Key Points
Question
Is tucatinib combined with trastuzumab and capecitabine (TTC) following treatment with trastuzumab-deruxtecan associated with improved outcomes in patients with ERBB2-positive metastatic breast cancer (MBC), including patients with and without brain metastasis?
Findings
In this cohort study of 101 patients with ERBB2-positive MBC treated in 12 French comprehensive cancer centers, TTC provided a clinically significant tumor response and progression-free survival after prior exposure to trastuzumab-deruxtecan.
Meaning
These findings suggest that TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC.
This cohort study evaluates the use of tucatinib combined with trastuzumab and capecitabine as a treatment option for patients with ERBB2-positive metastatic breast cancer who were previously treated with trastuzumab-deruxtecan.
Abstract
Importance
Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC).
Objective
To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan.
Design, Setting, and Participants
This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022.
Exposure
Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose.
Main Outcomes and Measures
Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR).
Results
A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months.
Conclusions and Relevance
In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.
Introduction
Recent guidelines have positioned trastuzumab-deruxtecan as the preferred second-line treatment for ERBB2 (previously HER2)-positive metastatic breast cancer (MBC) except in patients with active brain metastases.1,2 Tucatinib combined with trastuzumab and capecitabine (TTC) has been the preferred third-line treatment for ERBB2-positive MBC; however, little is known regarding its associated outcomes after trastuzumab-deruxtecan exposure. In this rapidly changing therapeutic landscape, outcome data according to sequencing represents a major issue for standard practice. Few studies have sought to elucidate the mechanisms underlying trastuzumab-deruxtecan resistance, and few clinical data on the outcomes of therapies beyond progression during trastuzumab-deruxtecan treatment have been available.3 Therefore, we evaluated the outcomes following TTC treatment in patients with ERBB2-positive MBC who had been previously treated with trastuzumab-deruxtecan.
Methods
This cohort study was conducted at 12 cancer centers in France. All patients with ERBB2-positive MBC who were treated with TTC and had prior exposure to trastuzumab-deruxtecan were included. The TTC regimen included tucatinib (300 mg orally twice daily throughout the treatment period) in combination with trastuzumab (6 mg/kg of body weight intravenously once every 21 days) and capecitabine (1000 mg/m2 of body surface area orally twice daily on days 1 to 14 of each 21-day cycle). Data were obtained from the patients’ medical records. Clinical end points included progression-free survival (PFS) (Response Evaluation Criteria in Solid Tumors [RECIST] guideline, version 1.1 [RECIST Working Group]) as determined by the local investigator; time to next treatment (TTNT), defined as the duration from TTC initiation to the beginning of the subsequent regimen; response rate in evaluable patients (RECIST guideline, version 1.1); and overall survival (OS). Brain metastases were classified as active (untreated or previously treated and progressing just before TTC initiation) or stable. An independent ethics committee approved our study protocol. Owing to the use of deidentified data, no formal dedicated informed consent was required; however, all patients had provided written approval of the reuse of their electronically recorded data. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki,4 the Good Clinical Practice guideline,5 applicable regulatory requirements, and the European General Data Protection Regulation. The Institut de Cancerologie de l’Ouest has made a commitment to the French Commission Nationale de l’Informatique et des Libertés to comply with Reference Methodology 4, and this project is registered in the public directory maintained by the National Institute for Health Data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Survival curves were estimated using the Kaplan-Meier method with 95% CIs. Overall survival was computed from TTC initiation to death or date of last follow-up (censored). Progression-free survival was computed from TTC initiation to progression or death. Patients who started a new treatment without progression and those with ongoing TTC treatment without progression at the time of analysis were censored. Time to next treatment was computed from TTC initiation to the beginning of the subsequent line, with ongoing treatment and deaths being censored. To minimize bias, in cases wherein a gap longer than 60 days with no treatment existed after TTC, the end date of the TTC was taken as a proxy for start date of a new line. We performed all analyses using R software, version 3.6.1 (R Project for Statistical Computing).
