MADRID—The addition of the monoclonal antibody pertuzumab (Perjeta) to trastuzumab-based regimens appears to present a practice-changing, “unprecedented,” improvement in overall survival for women diagnosed with metastatic breast cancer, researchers reported here at the European Society for Medical Oncology Congress.
In presenting the results, the final data from the CLEOPATRA trial, Sandra M. Swain, MD, Professor of Medicine at Georgetown University and Medical Director of Washington Cancer Institute at MedStar Washington Hospital Center, said the pertuzumab/trastuzumab combination with docetaxel increased overall survival in this large placebo-controlled study by 15.7 months and conferred this improvement without increasing toxicity when compared with the same regimen without pertuzumab.
“I can't tell you how happy I am to be here to tell you about our results,” she said at an ESMO news conference. “I think many of us work our entire careers to have these kinds of results, and I have been working in this field for 30 years.”
Women treated with chemotherapy plus trastuzumab and pertuzumab achieved a median overall survival of 56.5 months compared with 40.8 months for women treated with placebo plus trastuzumab and docetaxel, she said.
20 Months Longer than Previous Analysis
“I think these results are phenomenal,” she said. “These are the final overall survival analyses of the CLEOPATRA study. These results are 20 months longer than the previous analysis. The hazard ratio is 0.68 which is very significant.
“What is more important for us as clinicians rather than statistics is the median survival. The median survival for trastuzumab is already very good at 40.8 months. Trastuzumab therapy really changed things for HER2-positive breast cancer, and now adding pertuzumab increased median survival by 15.7 months to 56.5 months. That, to me, is incredible. I've never seen that in any other trial of metastatic breast cancer.
“The 56.5 month median overall survival is unprecedented in this indication and confirms the pertuzumab regimen as first-line standard of care for patients with HER2-positive metastatic breast cancer.”
Eric Van Cutsem, MD, the moderator of the news conference, who is Professor of Medicine at Leuven University, Belgium, said in an interview, “I think this information is going to be practice changing in metastatic breast cancer. Such a big difference in outcomes in survival with such little toxicity is compelling.”
204 Centers, 25 Countries, 808 Patients
For the trial, Swain, a past President of the American Society of Clinical Oncology (2012-2013) and her colleagues from 204 centers in 25 countries enrolled 808 patients in the CLEOPATRA study. A total of 406 women were assigned to receive trastuzumab plus docetaxel for at least six cycles of therapy unless they could not tolerate the drug—the actual median number of cycles completed was eight; the other 402 women were treated with the same regimen plus pertuzumab. Patients were treated until disease progression. About half the women in the study presented with advanced disease.
Pertuzumab was administered with a loading dose of 840 mg followed by a maintenance dose of 420 mg. A trastuzumab loading dose of 8 mg/kg was followed by a 6 mg/kg maintenance dose, and docetaxel was infused at a starting dose of 75 mg/m2, which could be escalated to 100 mg/m2 if tolerated. The drugs were given every three weeks.
Swain explained that preclinical and early clinical data suggested that the two drugs could be used together because the monoclonal antibodies were aimed at targeting the metastatic cancers at different sites in the cells.
In addition to the overall survival data, the researchers also performed an updated analysis of progression-free survival—finding that women who received pertuzumab appeared to gain an improvement of 6.3 months of progression-free survival.
“It does suggest that in this blinded study, progression-free survival was a good surrogate for overall survival,” she said. In the placebo arm, progression-free survival was 12.4 months; in the pertuzumab arm it was 18.7 months.
Pertuzumab did not seem to influence the emergence of adverse side effects, she said. “When you have additional treatments you often have additional toxicities, and rash, mucositis, and diarrhea were greater with pertuzumab.”
About 68 percent of patients receiving pertuzumab reported diarrhea compared with about 49 percent of patients on single-antibody therapy. Rash was observed in 37.5 percent of patients on the dual-antibody therapy compared with 24 percent of those getting trastuzumab plus placebo. Mucosal inflammation was observed in 27 percent of patients on pertuzumab and 20 percent of patients on trastuzumab.
“There was a concern when we started this trial that we would see more cardiac events when we were using two monoclonal antibodies. But actually, we don't,” Swain said. “Adverse events were very similar, and perhaps less with pertuzumab. Symptomatic left ventricular dysfunction—heart failure—was observed in 1.8 percent of patients on trastuzumab and in 1.5 percent of patients with pertuzumab plus trastuzumab. We did not have additional heart failure symptoms.
“Dropping of left ventricular pumping fraction to below 50 percent—and asymptomatic dysfunction—was also less in the placebo arm—7.4 percent with trastuzumab and 6.1 percent with the combination,” she reported. “One new heart failure event in the pertuzumab group did resolve after the antibodies were stopped. And in 88 percent of the cases in which asymptomatic decline left ventricular function was observed, the condition was reversed.”
In response to questions regarding subgroups of patients and whether there were any groups who might benefit from the use of trastuzumab without pertuzumab, Swain said, “Based on the study results, and the consistency in the subgroups, I would recommend personally that all patients who have the opportunity to be treated for metastatic breast cancer receive dual-antibody therapy with pertuzumab and trastuzumab.
“There are studies ongoing—particularly with women who have HER2-positive, estrogen receptor-positive tumors—to see if they need to include pertuzumab. Right now, pending results of these trials, I would still give them the combination.”
CLEOPATRA was a pivotal Phase III study, funded by F. Hoffmann-La Roche Ltd. and Genentech, Inc., evaluating the addition of pertuzumab to trastuzumab and chemotherapy. The study authors had previously reported that the pertuzumab regimen significantly extended progression-free survival and overall survival. The new data reports the results of survival in CLEOPATRA after a median of 50 months of follow-up.
The women who were enrolled in the trial were a median 54 years old. More than 35 percent were from Europe, about 31 percent were from Asia, 17 percent were from North America, and 14 percent were from South America. More than 75 percent of the metastases were visceral.
In the current analysis, overall survival was analyzed using all randomized patients, with no adjustments for cross over once the study treatments were unblinded. Patients who crossed over from the placebo arm to the pertuzumab arm were analyzed as part of the placebo arm, explained. “As such, this is a very conservative final analysis of survival,” she said.
PODCAST: Listen on the iPad edition of this issue to Sandra Swain, MD, elaborate on the clinical implications of the CLEOPATRA findings, telling OT reporter Sarah Maxwell why dual HER2 blockade with a combination of trastuzumab and pertuzumab should now become the standard of care. Also commenting is Professor Eric Van Cutsem MD, PhD, who suggests the possibility of a broader application of the approach in other tumor types
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