In a Swedish phase II trial (PREDIX HER2) reported in JAMA Oncology, Hatschek et al found no difference in pathologic complete response rate with neoadjuvant trastuzumab emtansine (T-DM1) vs a standard regimen of trastuzumab, pertuzumab, and docetaxel (DTP) in patients with HER2-positive breast cancer.
As stated by the investigators: “…T-DM1 is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as [neoadjuvant] monotherapy is so far unknown.”
Study Details
In the multicenter open-label trial, 197 evaluable women with tumors > 20 mm or lymph node metastases were randomly assigned between December 2014 and October 2018 to receive six 3-week courses of DTP (n = 99), consisting of docetaxel (first dose of 75 mg/m2, then 100 mg/m2), subcutaneous trastuzumab (600 mg), and pertuzumab (loading dose of 840 mg, then 420 mg) or T-DM1 at 3.6 mg/kg (n = 98). Response assessment was performed with fluorine-18–labeled fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) at baseline and after two and six cycles. Patient crossover during treatment was permitted. The primary endpoint was pathologic complete response defined as ypT0 or Tis ypN0.
Key Findings
"In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1."— Hatschek et al
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Overall, 17 patients switched from DTP to T-DM1, 4 due to stable disease and 13 due to grade 3 or 4 toxic effects or patient refusal to continue assigned treatment due to adverse effects. Nine patients switched from T-DM1 to DTP, four due to stable disease, three due to tumor progression, and two due to grade 3 or 4 toxic effects.
Pathologic complete response was observed in 45 patients in the DTP group (45.5%; 95% confidence interval [CI] = 35.4%–55.8%) vs 43 patients in the T-DM1 group (43.9%; 95% CI = 33.9%–54.3%), a nonsignificant difference (P = .82).
In a subgroup analysis, the pathologic complete response rate was higher in 72 patients with hormone receptor–negative tumors vs 125 with hormone receptor–positive tumors among all patients (62.5% vs 36.0%) and in both the DTP group (66.7% vs 36.4%) and T-DM1 group (59.0% vs 35.6%).
At the analysis cutoff date in December 2020, median follow-up from randomization was 40.4 months. No significant difference in event-free survival was observed between the DTP group and T-DM1 group (χ2 = 0.85, 95% CI = 0.60–4.13, P = .36.
Sensitivity analysis excluding all patients who crossed over to DTP or T-DM1 showed no significant alteration in pathologic complete response or event-free survival outcomes.
In exploratory analyses, tumor-infiltrating lymphocyte level above the median of 10% was significantly associated with pathologic complete response (odds ratio [OR] = 2.76, P = .003). Response assessment with 18F-FDG PET/CT showed that a relative decrease in maximum standardized uptake value by greater than the median of 31.3% was also associated with pathologic complete response (OR = 6.67, P < .001).
Grade 3 or 4 adverse events occurred in 39% of the DTP group vs 10% of the T-DM1 group, including neutropenic fever in 26% vs 3%. The most common adverse events of any grade were diarrhea, mucositis, exanthema, and sensory neuropathy in the DTP group and headache, mucositis, sensory neuropathy, and increased transaminases in the T-DM1 group. No deaths occurred during study treatment.
The investigators concluded: “In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1.” They added: “The first report from the PREDIX HER2 trial shows that standard neoadjuvant treatment with docetaxel, trastuzumab, and pertuzumab was equivalent to T-DM1 monotherapy, while T-DM1 demonstrated a more favorable toxic effect profile. With appropriate patient selection and dynamic therapy adaptation based on early response assessment, T-DM1 may have the potential to become a successful strategy for treatment de-escalation.”
Thomas Hatschek, MD, of the Breast Cancer Center, Karolinska University Hospital Solna, Stockholm, is the corresponding author of the JAMA Oncology article.
Disclosure: The study was supported by grants from Region Stockholm, Swedish Research Council, Swedish Cancer Society, Roche Sweden, and others. For full disclosures of the study authors, visit jamanetwork.com.
