This retrospective study evaluates the safety and efficacy of T-DM1 in a contemporary HER2-positive metastatic breast cancer group of patients. This is especially important to review as T-DM1 approval was based largely on a pertuzumab-naïve population, prior to adoption of the CLEOPATRA regimen as frontline therapy for HER2-positive metastatic disease. Our results indicate that T-DM1 remains an active and safe treatment option for patients previously treated with pertuzumab, as evidenced by a response rate, clinical benefit rate, survival distributions, and adverse reactions that were all comparable to estimates from pertuzumab-naïve patients. Although comparison of OS across the entire follow-up period did not reach statistical significance, we did observe higher 1-year and 2-year OS rates in the pertuzumab-pretreated cohort.
Our observed outcomes for patients who received pertuzumab prior to T-DM1 are consistent with most reports in the literature. Notably, our findings are similar to the overall response rate of 17.9% (95% CI: 9.4–26.4%) and median duration of T-DM1 of 4.0 months (95% CI: 2.7–5.1) in pertuzumab-pretreated patients as described by Dzimitrowicz et al. . However, it’s important to note that the ORR to T-DM1 in pertuzumab-naïve populations, as studied in both the EMILIA (43.6%) and TH3RESA (31.3%) trials was higher than the response rate observed in our study (14.3%). This may be due to limited sample size in our cohort, but also to differences in the frequency and consistency of radiographic assessments in EMILIA and TH3RESA in the setting of a clinical trial, especially when considering variability between investigator assessed and blinded radiology review on trial.
T-DM1 activity after progression on a regimen of trastuzumab and pertuzumab is further supported by an Italian multi-center study which demonstrated prolonged duration of therapy, defined as T-DM1 > 6 months, in one-third of its patients . However, a cohort of Japanese patients who received T-DM1 after progression on trastuzumab and pertuzumab had lower rates of response (11.1% vs. 25.0%) and shorter median PFS (2.8 months vs. 7.8 months) compared to a control group of pertuzumab-naïve patients .
Additionally, the median PFS of 9.5 months in our pertuzumab-pretreated cohort is comparable to the EMILIA trial (median PFS 9.6 months), which evaluated a similar population with a median of one prior therapy for metastatic disease, and slightly higher than the TH3RESA trial (median PFS 6.2 months), which evaluated a more heavily pretreated population compared to our cohort [9, 14]. An exploratory analysis of enrolled patients who were treated with T-DM1 after progression in CLEOPATRA and PHEREXA, two trials that assessed the benefit of adding pertuzumab to a regimen of trastuzumab and chemotherapy in the metastatic setting, provided further evidence that T-DM1 has clinical activity (median duration of therapy was 7.1 and 4.2 months in the respective trials) in patients with HER2-positive metastatic breast cancer after progression on dual HER2-directed therapy .
Our study also evaluated adverse events of special interest related to T-DM1 therapy, specifically, cardiac dysfunction and peripheral sensory neuropathy. In doing so, we have confirmed that T-DM1 is well tolerated as there were low rates of treatment discontinuation (4% in pertuzumab-pretreated, 10% in pertuzumab-naïve) due to drug-related toxicity and no grade ≥ 3 adverse events. Furthermore, there was no significant difference in the rates of these adverse events when comparing the two treatment groups.
However, important limitations to our study should be noted. First, the small number of patients in both cohorts reduced the statistical power to detect significant differences in both our primary and secondary clinical endpoints. Second, certain differences in the cohort characteristics, though not statistically significant, may have favored benefit in the pertuzumab pre-treated cohort. These include longer time from initial diagnosis to metastatic disease, as well as higher proportion of de-novo metastatic disease in the pertuzumab pre-treated cohort. It is important to note though that time from initial diagnosis to metastatic disease was more than 12 months in both cohorts, which would be consistent with the population in the CLEOPATRA trial . Lastly, our retrospective study based on real-world data would not have followed similar schedules of assessment as large-scale registration trials do, which limits direct comparison with clinical trial results. Prospective cooperative group-led trials attempting to determine real-world safety and efficacy of T-DM1 therapy in patients with metastatic HER2-positive breast cancer are ongoing. One such effort is the EORTC 75111 trial (NCT01597414) evaluating treatment outcomes in elderly patients with metastatic HER2-positive breast cancer . In this study, a group of 29 women who received T-DM1 as a pre-determined second-line treatment option had a median PFS of 5 months. Moreover, a Swiss trial (NCT01835236) is assessing sequential treatment with trastuzumab and pertuzumab with and without chemotherapy followed by T-DM1, with overall survival at 24 months as the primary endpoint.
As the MARIANNE trial did not show benefit of T-DM1 and pertuzumab compared to T-DM1 alone, the sequential approach of delivering pertuzumab-based therapy followed by T-DM1 represents the current clinical therapy algorithm for metastatic HER2-positive breast cancer . Currently, treatment with trastuzumab, pertuzumab, and a taxane followed by T-DM1 at time of disease progression has been adopted as standard-of-care first-line and second-line therapy, respectively, in patients with HER2-positive metastatic breast cancer and is endorsed by national guidelines [19,20,21]. Patients who progress on T-DM1 can be eligible for recently approved novel agents (Trastuzumab-deruxtecan, Tucatinib) [22, 23].