Pertuzumab-Pretreated Cohort
The cohort that received T-DM1 after progressing on a pertuzumab-containing regimen consisted of 23 women with a median age of 58 years at the time of metastatic diagnosis (range 34 to 86 years). The median time from initial breast cancer diagnosis to detection of metastases was two years (range 0 to 16 years), including 10 women diagnosed with de novo metastatic disease. The number of pre-T-DM1 systemic therapies (excluding pertuzumab) in the metastatic setting ranged from 0 (n = 6) to 8 with a median of 1. At the time of T-DM1 initiation, common sites of metastases in this cohort were the lungs (69.6% of women), bones (65.2%), liver (47.8%), and brain (43.5%). Patient-level characteristics are further summarized by treatment cohort in Table 1.
Table 1
Characteristic | | Pertuzumab-pretreated (n = 23) | Pertuzumab-naive (n = 10) | P value* |
Months from initial | | median: 23.5 | median: 14.7 | 0.763 |
Dx to Met Dx | | range: 0.0–192.5 | range: 0.0–53.6 | |
Initial Dx of Met | | No: 13 (56.5%) | No: 8 (80.0%) | 0.259 |
disease | | Yes: 10 (43.5%) | Yes: 2 (20.0%) | |
Age at Met Dx | | median: 58.0 | median: 52.0 | 0.377 |
| | range: 34.0–86.0 | range: 38.0–67.0 | |
Ethnicity | | white: 20 (87.0%) | white: 9 (90.0%) | 1.000 |
| | black: 3 (13.0%) | black: 1 (10.0%) | |
Num. prior therapies | | median: 1.0 | median: 1.0 | 0.586 |
in Met setting | | range: 0.0–8.0 | range: 0.0–7.0 | |
Num. prior therapies | | 0: 6 (26.1%) | 0: 1 (10.0%) | 0.397 |
in Met setting (binary) | | >=1: 17 (73.9%) | >=1: 9 (90.0%) | |
Brain mets | | No: 13 (56.5%) | No: 6 (60.0%) | 1.000 |
(at T-DM1 start) | | Yes: 10 (43.5%) | Yes: 4 (40.0%) | |
Bone mets | | No: 8 (34.8%) | No: 6 (60.0%) | 0.257 |
(at T-DM1 start) | | Yes: 15 (65.2%) | Yes: 4 (40.0%) | |
Lung mets | | No: 7 (30.4%) | No: 9 (90.0%) | 0.002 |
(at T-DM1 start) | | Yes: 16 (69.6%) | Yes: 1 (10.0%) | |
Liver mets | | No: 12 (52.2%) | No: 6 (60.0%) | 0.722 |
(at T-DM1 start) | | Yes: 11 (47.8%) | Yes: 4 (40.0%) | |
HR+ (ER + or PR+) | | No: 12 (52.2%) | No: 2 (25.0%) | 0.240 |
at metastasis | | Yes: 11 (47.8%) | Yes: 6 (75.0%) | |
Months from Met Dx | | median: 12.6 | median: 8.2 | 0.845 |
to T-DM1 therapy | | range: 0.3–69.8 | range: 0.4–60.2 | |
Months from Met Dx | | < 10: 10 (43.5%) | < 10: 6 (60.0%) | 0.465 |
to T-DM1 (binary) | | >=10: 13 (56.5%) | >=10: 4 (40.0%) | |
Months of T-DM1 | | median: 2.9 | median: 4.8 | 0.799 |
therapy | | range: 0.7–50.4 | range: 0.7–40.8 | |
T-DM1 dose | | No: 18 (78.3%) | No: 9 (90.0%) | 0.640 |
reduction | | Yes: 5 (21.7%) | Yes: 1 (10.0%) | |
Cardiac toxicity | | No: 22 (95.7%) | No: 8 (80.0%) | 0.212 |
(during T-DM1) | | Yes: 1 (4.3%) | Yes: 2 (20.0%) | |
Neuropathy | | No: 21 (91.3%) | No: 9 (90.0%) | 1.000 |
(during T-DM1) | | Yes: 2 (8.7%) | Yes: 1 (10.0%) | |
T-DM1 discontinuation | | No: 22 (95.7%) | No: 9 (90.0%) | 0.521 |
due to toxicity | | Yes: 1 (4.3%) | Yes: 1 (10.0%) | |
Overall response | | No: 18 (85.7%) | No: 7 (70.0%) | 0.358 |
(CR or PR) | | Yes: 3 (14.3%) | Yes: 3 (30.0%) | |
CBR (CR, PR, or SD | | No: 10 (47.6%) | No: 5 (50.0%) | 1.000 |
with T-DM1 > 6 mo) | | Yes: 11 (52.4%) | Yes: 5 (50.0%) | |
* P values from Fisher’s exact test (for categorical variables) or Kruskal-Wallis test (for continuous variables) |
The median time between diagnosis of metastatic disease and the start of T-DM1 in this pertuzumab-pretreated group was 12.6 months (range < 1 to 70 months). The duration of T-DM1 therapy varied from 3 weeks to 4 years with a median of 2.9 months. Ten of the 23 women (43%) were given T-DM1 for more than 6 months. Patient follow-up (starting from the first T-DM1 infusion) ranged from 1 to 50 months (median 17). T-DM1-related adverse events included one patient with grade 1 cardiac dysfunction and two patients with grade ≤ 2 peripheral sensory neuropathy. Five patients (21.7%) required a T-DM1 dose reduction. Among the 21 women formally evaluated for response to T-DM1 (RECIST v1.1), there were no complete responses, 3 patients had a partial response, and 8 other patients had stable disease with > 6 months of T-DM1 treatment, leading to an overall response rate of 14.3% (95% CI: 3.0% – 36.3%) and clinical benefit rate of 52.4% (95% CI: 29.8% – 74.3%).
