The clinical characteristics of the 39 patients are shown in Table 1.
Table 1
Patients | (n = 39) N (%) |
Age median (range) | 55 (35–72) |
Performance Status ECOG (n.; %) 0 1 2 | 12 (30.8) 20 (51.3) 7 (17.9) |
Hormonal Receptor status (n.; %) Estrogen Positive Progesterone Positive | 25 (64.1) 21 (53.8) |
HER2 Status (IHC) (n.; %) HER2 2 + SISH/FISH^ Amplification HER2 3+ | 6 (15.4) 33 (84.6) |
Previous Neo-adjuvant therapies (n.; %) Trastuzumab with or without Pertuzumab regimens Anthracycline-taxanes regimens Anthracycline-sparing regimens | 20 (51.3) 10 (25.6) 10 (25.6) 0 |
Previous adjuvant therapies (n.; %) Trastuzumab with or without Pertuzumab regimens Anthracycline-taxanes regimens No anthracycline regimen | 24 (61.5) 21 (53.8) 11 (28.2) 13 (33.3) |
Previous Hormonal adjuvant therapies (n.; %) | 23 (59) |
Median lines for metastatic disease (range) | 2 (0–5) |
Previous anti-HER2 lines for metastatic disease (n.; %) 0 1 2 3 > 4 | 2 (5.1) 15 (38.5) 10 (25.6) 8 (20.5) 4 (10.3) |
Previous anti-HER2 therapies for metastatic disease (n.; %) Pertuzumab/trastuzumab/taxane T-DM1 Lapatinib/capecitabine Tucatinib/Lapatinib/capecitabine Trastuzumab + chemotherapy: Paclitaxel Vinorelbine Docetaxel + vinorelbine Trastuzumab + Hormonal therapy | 37 (94.8) 33 (84.6) 21 (53.8) 12 (30.8) 1 (2.6) 9 (23.1) 3 (7.7) 3 (7.7) 3 (7.7) 1 (2.6) |
Median Disease Free Interval from BMs (months, range) Since initial diagnosis Since metastatic diagnosis | 46 (0-199) 14 (0–96) |
N° of brain metastases (n.; %) 1 2 3 4 Not reported | 6 (15.4) 2 (5.1) 5 (12.8) 23 (59.0) 3 (7.7) |
N° of patients with neurological symptoms (n.; %) Yes No | 18 (46.1) 21 (53.9) |
Previous BM local therapy (n.; %) No therapy SRS° WBRT§ Surgery + SRS Surgery + WBRT WBRT + SRS + surgery | 5 (12.8) 16 (41.0) 13 (33.3) 3 (7.7) 1 (2.6) 1 (2.6) |
Extracranial metastatic sites (n.; %) 0 1 2 3 >=4 missing | 7 (17.9) 4 (10.3) 12 (30.8) 5 (12.8) 9 (23.1) 2 (5.1) |
Dominant metastatic sites (n.; %) Liver Lung Bone Soft tissues Only brain | 14 (35.9) 7 (17.9) 7 (17.9) 2 (5.1) 9 (23.1) |
Median progression Free Survival of previous I line (months and range) | 10 (4–96) |
Median progression Free Survival of previous II lines (months and range) | 8 (2–29) |
Time from the end of local brain treatments to T-Dxd (median, range) | 7 (0–27) |
T-Dxd line 1 2 3 4 >=5 | 2 (5.1) 12 (30.8) 8 (20.5) 8 (20.5) 9 (23.2) |
* IHC : Immunoistochemistry; ^ SISH/FISH: Silver in situ hybridization/Fluorescent in situ hybridization; |
°SRS: Stereotactic Radiosurgery; §WBRT: Whole Brain Radiotherapy |
Median age was 55 years (35–72). Thirty-six (92.3%) patients had estrogen and/or progesterone receptor positive tumors, with 23 (59.0%) previously treated with anti-hormonal treatment in adjuvant setting.
In the curative setting, 10 (25.6%) patients received both trastuzumab +/- pertuzumab and anthracycline +/- taxanes based regimens as a neoadjuvant treatment, while 24 (61.5%) patients received adjuvant therapy: 21 (53.8%) trastuzumab +/- pertuzumab of which 11 (28.2%) combined to anthracycline and taxanes based-regimens and 13 (33.3%) combined to anthracycline-sparing therapy.
In the advanced setting, 37 (94.8%) patients received previous anti-HER2 treatments: 33 (84.6%) trastuzumab + pertuzumab and taxane (docetaxel/paclitaxel), 21 (53.8%) T-DM1, 12 (30.8%) Lapatinib plus capecitabine, and 9 (23.1%) trastuzumab plus chemotherapy regimens. Only 1 (2.6%) patient received trastuzumab plus anti-hormonal therapy.
Before administering T-Dxd, median PFS (mPFS) of first line treatments was 10 months (4–96), while mPFS of second line treatments was 8 months (2–29).
Median previous treatment lines for HER2 + metastatic disease was 2 (0–5); T-Dxd was administered as a first line treatment for advanced disease in 2 patients (5.1%), as a second line in 15 patients (38.5%), as a third, fourth, fifth or later line in 10 patients (25.6%), 8 patients (20.5%) and 4 patients (10.3%), respectively.
Six (15.4%) out of 36 patients had only one BM, 2 (5.1%) and 5 (12.8%) patients had two and three BMs, respectively, while most patients (23, 59.0%) had four or more brain lesions. The exact number of BMs was not reported for three (7.7%) patients. Eighteen (46.1%) patients reported neurological symptoms while starting T-Dxd.
