Frontline Pyrotinib Plus Trastuzumab and Docetaxel Improves PFS in HER2+ Metastatic Breast Cancer

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The addition of pyrotinib to trastuzumab (Herceptin) and docetaxel led to a significant improvement in progression-free survival (PFS) compared with placebo plus trastuzumab and docetaxel in patients with newly diagnosed, HER2-positive metastatic breast cancer, according to findings from the phase 3 PHILA trial (NCT03863223) published in The British Medical Journal.

At a median follow-up of 15.5 months, the median PFS was 24.3 months (95% CI, 19.1-33.0) with pyrotinib vs 10.4 months (95% CI, 9.3-12.3) with placebo (HR, 0.41; 95% CI, 0.32-0.53; one sided P < .01). The estimated 12- and 24-month PFS rates with pyrotinib were 74.3% (95% CI, 68.1%-79.5%) and 50.3% (95% CI, 41.9%-58.1%), respectively, vs 44.0% (95% CI, 37.5%-50.3%) and 16.6% (95% CI, 10.7%-23.7%), respectively, with placebo.

Additionally, PFS benefits in favor of pyrotinib were seen across all subgroups including in patients who received prior neoadjuvant or adjuvant therapy (HR, 0.23; 95% CI, 0.12-0.46), those without prior neoadjuvant or adjuvant trastuzumab (HR, 0.45; 95% CI, 0.34-0.59), those with a treatment-free interval (TFI) between 12 but under 24 months for prior adjuvant therapy (HR, 0.22; 95% CI, 0.22-0.50), and those with a TFI of 24 months or greater for prior adjuvant therapy (HR, 0.57; 95% CI, 0.37-0.87).

“To our knowledge, this is the first phase 3 study to show benefits in PFS from dual HER2 inhibition with the use of a monoclonal antibody plus a small molecule TKI in the first-line setting of HER2-positive metastatic breast cancer,” lead study author Fei Ma, MD, a professor in the Department of Medical Oncology at the Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, and colleagues wrote in summation of the study results.

The current frontline standard of care for this population is the combination of pertuzumab (Perjeta), trastuzumab, and docetaxel, having shown a median PFS of 18.7 months in the pivotal phase 3 CLEOPATRA trial (NCT00567190).

However, pyrotinib is a small molecule, irreversible, pan-HER receptor TKI that targets EGFR, HER2, and HER4, which may lead to prolonged inhibition of HER signaling and antitumor activity compared with reversible EGFR- and HER2-directed TKIs.

The randomized, multicenter, double-blind, placebo-controlled trial was conducted at 40 centers in China. Between May 6, 2019, and January 17, 2022, 798 patients were screened, and 590 patients were randomly assigned to treatment with pyrotinib (n = 297) or placebo (n = 293).

The study enrolled women between the ages of 18 and 75 with histologically confirmed HER2-positive (immunohistochemistry [IHC] 3+ or in situ hybridization positive) recurrent or metastatic breast cancer. Patients were required to be naive to systemic antitumor therapy for recurrent or metastatic disease and have at least 1 measurable lesion according to RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

Patients with prior exposure to HER2-directed therapy other than trastuzumab in the neoadjuvant or adjuvant setting, a disease-free interval of less than 12 months after completing curative-intent therapy, central nervous system metastases, or other malignancies were excluded. 

Eligible patients were randomly assigned 1:1 to receive 400 mg of oral pyrotinib once daily or placebo, plus 8 mg/kg of intravenous trastuzumab in cycle 1 and 6 mg/kg thereafter and 75 mg/m2 of docetaxel on day 1 of each 3-week cycle. Treatment was administered until disease progression, unacceptable toxicity, death, consent withdrawal, or investigator’s decision. Up to 16 mg of loperamide hydrochloride per day could have been introduced for secondary prevention of and intervention for diarrhea.

Stepwise dose reductions for pyrotinib from 400 mg to 320 mg to 240 mg were allowed for toxicity management. Only patients who experienced more than 10% reduction in body weight were allowed to receive a lower dose of trastuzumab, and no less than 60 mg/m2 of docetaxel was permitted.

Patients in each arm were stratified by prior exposure to trastuzumab in the neoadjuvant or adjuvant setting (yes vs no) and hormone receptor status (estrogen receptor [ER] and/or progesterone receptor [PR] positive vs ER and PR negative).

The primary end point of the trial was investigator-assessed PFS. Secondary end points were PFS per independent review committee (IRC) assessment, overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and safety.

