Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer (PICTURE): a single-arm, multicenter phase 2 trial

This was an investigator-initiated, single-arm, phase 2 trial conducted at 16 sites in China. Patients were included if they were females aged 18–70 years; had pathologically confirmed HER2-positive (score 3 + by immunohistochemistry, or 2 + with positive results of fluorescence in-situ hybridization) locally advanced or metastatic breast cancer; had primary resistance to trastuzumab; had an Eastern Cooperative Oncology Group performance status of 0 or 1; had known hormone receptor status; had an expected survival of ≥ 3 months; had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 [37]; and had adequate bone marrow (neutrophil count ≥ 1.5 × 10⁹/L; platelet count ≥ 100 × 10⁹/L; hemoglobin ≥ 90 g/L), hepatic (total bilirubin ≤ 1.5 × upper limit of normal [ULN]; alanine aminotransferase and aspartate aminotransferase ≤ 3 × ULN [≤ 5 × ULN for patients with liver metastases]), renal (creatinine ≤ 1.5 × ULN; creatinine clearance rate ≥ 50 mL/min), and cardiac (left ventricular ejection fraction ≥ 50%; Fridericia’s corrected QT interval < 480 ms) function. Based on the definitions used in previous clinical trials [14], primary trastuzumab resistance was defined as progression during (neo)adjuvant trastuzumab (subgroup A) or within 12 months of completing (neo)adjuvant trastuzumab (subgroup B; treatment must have been for ≥ 9 weeks), or progression within 6 months after initiation of first-line trastuzumab for advanced disease (subgroup C; treatment must have been for ≥ 6 weeks). A washout period of 4 weeks was required after last trastuzumab-based therapy. Patients with brain metastases that had been treated with local treatment or patients with stable brain metastases could be enrolled if they did not require dexamethasone or mannitol. The key exclusion criteria were meningeal and/or spinal cord metastases; other malignancies within 5 years, except for cured cervical cancer in situ, skin basal cell carcinoma, and skin squamous cell carcinoma; previous use of anti-HER2 TKI or antibody–drug conjugate with proven efficacy; active hepatitis B or C; history of transplantation; uncontrolled hypertension or diabetes mellitus; or lactating or pregnant women.

The study was conducted in accordance with the Declarations of Helsinki and Good Clinical Practice and was approved by the ethics committee of each participating center. Written informed consent was obtained from each patient. The study was registered with ClinicalTrials.gov, NCT04001621.

Patients received oral pyrotinib 400 mg once daily and oral capecitabine 1000 mg/m² twice a day on days 1–14 of each 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. Dose reductions, interruptions, and discontinuations of study drugs were allowed according to AEs. The dose of pyrotinib could be reduced stepwise from 400 to 320 mg to 240 mg. The dose of capecitabine was permitted to be reduced stepwise by 25%. Dose escalation was not permitted upon resolution of toxicity. The cumulative interruption time of pyrotinib should be no more than 14 days in each cycle; otherwise, patients would be withdrawn from the study.

Imaging examinations were performed every 6 weeks for the first 20 treatment cycles, and every 12 weeks thereafter. Radiological response was assessed by investigators according to RECIST 1.1. For patients who discontinued the study treatment before disease progression or death, subsequent imaging examinations were performed every 12 weeks until the initiation of other anti-cancer therapies, disease progression, or death. OS was followed every 12 weeks until loss to follow-up, death, or completion of the study. Adverse events (AEs) during the study treatment and until 28 days after the last dose of study drug were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

The primary endpoint was PFS, defined as the time from the initiation of study treatment to the first disease progression per RECIST 1.1 or any-cause death, whichever came first.

Secondary endpoints included objective response rate (ORR; defined as the proportion of patients with the best response of complete response [CR] or partial response [PR] per RECIST 1.1), duration of response (defined as the time from the first CR or PR to disease progression per RECIST 1.1 in patients with confirmed objective response), disease control rate (DCR; defined as the proportion of patients with the best response of CR, PR, or stable disease per RECIST 1.1), overall survival (OS; defined as the time from the initiation of study treatment to any-cause death), and safety.

