Real-World Data For Pertuzumab and T-DM1 Demonstrates Inferior Outcomes Versus HER2+ Breast Cancer Clinical Trials


Compared with pivotal phase 3 trials, the use of pertuzumab in the frontline and T-DM1 in the second-line setting for HER2-positive metastatic breast cancer may lead to shorter survival outcomes.

In a population-based retrospective cohort study reported in JAMA Oncology, overall survival (OS) in patients with HER2-positive metastatic breast cancer who were treated with pertuzumab (Perjeta) or trastuzumab emtansine (Kadcyla; T-DM1) in the real-world setting was inferior to results reported in clinical trials.1

The database review that identified patients treated with pertuzumab concurrent with trastuzumab (Herceptin) in the first-line setting or T-DM1 in the second-line setting following reimbursement approval in a single-payer public health system showed that OS outcomes in most patient subgroups were inferior to those recorded in phase 3 clinical trials of CLEOPATRA (NCT00567190) and EMILIA (NCT00829166).

“The concept of the efficacy-effectiveness gap is increasingly recognized as an important limitation in the real-world application of clinical trial results, with growing evidence that outcomes observed for patients selected to participate in trials (efficacy) differ from those observed with the same drug in real-world circumstances (effectiveness),” wrote the study investigators who were led by Josee-Lyne Ethier, MD, MSc, of Queen’s University in Kingston, Ontario, Canada.

In 2012, the results of CLEOPATRA trial supported the approval of pertuzumab in combination with trastuzumab and docetaxel for use in women with treatment-naïve HER2-positive breast cancer. The addition to pertuzumab to trastuzumab in patients with HER2-positive metastatic breast cancer resulted in a statistically significantly longer median OS of 56.5 months versus 40.8 months with trastuzumab alone (HR, 0.68; 95% CI, 0.56-0.84; P <.001).2

In 2013, results from EMILIA served as evidence for the efficacy of T-DM1 in patients with HER2-positive metastatic tumors who had previously received trastuzumab therapy and a taxane, supporting FDA approval in this setting. A descriptive analysis of final OS showed that T-DM1 vs capecitabine and lapatinib (Tykerb) in patients with HER2-positive unresectable, locally advanced, or metastatic HER2-positive breast cancer led to a 25% reduction in the risk of death (0.75; 95% CI, 0.64-0.88) following prior trastuzumab-based therapy, with corresponding medians of 29.9 months and 25.9 months, respectively.3

Women receiving pertuzumab (n = 795) or T-DM1 (n = 506) in the study had a median age of 57 years (interquartile range [IQR], 49-67) and 56 (IQR, 48-66), respectively. In the total cohort, the median time on treatment was 14 months (IQR, 6.0-26.2) and the median OS was 43 months (IQR, 16.2-unavailable). Of note, in each successive year from 2014 through 2017, the number of pertuzumab-naïve patients recruited to the T-DM1 group decreased (P <.001), whereas none of the patients treated on the EMILIA trial had received prior pertuzumab.

In the pertuzumab group, the median OS was 43 months (IQR, 18.2-unavailable). Older age (HR, 1.30; 95% CI, 1.18-1.43; P <.001) was associated with poorer outcomes whereas initiating therapy within 3 months of diagnosis was linked with better results (HR, 0.55; 95% CI, 0.37-0.82; P = .001).

In the TDM-1 group, the median OS from T-DM1 initiation was 15 months, 12 months in patients who received prior pertuzumab (n = 323) and 19 months in those without prior exposure (n = 183). Similarly, median time on treatment was also shorter in patients with prior receipt of pertuzumab compared with the pertuzumab-naive subgroup, at 3 months vs 8 months, respectively; the median overall was 4 months. Factors associated with longer OS were lack of both prior pertuzumab (HR, 0.70; 95% CI, 0.55-0.89; P = .004) and primary breast surgery, such as mastectomy or partial mastectomy, within 10 years (HR, 0.72; 95% CI, 0.54-0.97; P = .03).

Limitations of the study include the large sample size, lack of comparative data, and its inability to assess for progression-free survival outcomes, which served as a primary end point in both trials. 

“Results of this population-based cohort study show that there has been substantial uptake of pertuzumab and T-DM1 treatment in patients with advanced [HER2]-positive breast cancer since publication of the CLEOPATRA and EMILIA trials,” the investigators wrote. “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.”


1. Ethier JL, Desautels D, Robinson A, Amir E, Kong W, Booth CM. Practice Patterns and Outcomes of Novel Targeted Agents for the Treatment of ERBB2-Positive Metastatic Breast Cancer. JAMA Oncol. Published online July 8, 2021. doi:10.1001/jamaoncol.2021.2140

2. Swain SM, Baselga J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513

3. Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive

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