Results
We included 101 patients with MBC (median age, 56 [range, 31-85] years); patient characteristics are summarized in Table 1. Racial and ethnic data were not collected in conformity to French law. These patients were treated between August 1, 2020, and December 31, 2022. Accordingly, the median number of prior treatment lines for MBC at TTC initiation was 4 (range, 2-15), with 82 patients (81.2%) having previously received trastuzumab and/or pertuzumab and 94 (93.1%) having received ado-trastuzumab-emtansine. The TTC regimen was given as a third- or a fourth-line treatment for MBC in 37 patients (36.6%). At TTC initiation, 39 patients (38.6%) had known brain metastases. With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 patients (75.2%) stopped TTC due to disease progression and 25 (24.8%) due to toxic effects. The median PFS in the entire cohort was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months (Table 2). The overall response rate (ORR) was 32.6% (29 of 89 patients) with 2 complete responses, and disease control rate (DCR) was 64.0% (57 of 89 patients). Patients treated with TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months, median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Patients who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Two patients without known brain metastases had brain metastases documented as a site of progression during TTC treatment. Patients with active brain metastases (n = 16) had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TNTT of 5.6 (95% CI, 4.4-NR) months, and median OS of 12.4 (95% CI, 8.3.1-NR) months. The intracranial ORR was 20.0% (3 of 15 patients) with 2 complete responses, whereas the DCR was 66.7% (10 of 15 patients). Details regarding the ORR are presented in Table 3.
Table 1. Patient Characteristicsa.
| Characteristic | Patient data (N = 101) |
|---|---|
| Age, y | |
| Median (range) | 56 (31-85) |
| <65 | 79 (78.2) |
| ≥65 | 22 (21.8) |
| Stage IV disease at initial diagnosis | 34 (33.7) |
| Hormone receptor status | |
| ER and/or PR positive | 72 (71.3) |
| ER and PR negative | 29 (28.7) |
| Prior lines of therapy, median (range) | |
| Overall | 5 (2-16) |
| Metastatic setting | 4 (2-15) |
| Previous therapies for metastatic breast cancer | |
| Trastuzumab | 100 (99.0) |
| Pertuzumab | 82 (81.2) |
| Ado-trastuzumab-emtansine | 94 (93.1) |
| Lapatinib | 33 (32.7) |
| Trastuzumab-deruxtecan | 101 (100) |
| Duration of trastuzumab-deruxtecan therapy, median (range), mo | 8.9 (1.4-25.8) |
| Reason for trastuzumab-deruxtecan discontinuation | |
| Progression | 82 (81.2) |
| Toxicity | 18 (17.8) |
| Unknown | 1 (1.0) |
| TTC immediately after trastuzumab-deruxtecan | 86 (85.1) |
| Known brain metastases prior to TTC | |
| Yes | 39 (38.6) |
| No | 62 (61.4) |
| Classification of brain metastasesb | |
| Previous local treatment and stable brain metastases prior to TTC | 20 (51.3) |
| Previous local treatment and progressive brain metastases prior to TTC | 15 (38.5) |
| No previous local treatment and stable brain metastases prior to TTC | 3 (7.7) |
| No previous local treatment and progressive brain metastases prior to TTC | 1 (2.6) |
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; TTC, tucatinib combined with trastuzumab and capecitabine.
Unless indicated otherwise, data are expressed as No. (%) of patients.
Includes the 39 patients with known brain metastases prior to TTC.
Table 2. Outcomes of Treatment With Tucatinib Combined With Trastuzumab and Capecitabine (TTC).