Trastuzumab plus vinorelbine was the backbone treatment for trastuzumab-pretreated patients in 2019 in China; thus, the median PFS (5.78 months) of the control group in BOLERO-3 was considered as the historical control in our study [13]. The study treatment was expected to increase the median PFS to 8.0 months. Assuming that the survival time was in accordance with exponential distribution, 64 disease progression or death events were required to test the difference between the study treatment and historical control with a significance level of 5% and a power of 80%. The planned enrollment period was 32 months and the planned follow-up period was 24 months. Considering a dropout rate of 5%, 96 patients were required.

Between June 20, 2019, and September 19, 2021, a total of 108 patients were screened for eligibility, and 100 patients were enrolled and included in the efficacy and safety analyses (Fig. 1). Baseline characteristics are shown in Table 1. Of 100 patients, 65 (65.0%) had hormone receptor-negative disease, 94 (94.0%) had metastatic disease, 66 (66.0%) had visceral metastases, and 21 (21.0%) had prior use of pertuzumab. By the data cutoff date on August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3–38.2). Median duration of the study treatment was 9.3 months (range, 0.2–38.2). Twenty-six (26.0%) patients were still on treatment.

By the data cutoff date, 66 (66.0%) of 100 patients had disease progression or died. The median PFS was 11.8 months (95% CI, 8.4–15.1; Fig. 2A). Twenty-five deaths occurred, and the median OS was not reached (95% CI, 29.0–not reached). The 1-year OS rate was 86.6%.

Further analyses showed that the median PFS was 8.2 months (95% CI, 3.0–20.7) in subgroup A (progression during adjuvant trastuzumab; n = 21), 17.8 months (95% CI, 13.8–not reached) in subgroup B (progression within 12 months of completing adjuvant trastuzumab; n = 49), and 5.6 months (95% CI, 4.1–6.9) in subgroup C (progression within 6 months after initiation of first-line trastuzumab for advanced disease; n = 30; Fig. 2B). No significant difference in median PFS was observed in subgroup by hormone receptor status (hormone receptor-positive: 9.7 months [95% CI, 6.4–18.4]; hormone receptor-negative: 12.3 months [95% CI, 8.2–17.8]; hazard ratio, 0.926 [95% CI, 0.559–1.533]; P = 0.765; Fig. 2C).

Seven of 100 patients achieved confirmed CR and 63 achieved confirmed PR, with a confirmed ORR of 70.0% (95% CI, 60.0–78.8). Median duration of response was 13.8 months (95% CI, 10.2–19.3). Seven patients with CR were all from subgroup B. The ORR was significantly higher in subgroup B than in subgroups A and C (Additional file 1: Table S1), showing a similar trend with PFS. The DCR was 87.0% (95% CI, 78.8–92.9). Waterfall plot for best percent change in target lesions from baseline among individual patients is shown in Fig. 3.

Treatment-emergent AEs (TEAEs) are summarized in Table 2. All patients had TEAEs, and 56 (56.0%) reported grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAEs included diarrhea (24 [24.0%]), palmar-plantar erythrodysesthesia syndrome (nine [9.0%]), decreased neutrophil count (eight [8.0%]), hypokalemia (six [6.0%]), and anorexia (five [5.0%]). No grade 4 diarrhea occurred, while grade 3 diarrhea mostly (17/24, 70.8%) occurred in the first treatment cycle (Additional file 1: Fig. S1).

Twelve (12.0%) of 100 patients had dose reductions of pyrotinib due to AEs, and 37 (37.0%) had dose reductions of capecitabine. Four (4.0%) patients discontinued capecitabine due to increased blood bilirubin, anemia, dyspepsia, and palmar-plantar erythrodysesthesia syndrome, respectively. No AEs leading to discontinuation of pyrotinib occurred. No treatment-related deaths occurred.