In a Canadian population-based retrospective cohort study reported in JAMA Oncology, Ethier et al identified real-world survival outcomes among women receiving pertuzumab and trastuzumab emtansine (T-DM1) for stage IV HER2-positive breast cancer, observing that outcomes appeared to be poorer than those reported in pivotal clinical trials of the agents.
As stated by the investigators, “Clinical trials have shown that the addition of pertuzumab to trastuzumab-based chemotherapy for first-line treatment of HER2-positive metastatic breast cancer is associated with considerable improvement in overall survival. In the second-line setting, T-DM1 improves overall survival compared with capecitabine/lapatinib in patients previously treated with trastuzumab-based chemotherapy. However, there are few data describing long-term real-world outcomes with these agents.”
Study Details
All patients treated with pertuzumab and T-DM1 following reimbursement approval in Ontario were identified using the Ontario Cancer Registry linked to electronic treatment databases. The current analysis included women with stage IV disease receiving pertuzumab for first-line treatment from December 2013 through December 2017 and those treated with second-line T-DM1 from May 2014 through December 2017.
In this population-based cohort study, the survival of patients treated with pertuzumab and T-DM1 in routine practice appeared inferior to results from pivotal clinical trials. Differences in outcome likely reflect differences in patient population and previous lines of therapy in routine practice. Further work is needed to understand the effectiveness of T-DM1 after pertuzumab exposure.— Ethier et al
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Key Findings
A total of 795 women received pertuzumab (median age = 57 years) and a total of 506 received T-DM1 (median age = 56 years).
Among all patients receiving pertuzumab, median overall survival was 43 months (interquartile range [IQR] = 16.2 months–not available) and median time on treatment was 14 months (IQR = 6.0–26.2 months). Older age (hazard ratio [HR] per 10-year increase = 1.30, 95% confidence interval [CI] = 1.18–1.43, P < .001) was associated with shorter overall survival, whereas time from diagnosis to pertuzumab initiation of less than 3 months was associated with longer survival (HR = 0.55, 95% CI = 0.37–0.82, P = .001).
In the T-DM1 cohort, the proportion of pertuzumab-naive patients decreased over time from 68 (74.7%) of 91 in 2014 to 16 (18.0%) of 89 in 2017 (P < .001). Median overall survival was 15 months (IQR = 6.7–27.7 months) and median time on treatment was 4 months (IQR = 1.4–9.0 months). Median overall survival was 19 months among 183 pertuzumab-naive patients vs 12 months among 323 with prior pertuzumab treatment (HR = 0.70, 95% CI = 0.55–0.89, P = .004). Not having undergone primary breast surgery (mastectomy or partial mastectomy) within the prior 10 years was also associated with improved overall survival (HR = 0.72, 95% CI = 0.54–0.97, P = .03).
In discussing their findings in the context of outcomes in pivotal trials, the investigators noted that median overall survival in the pertuzumab group in the CLEOPATRA trial was 57 months, compared with 43 months in the current analysis. Median progression-free survival was 19 months in CLEOPATRA, compared with median time on treatment (as a surrogate for progression-free survival) of 14 months in the current analysis. In the EMILIA trial, median overall survival was 30 months in the T-DM1 group, compared with 15 months in the current analysis; however, the EMILIA trial differed from the T-DM1 cohort in the current analysis in that pertuzumab was not approved for use in the metastatic setting during the trial, whereas two-thirds of patients in the current T-DM1 cohort received prior pertuzumab. This observation—combined with the poorer overall survival among pertuzumab-pretreated patients in the T-DM1 cohort in the current analysis—suggests that real-world patients who have been pretreated with pertuzumab may be less responsive to subsequent anti-HER2 therapy.
The investigators concluded, “In this population-based cohort study, the survival of patients treated with pertuzumab and T-DM1 in routine practice appeared inferior to results from pivotal clinical trials. Differences in outcome likely reflect differences in patient population and previous lines of therapy in routine practice. Further work is needed to understand the effectiveness of T-DM1 after pertuzumab exposure.”
Josee-Lyne Ethier, MD, MSc, of the Department of Oncology, School of Medicine, Queen’s University, Kingston, Ontario, is the corresponding author for the JAMA Oncology article.
Disclosure: This study was supported by a Canadian Institutes of Health Research Operating Grant. For full disclosures of the study authors, visit jamanetwork.com.
