological agents and chemotherapy in first-line therapy without the side effects seen with traditional chemotherapy.” ALTTO: 2 Study Designs The findings offer strong support for the Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) study, whose total accrual goal is 8,000 patients, she said. The multicenter open-label trial is employing two study designs: In Design 1, which is now closed to enrollment, all neoadjuvant and adjuvant chemotherapy is completed prior to administration of trastuzumab and/or lapatinib. In Design 2, all anthracycline-based neoadjuvant and adjuvant chemotherapy is completed prior to administration of trastuzumab and/or lapatinib, while paclitaxel is given concurrently with the drug(s). In both designs, the trial will compare four treatment options: Trastuzumab alone for 52 weeks; lapatinib alone for 52 weeks; trastuzumab for 12 weeks, followed by a 6-week break, followed by lapatinib for 34 weeks; and lapatinib in combination with trastuzumab for 52 weeks. ‘Significant for Many Reasons’ Asked to comment on the findings, Edith A. Perez, MD, Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL, said, “In the US, there's a tendency of doctors to take women off trastuzumab once it fails to help, but this shows significant benefit to continuing with it and adding a second targeted agent. “The results of this trial are significant for many reasons,” she continued. “This is the first time that someone has shown that continuing with trastuzumab through progression and adding a second type of HER2-therapy leads to a significant survival improvement. It really validates the concept that trastuzumab is an important drug to maintain.” The study was funded by GlaxoSmithKline PLC. Kathleen Pritchard: Already Shown? During the question-and-answer period, Kathleen I. Pritchard, MD, Head of Clinical Trials & Epidemiology at Toronto Sunnybrook Regional Cancer Centre, said, “With all due respect, I think we have already shown that continuing trastuzumab in this setting is useful. There is evidence to suggest that just trastuzumab [would be effective]. It would have been good to have a trastuzumab-alone arm.” Dr. Blackwell replied that since the patients in the study had just progressed on trastuzumab, “that design was not considered feasible.” Dr. Pritchard countered that she found that unfortunate. Another member of the audience asked if the findings justify the routine use of trastuzumab and lapatinib in patients who progress on trastuzumab. Dr. Blackwell said that in her own practice, she will consider the combination for patients who had documented benefit from HER2-directed therapy. Trastuzumab+Ridaforolimus Effective in Heavily Pretreated Patients SABCS Abstract 3091 A combination of trastuzumab and the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus is well tolerated, with encouraging antitumor activity in heavily pretreated trastuzumab-resistant HER-positive metastatic breast cancer patients, researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium. “We saw better than expected [progression-free] survival in this group of heavily pretreated women. And there really were no safety issues,” said Denise A. Yardley, MD, Director of Breast Cancer Research at the Sarah Cannon Research Institute. Dr. Yardley said that mTOR, a key regulator in cell growth and division, is an attractive target for cancer therapy since activation of the mTOR pathway is observed in a substantial proportion of breast cancers that are associated with reduced PTEN activity. In patients with advanced HER2-positive breast cancer, PTEN loss is implicated in 50% of cases of trastuzumab resistance, she said. The new study aimed to determine if ridaforolimus with trastuzumab be in breast cancer patients with trastuzumab Design The Phase II trial included patients with HER2-positive metastatic breast cancer who had developed to trastuzumab, as disease progression on trastuzumab treatment with no more than two prior trastuzumab regimens. All the patients were given administered at mg once for five a also received trastuzumab at a loading dose of 4 followed by 2 The treatment for both agents was four weeks. In of the trial, patients were for safety after at least one of therapy, and the objective response rate was every two cycles to The study design that if one or more patients an objective patients would to 2, they would on study treatment disease The cohort included 34 patients with a median age of had three or more prior chemotherapy and 56% had two or more prior trastuzumab regimens. Dr. Yardley one After the treatment with four cycles of and followed by After metastases, the patient was on first-line paclitaxel plus trastuzumab, followed by plus trastuzumab. The eventually had disease progression on trastuzumab plus Dr. Yardley said. included and The patient developed while on and