Tumor evaluations were performed by computed tomography or magnetic resonance imaging at baseline, every 9 weeks for the first 18 months, and every 12 weeks thereafter. All patients received at least 1 dose of study treatment and were included in the full analysis set and safety set.

Baseline characteristics demonstrated that the median patient age was 52 years in both arms. Notably, most patients were under the age of 65, had an ECOG performance status of 0, visceral metastases, and positive hormone receptor expression. Additionally, most patients in both arms had HER2 amplification (IHC 3+), positive or undetermined HER2 status according to FISH, and a TFI with prior adjuvant therapy that was unknown or at least 24 months. Approximately half of patients in each arm had received prior neoadjuvant or adjuvant systemic therapy.

Additional efficacy results demonstrated higher ORRs with pyrotinib vs placebo at 83% (95% CI, 78%-87%) and 71% (95% CI, 65%-76%), respectively (difference, 12.2%; 95% CI, 5.4%-18.9%; stratified one-sided P < .001). The CBR rate was 87% (95% CI, 83%-91%) with pyrotinib vs 80% (95% CI, 74%-84%) with placebo. The median DOR was 25.9 months (95% CI, 17.3–not reached) with pyrotinib vs 9.5 months (95% CI, 8.3-10.6) with placebo.

The median OS in both arms was immature, with a mortality rate of 10% for pyrotinib and 11% for placebo.

The study authors noted that the efficacy results assessed by IRC were generally consistent with the findings assessed by the investigator.

At data cutoff, 56% patients in the pyrotinib arm and 33% in the placebo arm remained on therapy. The most common reason for treatment discontinuation in the pyrotinib and placebo arms, respectively, was radiological progression (31% vs 55%).

The median duration of treatment exposure to pyrotinib and placebo was 11.1 months (interquartile range [IQR], 6.2-16.9) and 8.6 months (IQR, 5.6-12.7), respectively. Patients received a median of 15.0 (IQR, 9.0-24.0) and 12.0 (IQR, 8.0-18.0) cycles of trastuzumab in the pyrotinib and placebo arms, respectively, and a median of 8.0 (IQR, 6.0-9.0) and 8.0 (IQR, 6.0-10.0) cycles of docetaxel.

Regarding safety, all patients experienced treatment-related adverse effects (TRAEs) in both arms. Grade 3 or greater TRAEs occurred in 90% of patients in the pyrotinib arm and 76% of those in the placebo arm, with decreased neutrophil count (63% vs 65%), decreased white blood cell count (53% vs 51%), and diarrhea (46% vs 3%) being the most common. Serious TRAEs occurred in 25% and 6% of patients in the pyrotinib and placebo arms, respectively, the most common of which included diarrhea (5% vs 0%), increased alanine aminotransferase (3% vs <1%), and febrile neutropenia (3% vs 2%).

TRAEs leading to dose reduction of any study treatment occurred in 26% of patients in the pyrotinib arm vs 3% of those in the placebo arm. TRAEs leading to treatment interruption occurred in 57% and 24% of patients in the pyrotinib and placebo arms, respectively, and discontinuations resulting from TRAEs occurred in 13% and 7% of patients, respectively.

No treatment-related deaths occurred in the pyrotinib arm vs one case of diabetic hyperosmolar coma in the placebo arm.

Grade 3 diarrhea occurred primarily during the first treatment cycle at a frequency of 36% in the pyrotinib arm (cycle 2, 20%) vs 1% in the placebo arm. No grade 4 or 5 diarrhea occurred. The median time to the onset of grade 3 diarrhea was 8 days (IQR, 6.0-15.0) in the pyrotinib arm and 71 days (IQR, 23.0-178.0) in the placebo arm. The median duration of grade 3 diarrhea was 1.0 day (IQR, 1.0-1.0) in both arms, and the median cumulative duration was 3.0 days (IQR, 2.0-6.0) and 1.0 day (IQR, 1.0-2.0) in the pyrotinib and placebo arms, respectively. Notably, no patients discontinued study treatment because of grade 3 diarrhea in either arm.

“Regarding the generalizability of the combination of pyrotinib, trastuzumab, and docetaxel to populations outside China, we propose that the efficacy of this combination therapy may generally remain consistent across different racial groups of patients with HER2-positive metastatic breast cancer…These pieces of evidence potentially support the extrapolation of the results from the PHILA study to other populations with HER2-positive metastatic breast cancer, but this hypothesis needs further validation in subsequent studies,” the authors concluded.

Reference

Ma F, Yan M, Li W, et al. Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial. BMJ. 2023;383:e076065. doi:10.1136/bmj-2023-076065