| No. of patients | PFS | OS | TTNT, median (95% CI), mo |
|||
|---|---|---|---|---|---|---|
| Median (95% CI), mo | 6-mo rate (95% CI) | Median (95% CI), mo | 6-mo rate (95% CI) | |||
| Whole population | 101 | 4.7 (3.9-5.6) | 33.1 (24.8-44.3) | 13.4 (11.1-NR) | 77.0 (69.0-86.0) | 5.2 (4.5-7.0) |
| Reason for trastuzumab-deruxtecan discontinuation | ||||||
| Toxic effects | 18 | 7.3 (3.0-NR) | 61.1 (42.3-88.3) | NR | 81.7 (64.9-100.0) | 7.8 (3.1-NR) |
| Progression | 82 | 4.4 (3.9-5.5) | 28.4 (19.9-40.6) | 12.9 (11.1-NR) | 75.7 (66.8-85.9) | 5.2 (4.5-6.3) |
| Duration of previous trastuzumab-deruxtecan treatment in patients stopping for progression, mo | ||||||
| <6 | 23 | 4.7 (3.2-5.7) | 17.4 (7.1-42.4) | 10.6 (5.5-NR) | 59.8 (42.6-84.1) | 5.5 (4.8-NR) |
| ≥6 to ≤12 | 36 | 3.9 (2.9-6.0) | 23.1 (12.2-43.9) | NR | 82.1 (70.1-96.2) | 4.0 (3.5-6.1) |
| >12 | 23 | 5.6 (4.4-NR) | 47.8 (31.2-73.3) | NR | 81.7 (66.9-99.7) | 7.2 (5.2-NR) |
| Line of treatment | ||||||
| Third to fourth | 37 | 4.4 (3.4-8.0) | 33.8 (21.0-54.2) | 12.9 (10.2-NR) | 79.6 (67.2-94.3) | 4.8 (3.9-9.9) |
| Fifth or greater | 64 | 4.7 (3.7-5.7) | 32.8 (22.8-47.3) | 13.4 (10.7-NR) | 75.3 (65.2-87.1) | 5.3 (4.7-7.0) |
| TTC immediately after trastuzumab-deruxtecan treatment | ||||||
| Yes | 86 | 5.0 (4.2-6.0) | 36.1 (26.9-48.4) | 13.4 (11.9-NR) | 78.0 (69.5-87.6) | 5.5 (4.8-7.2) |
| No | 15 | 3.5 (2.8-NR) | 16.7 (5.0-56.1) | 11.1 (8.3-NR) | 72.0 (51.9-99.8) | 3.8 (2.8-NR) |
| Population with brain metastases | ||||||
| Yes | 39 | 5.0 (3.9-6.8) | 32.4 (20.4-51.3) | 12.9 (9.6-NR) | 76.0 (63.4-91.1) | 5.7 (4.7-8.6) |
| No | 62 | 4.4 (3.5-6.0) | 33.6 (23.2-48.8) | 19.9 (10.7-NR) | 77.7 (67.7-89.2) | 4.8 (3.9-6.3) |
| Type | ||||||
| Active | 16 | 4.7 (3.0-7.3) | 25.0 (10.7-58.4) | 12.4 (8.3-NR) | 81.2 (64.2-100.0) | 5.6 (4.4-NR) |
| Nonactive | 23 | 5.2 (3.4-8.0) | 37.9 (22.3-64.7) | 17.0 (13.4-NR) | 72.4 (55.7-94.2) | 5.7 (4.7-NR) |
Abbreviations: NR, not reached; OS, overall survival; PFS, progression-free survival; TTNT, time to next treatment.
Table 3. Response to Treatment With Tucatinib Combined With Trastuzumab and Capecitabine (TTC) According to RECIST, Version 1.1, Criteria per Local Investigatora.
| RECIST criteria response | Tumor response | Brain tumor response in patients with active brain metastases prior to TTC initiation (n = 16) | ||
|---|---|---|---|---|
| Overall population (n = 101) | Progression during trastuzumab-deruxtecan treatment (n = 82) | Stopped trastuzumab-deruxtecan treatment for toxic effects (n = 18) | ||
| Complete response | 2/89 (2.2) | 0/72 | 2/16 (12.5) | 1/15 (6.7) |
| Partial response | 27/89 (30.3) | 23/72 (31.9) | 4/16 (25.0) | 2/15 (13.3) |
| Stable disease | 28/89 (31.5) | 22/72 (30.6) | 6/16 (37.5) | 7/15 (46.7) |
| Progressive disease | 32/89 (36.0) | 27/72 (37.5) | 4/16 (25.0) | 5/15 (33.3) |
| No. not available | 12 | 10 | 2 | 1 |
| Overall response rate | 29/89 (32.6) | 23/72 (31.9) | 6/16 (37.5) | 3/15 (20.0) |
| Disease control rate | 57/89 (64.0) | 45/72 (62.5) | 12/16 (75.0) | 10/15 (66.7) |
Abbreviation: RECIST, Response Evaluation Criteria in Solid Tumors.
