KRISTINE: trastuzumab emtansine plus pertuzumab versus chemotherapy with dual HER2-targeted blockade in her2-positive breast cancer

The final results were presented of the phase III KRISTINE trial in which a combination therapy of trastuzumab emtansine (T-DM1) plus pertuzumab was compared to neoadjuvant trastuzumab and pertuzumab (TCHP), also known as chemotherapy, for HER2-positive breast cancers. The reported data do not justify the replacement of chemotherapy as the standard treatment.

Background

Standard-of-care neoadjuvant therapy for HER2-positive breast cancer is chemotherapy plus dual HER2 blockade with trastuzumab and pertuzumab, followed by continued HER2 blockade in the adjuvant setting. However, a subgroup of these patients will relapse and systemic chemotherapy is associated with systemic toxicity. Therefore, researchers are looking to find new treatment strategies to replace traditional chemotherapy.

Trial set-up

KRISTINE (NCT02131064) was a randomised study comparing neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) versus docetaxel, carboplatin, and trastuzumab plus pertuzumab (TCHP). Patients with HER2-positive stage II–III breast cancer received 6 cycles of neoadjuvant T-DM1+P or TCHP q3w. Patients receiving T-DM1+P (n=223) continued adjuvant T-DM1+P; patients receiving TCHP (n=221) received adjuvant HP, for 12 cycles in each arm. Patients in the T-DM1+P arm without pathological complete response (pCR) were encouraged to receive standard adjuvant chemotherapy before adjuvant T-DM1+P. Primary endpoint was pCR. Secondary endpoints, analysed with descriptive statistics, included event-free survival (EFS; all events pre- and post-surgery), invasive disease-free survival (IDFS; invasive events post-surgery), overall survival, and safety.

Results

Results from the primary endpoint have been reported before; neoadjuvant TCHP resulted in a superior pCR rate compared to T-DM1+P (56% vs 44%; p=0.0155). At median follow-up of 37 months, EFS favoured TCHP (HR 2.61; 95%-CI 1.36-4.98), due to more locoregional progression events in the T-DM1+P arm before surgery (6.7% vs 0%). Achieving pCR was associated with a reduced risk of an IDFS event (HR 0.24; 95%-CI 0.09-0.60) regardless of treatment arm. There were 5 deaths (2.3%) in the TCHP arm and 6 (2.7%) in the T-DM1+P arm.

Patient-reported outcomes favoured the T-DM1+P treatment in the neoadjuvant phase. No clinically meaningful differences were observed between treatment arms in the adjuvant phase.

Overall, there were more grade ≥3 adverse events with TCHP, but a higher rate of adverse events leading to treatment discontinuation with T-DM1+P. When only the adjuvant phase was considered, patients in the TCHP arm reported less grade ≥3 adverse events than the reference arm.

Conclusions

T-DM1+P was associated with fewer grade ≥3 adverse events, but increased treatment discontinuation. EFS numerically favours TCHP due to locoregional progression events with T-DM1+P prior to surgery. The similar risk of an invasive disease-free survival event with T-DM1+P and TCH+P suggests that systemic chemotherapy may be unnecessary for some patients who may be looking for other treatment options, but the clinical utility of systemic chemotherapy-sparing regimens needs to be confirmed.

Reference

Hurvitz SA, Martin M, KH Jung, et al. Neoadjuvant trastuzumab (H), pertuzumab (P), and chemotherapy versus trastuzumab emtansine (T-DM1) and P in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC): Final outcome results from the phase III KRISTINE study. Presented at ASCO 2019; abstract 500.