the study a month are heavily pretreated Dr. Yardley said. Safety Profile as effects were the expected safety profile of either she said, and One patient died due to a large which was by investigators as being to One patient Grade 4 Grade events included four cases of and two cases each of and There was one of Grade nausea and one of Grade In addition to the patient who four patients discontinued therapy before the first disease assessment, three due to adverse Of the patients, five showed partial had stable disease, and to The median progression-free survival time was weeks, and at the time of the eight patients remained on study The study was funded by than “We to show a response rate of at least 5% and it was Dr. Yardley ridaforolimus with trastuzumab or other HER2-directed is of Asked her for this MD, Associate Professor of Medicine in the Division of Oncology at Cancer that as effective as trastuzumab has to some patients eventually “The we on clinical activity by continuing therapy and adding This combination shows early but is after SABCS Abstract trastuzumab-DM1 has activity in a heavily pretreated population of patients with metastatic breast cancer who had to to a median of other and who received more than two years of prior HER2-directed therapy, to results of a Phase II trial reported at the CTRC-AACR San Antonio Breast Cancer Symposium. of women whose tumors had progressed after treatment with an anthracycline, a taxane, trastuzumab, and lapatinib had an objective response to said MD, Professor of Medicine at Medical and a at the Breast Oncology Center at Cancer Institute. At the San Antonio Breast Cancer was shown to have activity in and patients. “This study those results to a different population of patients with very Dr. said. that is an designed for the targeted of the trastuzumab. The a very stable with trastuzumab so that is not trastuzumab that have HER2 “The cytotoxic drug to the cancer so it's not and other And trastuzumab does all the that trastuzumab Dr. his poster prior to his early oral poster The study involved patients with HER2-positive metastatic breast cancer with prior to an anthracycline, a taxane, trastuzumab, and lapatinib and who had received at least two HER2-directed regimens in the metastatic All had disease progression on the last regimen they The median age of the patients was had an Eastern Cooperative Oncology Group performance status of and had a performance status of patients had three or more metastatic and had received a median of and to 15 agents for metastatic disease, and a median of eight agents in all All but one patient had received five prior The median duration of prior trastuzumab therapy was and the median duration of prior lapatinib therapy was The women received an of mg/kg of given as an intravenous every three weeks. A median of were patients a dose reduction to mg/kg and six a dose reduction to The for the dose included Grade 2 and Grade 4 Study Results The objective response rate as by an was the primary all of which were partial The duration of response from to The clinical benefit as stable disease or or partial response for at least days, was as by the The of patients confirmed to have HER2-positive disease had better objective response rate of and a clinical benefit rate of There were no new or safety with the Dr. said, adding that most were and patient died of disease, but he had and disease, so we if it was due to the study Dr. Overall, of patients had a adverse or A total of of patients discontinued therapy because of an adverse Two patients had a drop in left ventricular ejection fraction of to but developed heart “This is the first study at women who have so many other treatments. But we think these results are as good as seen is a Dr. said. Results the new “The response rate in the study is in a group of patients this said Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Oncology at the Mayo Clinic in Jacksonville, She with Dr. that the death due to failure is not given the overall patients are very and now we have no to offer The of the poster Jose Baselga, MD, Chairman of the Medical Oncology Service and Director of the Division of Medical Oncology, Hematology, and Radiation Oncology at Vall d'Hebron University Hospital in said, “We think it was to see a good in patients treated with a median of other “This is very and the is This has activity in the HER2 One has to be very and a drug that Dr. that the data is to the it is only Phase because these patients have no other Phase II Trials in the Dr. Baselga the audience that Phase II and Phase II of in setting are or The current study was funded by and and to the is being evaluated in Phase II and Phase III clinical in patients with locally advanced or metastatic HER2-positive breast cancer who have disease progression on a chemotherapy regimen trastuzumab.