Thirty-four (87.2%) patients received one or more local approach for intracranial control of brain lesions, with most of them receiving Stereotactic Radiosurgery [SRS (16 (41%) and WBRT (15, 38.4%)]. Five (12,8%) had no previous locoregional treatment.
The median time from the end of local brain treatments to the first administration of T-DxD was 7 months (range 0–27).Seven (17.9%)patients had no evidence of extracranial involvement, whilst 4 (10.3%), 12 (30.8%), 5 (12.8%), and 9 (23.0%) patients had one, two, three, and four or more extracranial metastatic sites, respectively. Data were missing for two patients (5.1%).
Intracranial efficacy
Regarding the single outcomes, one patient (2.6%) achieved a complete response (CR), twenty-two (56.4%) a partial response (PR, for an overall response rate of 59.0%), fourteen patients (35.9%) had a stable disease (SD), while two showed (5.1%) an intracranial progressive disease (PD) (Table 2b).
Table 2
a. Intracranial Efficacy of T-Dxd
mPFS (months) | 15.6 (95% CI: 10.5–20.8) |
Disease Control Rate (%) | 94.9 (87.9–100.0) |
Duration of Response (months) | 11.9 (10.1–13.7) |
Clinical Benefit (%) 6 months 12 months | 27 (69.2) 23 (59.0) |
Overall Survival at 12 months (%) | 76.6 |
Table 2
b. Intracranial and Global best responses with T-DxD
Response to T-Dxd Complete Response Partial Response Overall Response rate Stable Disease Progressive disease | Intracranial Best Response n. (%) 1 (2.6) 22 (56.4) 23 (59) 14 (35.9) 2 (5.1) | Global Best Response n. (%) 0 27 (69.2) 27 (69.2) 10 (25.6) 2 (5.1) |
When considering the treatment line, there were one PR and one SD in first line, eleven PR and one SD in second line, one CR, five PR, and two SD in third line, three PR, four SD, and one PD in fourth line, two PR, six SD, and one PD in fifth or later lines (Table 3a).
Table 3. Efficacy of T-DxD based on treatment line
Table 3
Line of treatment Complete Response Partial Response Stable Disease Progressive disease Median icPFS (range) | I line (n = 2) 0 1 1 0 NE | II line (n = 12) 0 11 1 0 14.2 (NE) | III line (n = 8) 1 5 2 0 15.5 (10.1–21.1) | IV line (n = 8) 0 3 4 1 11.1 (6.8–15.6) | >IV line (n = 9) 0 2 6 1 16.5 (NE) |
° icPFS: intracranial progression free survival; NE: not evaluable |
Table 3
Line of Treatment Complete Response Partial Response Stable Disease Progressive disease Median PFS (range) | I line (n = 2) 0 2 0 0 NE | II line (n = 12) 0 10 2 0 14.1 (6.8–21.3) | III line (n = 8) 0 7 1 0 15.5 (8.5–22.4) | IV line (n = 8) 0 4 3 1 11.1 (6.9–15.4) | >IV line (n = 9) 0 4 4 1 7.9 (5.8–10.6) |
PFS: progression free survival; NE: not evaluable |
At a median follow up of 12 months intracranial mPFS was 15.6 months (10.5–20.8).
When dividing patients according to the intracranial responses (CR/PR vs SD/PD), a statistically significant difference in mPFS [15.8 (14.1–17.5) vs 11.2 (3.2–19.2), p = 0.01)] was found (Fig. 1).
No difference (p = 0.75) were observed in mPFS between patients that did [15.6 (10.8–20.4)] or did not 5.8 (n.e.)] receive a local approach.
iDCR was 94.9% (87.9–100.0), iDoR was 11.9 months (10.1–13.7), and iCBr at 6 and 12 months were 69.2% and 59%, respectively.
OS was not reached, with an overall rate of 77.9% of patients alive at 12 months.
Data regarding intracranial activity are summarized in Table 2a.
Global (intra + extracranial) activity
For global disease activity, no CR was observed, while twenty-seven (69.2%) PR, ten (25.6%) SD, and two (5.1%) PD were documented.
Results of best intra and global responses are summarized in Table 2b. Data between the two groups were substantially balanced in terms of responses.
When considering the global activity, there were two PR in first line, ten PR and two SD in second line, seven PR and one SD in third line, four PR, three SD, and one PD in fourth line, four PR, four SD, and one PD in fifth or later lines.
Intra- and global activity of T-Dxd according to treatment line is available at Table 3.
Considering all treatment lines together, global mPFS was 11.8 months (8.5–15.0).
Safety
Median treatment duration with T-Dxd was 9.5 months (range: 1.5–16.5).
32 patients (82%) experienced an any grade toxicity from treatment with T-Dxd.
The main grade 1/2 hematological toxicities were neutropenia (35.9%) and anemia (23.1%). Grade 1/2 non-hematological adverse events (AEs) that occurred in more than 10% of the patients were alopecia (59%), fatigue (53.8%), nausea (46.1%), constipation (30.7%), diarrhea (28.2%), and vomiting (10.2%).
Grade 3/4 hematological toxicities consisted of neutropenia (15.3%), anemia (5.1%) and piastrinopenia (2.5%). Grade 3/4 non-hematological AEs were fatigue (18%), diarrhea (10.2%), nausea (7.7%), mucositis (5.1%), vomiting (2.5%), pneumonitis (2.5%), and increase in liver transaminase (2.5%).
With regard to AEs of special interest, grade 1 drop of LVEF was observed in one patient (2.5%).
Toxicities are available in the supplementary material (Table 1 suppl.).