Unless otherwise indicated, data are expressed as No./total No. (%) of patients with data available.
Discussion
Recent studies have shown that trastuzumab-deruxtecan (an antibody-drug conjugate) and TTC (a combination of tucatinib [a highly selective tyrosine kinase inhibitor (TKI) for ERBB2] combined with trastuzumab and capecitabine) outperformed standard chemotherapy for ERBB2-positive MBC.6,7 Since the results of the DESTINY-Breast03 trial were published,7 trastuzumab-deruxtecan is the preferred option for the second-line treatment of ERBB2-positive MBC, except for patients with active brain metastases. However, appropriate sequencing of these drugs has remained challenging given that only 15% of the patients in the DESTINY-Breast03 trial had received a previous TKI, while no patients enrolled in the HER2CLIMB clinical trial had received prior trastuzumab-deruxtecan. Clinical data are even scarcer. In the current study, TTC demonstrated significant activity, although the median PFS is lower than that reported in the registration trial (4.7 [95% CI, 3.9-5.6] vs 7.8 [95% CI, 7.5-9.6] months). The greater median number of previous treatment lines for MBC (4 in our study vs 3 in the HER2CLIMB trial), absence of trastuzumab-deruxtecan exposure, and higher proportion of patients who received lapatinib (another anti-ERBB2 TKI) (33 of 101 [32.7%] vs 6.9%) in the present study may explain these discrepancies. In addition, 25 patients (24.7%) stopped TTC for toxic effects in our population, reflecting a more heavily treated population compared with the HER2CLIMB population, where 5.7% stopped tucatinib treatment and 10.1% stopped capecitabine treatment due to toxic effects.
We also evaluated TTNT, a useful end point for clinical evidence studies, given the lack of a standardized evaluation. Accordingly, we found that the TTNT was 5.2 (95% CI, 4.5-7.0) months. Two prior small studies8,9 had evaluated TTNT with TTC after trastuzumab-deruxtecan exposure. The Flatiron Health Analytic Database study reported a median TTNT of 8.1 (95% CI, 4.0 to NR) months in 29 patients.8 The second study reported a median TTNT of 7.5 (95% CI, 5.0-13.3) months in 61 patients receiving TTC after trastuzumab-deruxtecan exposure.9 Importantly, patients in these 2 studies had received a median of 2 previous lines for MBC, with less than 50% of patients previously treated with ado-trastuzumab-emtansine compared with 93.1% in our cohort.
Estimates show that up to 50% of patients with ERBB2-positive MBC will develop brain metastases.10 The HER2CLIMB trial has demonstrated that TTC improved OS, including in patients with active brain metastases, while reducing the risk of developing new brain lesions.10 Despite trastuzumab-deruxtecan preexposure, the present study found a meaningful intracranial DCR of 62.5% based on the RECIST guideline, version 1.1, with an ORR of 18.8%, a median PFS of 4.7 (95% CI, 3.0-7.3) months, and a median TTNT of 5.6 (95% CI, 4.4-NR) months in patients with active brain metastases at TTC initiation.
Limitations
We acknowledge several limitations of this study, including the retrospective design and potential inclusion bias inherent to the selection of patients who had received this sequence of treatments. Indeed, given the recent approval of these 2 drugs, our cohort may have included patients who experience rapid disease progression during trastuzumab-deruxtecan treatment, potentially explaining the lower PFS with TTC in the present study compared with the HER2CLIMB trial.
Conclusions
In this retrospective cohort study, TTC therapy was associated with clinically meaningful outcomes among patients with ERBB2-positive MBC who had been previously exposed to trastuzumab-deruxtecan, including those with active brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.
Data Sharing Statement
References
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Associated Data
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Supplementary Materials
Data Sharing Statement