Pertuzumab-Naïve Cohort (Control):
The concurrent control group of HER2-positive breast cancer patients administered T-DM1 without antecedent pertuzumab in the metastatic setting consisted of 10 women, 2 of whom were diagnosed with de novo metastatic disease. With a median age of 52 years (range 38 to 67), this cohort was younger yet not statistically different than the pertuzumab-pretreated group. Pertuzumab-naive women received from 0 (n = 1) to 7 systemic therapies (median 1) between metastatic diagnosis and commencement of T-DM1.
Median duration of T-DM1 therapy was 4.8 months (range 3 weeks to 41 months). As in the pertuzumab group, T-DM1 was well tolerated, with only one out of ten patients requiring T-DM1 dose reduction. T-DM1 related adverse events included two patients experiencing cardiac dysfunction (both grade 1) and one with peripheral sensory neuropathy (grade 2). The overall response rate was 30.0% (95% CI: 6.7% – 65.2%) and clinical benefit rate was 50.0% (95% CI: 18.7% – 81.3%) based on three pertuzumab-naïve patients achieving a partial response and two others having stable disease while receiving T-DM1 for greater than 6 months.
The only patient characteristic that significantly differed between cohorts was metastasis to the lungs (p = 0.002, Table 1), which was observed in 10% of patients in the control group compared to 70% of pertuzumab-pretreated patients. All other patient features were similar across the two patient groups (p-values > 0.200, Table 1).
Survival Outcomes
Among the 23 pertuzumab-pretreated patients, the one-year PFS rate was 47.8% (95% CI: 31.2% – 73.3%) with a median PFS of 9.5 months (Fig. 1). Within this cohort, black race (HR = 4.02 [95% CI: 1.07–15.10] compared to white; p = 0.026) and liver metastasis (HR = 7.78 [95% CI: 2.07–29.26]; p < 0.001) were significantly associated with worse PFS (Table 2). Among the 10 pertuzumab-naïve patients, the 1-year PFS rate was 20.0% (95% CI: 5.8% – 69.1%), with a median PFS of 7.3 months. Thus, the pertuzumab-pretreated group had a favorable, albeit non-significant, PFS distribution compared to the pertuzumab-naïve group (HR = 0.66 [95% CI: 0.30–1.47]; p = 0.310; Table 2). Starting at 9 months after T-DM1 initiation, the proportion of patients who were alive and progression-free was greater in the pertuzumab-pretreated cohort (Fig. 1). However, 11 of the 17 PFS events in the pertuzumab group occurred before 9 months and the Prentice modification test that assigns more weight to earlier differences between groups had a p-value of 0.500 (> log-rank p-value of 0.310). Interestingly, there was a strong interaction effect on PFS between pertuzumab exposure and hepatic malignancy; pertuzumab-naïve patients with liver metastasis at the start of T-DM1 had a reduced risk of disease progression or death (HR = 0.20 [95% CI: 0.04–0.88]; p = 0.033; Table 2) compared to other control group women, which was contrary to the above mentioned greater risk of progression or death for pertuzumab-pretreated women with cancer in the liver.
Table 2
Progression Free Survival
Covariate(s) in model | Patients | Hazard Ratio (Pertuz vs. Control) | HR 95% CI | P value |
None | All | 0.66 | 0.30–1.47 | 0.310 |
Months from initial Dx to Met Dx | All | 0.78 | 0.35–1.76 | 0.549 |
Race | All | 0.59 | 0.25–1.38 | 0.222 |
Liver Met; interaction | Liver mets | 4.26 | 1.10–16.60 | 0.036 |
Liver Met; interaction | No liver mets | 0.11 | 0.03–0.42 | 0.001 |
There were 9 observed deaths among the 23 women in the pertuzumab-pretreated group, with deaths occurring 0.8 to 18.6 months after start of T-DM1 therapy (median 4.4 months). Median follow-up for this group was 16.9 months. The one-year OS rate was 67.4% (95% CI: 50.0% − 90.9%) and median OS was not reached (Fig. 2). None of the baseline patient demographic or disease features were associated with OS in the pertuzumab-pretreated cohort. Among the 10 pertuzumab-naïve patients, there were 9 deaths (range 5.5 to 53.1 months after starting T-DM1; median 14.0 months) and both median follow-up and median OS were 14.4 months. Patients with exposure to pertuzumab had higher 1-year (67.4% vs 60.0%) and 2-year (56.2% vs 30.0%) OS rates compared to the pertuzumab-naïve group; however, when evaluated over the entire follow-up period, this survival advantage was not statistically significant (HR = 0.56 [95% CI: 0.22–1.46]; p = 0.230; Table 3).
Table 3
Covariate in model | Patients | HR (Pertuz vs. Control) | HR 95% CI | P value |
None | All | 0.56 | 0.22–1.46 | 0.230 |
Number prior therapies in Met setting | All | 0.57 | 0.22–1.50 | 0.257 |
Compared to the respective univariable model, there was minimal change in the association between pertuzumab exposure and each time-to-event outcome when adjusting for lung metastasis (the only patient feature that significantly differed across treatment cohorts) as a covariate: PFS HR = 0.46 (95% CI: 0.17–1.20), OS HR = 0.47 (95% CI: 0.16–1.40). In regards to inferences drawn from the estimated effect of pertuzumab on survival outcomes, false negative results are an uncontrolled risk since this retrospective study was not powered to detect differences between the two treatment groups.