Pertuzumab Added to Trastuzumab and Chemotherapy Improves Survival in HER2+ Breast Cancer

The combination of pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel-maintained improvements in survival for more than 8 years of follow-up in the first-line treatment of patients with HER2-positive metastatic breast cancer, according to long-term results from the phase III CLEOPATRA study published in the Lancet Oncology. This represents the longest known follow-up for this patient population.

“HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%,” wrote the study authors, led by Sandra M. Swain, MD, FACP, of the Georgetown University Medical Center.

In the study, 808 patients were randomized to receive either placebo plus trastuzumab and docetaxel (n = 406) or pertuzumab in combination with trastuzumab and docetaxel (n = 402). Of the patients enrolled in the intention-to-treat (ITT) population, only 396 in the placebo arm were treated and included in the safety population. In the pertuzumab arm, there were 9 patients who crossed over from the placebo arm who received non-randomized treatment and 2 patients from the pertuzumab arm who did not receive treatment, which left 408 patients in the ITT population for the cohort.

Overall survival (OS) events occurred in 58% of the ITT population who received the placebo combination (n = 235), and in 69% of patients who were given the pertuzumab combination (n = 280). The median OS in the pertuzumab arm was 57.1 months (95% CI, 50-72) versus 40.8 months (95% CI, 36-48) in the placebo group (HR, 0.69; 95% CI, 0.58-0.82).OS was also reviewed in a landmark analysis at 5, 6, 7, and 8 years. The 8-year landmark OS rate, most notably, was 37% (95% CI, 31%-42%) in the pertuzumab group and 23% (95% CI, 19%-28%) in the placebo group.

Progression-free survival (PFS) outcomes were investigator-assessed more than 4 years after data cutoff. The median investigator-assessed PFS observed in the pertuzumab group was 12.4 months (95% CI, 10-14) compared with 18.7 months (95% CI, 17-22) in the placebo group (HR, 0.69; 95% CI, 0.59-0.81), which included 304 PFS events in the pertuzumab arm and 329 in the placebo arm.

The patient subgroups included in the CLEOPATRA study included patients who received prior trastuzumab, as well as patients with PIK3CA wild-type tumors and PIK3CA-mutant tumors. A post-hoc subgroup analysis demonstrated efficacy results that were similar to the overall population. Specifically, individuals who were previously treated with trastuzumab had a median OS of 53.8 months (95% CI, 41-71) in the pertuzumab group and 46.6 months (95% CI, 30-70) in the placebo group (HR, 0.86; 95% CI, 0.51-1.43). This trend was consistent among patients with both PIK3CA wild-type and PIK3CA-mutant tumors.

Follow treatment in the CLEOPATRA study, 25 patients were enrolled in a pertuzumab extension study (PEREX). Eleven patients from the CLEOPATRA study went on to a post-trial access program, while 23 other patients received ongoing pertuzumab as the standard of care for HER2-positive metastatic breast cancer.

Responses to treatment with pertuzumab in combination with trastuzumab and docetaxel appeared to be durable in this patient population. In total, 99 pertuzumab responders were classified as long-term responders versus only 53 patients who responded to the placebo combination. The durability of responses differed depending on baseline ECOG score, estrogen and progesterone receptor status, HER2 immunohistochemistry status, histological tumor grade, and whether or not patients had previous anthracyclines, radiotherapy, taxanes, or trastuzumab. Notably, in the pertuzumab group, HER2 immunohistochemistry of 3 or higher and PIK3CA mutation showed the largest differences in response.

In terms of safety, the profiles of each drug utilized in the study were consistent with the known safety. Patients treated with pertuzumab had higher incidences of any-grade diarrhea and rash while patients in the placebo arm had higher incidences of grade 3/4 adverse events (AEs). The most common grade 3/4 AE overall was neutropenia, which was observed in 49% of patients in the pertuzumab arm (n = 200) and 46% in the placebo arm (n = 183).

There were 238 patient deaths in the pertuzumab arm prior to crossover. The placebo arm also had 261 deaths, which were predominantly due to disease progression. Eight patients who received pertuzumab and 12 who received placebo died as a result of AEs. The most common death-causing AEs were febrile neutropenia in the pertuzumab group (n = 3) and myocardial infarction in the placebo group (n = 3). Treatment-related deaths were observed in both cohorts with 3 patients experiencing febrile neutropenia, respiratory tract infection, or somnolence in the pertuzumab group and 3 patients experiencing intestinal perforation, pneumonia, sepsis, myocardial infarction, and/or cerebrovascular accident in the placebo group.

Fifty patients from the crossover population died due to either disease progression (24%), metastasis (1%), or an unknown cause (1%).

CLEOPATRA was double-blinded, randomized, and placebo-controlled. Patients in the study were administered the study drugs intravenously every 3 weeks. Pertuzumab was administered at a dose of 840 mg on day 1 of each cycle, as was the matching placebo. The dosage of pertuzumab was decreased to 420 mg in subsequent cycles. Patients received trastuzumab on day 2 of the first cycle, at a dose of 8 mg/kg, which was lowered to 6 mg/kg for subsequent cycles. Docetaxel chemotherapy was administered on day 2 also, at a dose of 75 mg/m2 on the first cycle and 100 mg/m2 for all subsequent cycles.

The study authors noted that historically, the overexpression of HER2 in metastatic breast cancers leads to aggressive disease and poor outcomes. Anti-HER2 monoclonal antibodies like trastuzumab showed promise in other studies as treatment of these patients when added to chemotherapy. However, it was hypothesized that outcomes observed with trastuzumab could be improved upon. The CLEOPATRA study has confirmed this hypothesis.

_Reference:

_{Swain SM, Miles D, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. doi: 10.1016/ S1470-2045(19)30863-0.}