Adjuvant T-DM1/Pertuzumab Combo Misses iDFS End Point in High-Risk HER2-Positive Breast Cancer

Nadia Harbeck, MD, PhD

Anthracycline-based chemotherapy followed by ado-trastuzumab emtansine (T-DM1; Kadcyla) plus pertuzumab (Perjeta; AC-KP) did not show statistically significant or clinically meaningful improvement in invasive disease-free survival (iDFS) in patients with high-risk HER2-positive early breast cancer, missing the primary end point of the phase 3 KAITLIN trial (NCT01966471).

Results presented during the 2020 ASCO Virtual Scientific Programshowed that the AC-KP regimen failed to reduce the risk of an IDFS event versus taxane treatment plus concurrent trastuzumab (Herceptin) and pertuzumab (AC-THP) in node-positive patients. The number of iDFS events reported on the AC-KP arm (n = 832) was 80 (9.6%) versus 82 (9.9%) on the AC-THP arm (n = 826; stratified hazard ratio [HR], 0.97; 95% CI, 0.71-1.32; P =.8270). Moreover, the 3-year iDFS rates were 92.8% versus 94.1% with AC-KP and AC-THP, respectively.

The investigational regimen also failed to reduce the risk of iDFS in the intent-to-treat (ITT) population, with 86 events (9.3%) reported on the AC-KP arm (n = 928) and 88 events (9.6%) reported on the AC-THP arm (n = 918; stratified HR, 0.98; 95% CI, 0.72-1.32). The 3-year iDFS rates in this population were 93.1% in the investigational arm and 94.2% in the comparator arm.

Notably, the iDFS results proved to be consistent across all patient subgroups analyzed.

“Given the KAITLIN results, adjuvant trastuzumab and pertuzumab and chemotherapy remains a standard of care for patients with high-risk, HER2-positive early breast cancer, given that patients and physicians want to follow the adjuvant treatment approach,” said lead author Nadia Harbeck, MD, PhD, head of the Breast Cancer and chair for Conservative Oncology in the Department of OB&GYN at the University of Munich, during a virtual presentation.

Chemotherapy in combination with HER2 targeted therapy followed by continued targeted therapy is the standard of care for patients with early HER2-positive breast cancer, according to Harbeck, and in those with residual invasive disease following neoadjuvant therapy, T-DM1 is the standard in the adjuvant setting. In high-risk patients, recurrence remains a challenge faced in clinical practice, along with toxicities associated with systemic chemotherapy.

In the phase 3 KAITLIN trial, investigators set out to determine whether efficacy can be improved, and toxicity can be reduced, by using T-DM1 instead of taxanes and trastuzumab. Notably, at the time of that the study was being designed, T-DM1 had proven be effective in patients with taxane/trastuzumab-resistant cancers within the metastatic setting.

The trial enrolled a total of 1,846 patients with centrally confirmed early HER2-positive breast cancer, with either node-positive or -negative disease. Patients with node-negative disease had to have tumors that were hormone receptor negative and larger than 2 cm. Following surgery, all patients received 3 to 4 treatment cycles with anthracycline combination chemotherapy. In the control arm, patients then received 3 to 4 cycles or 12 weeks of a taxane, plus trastuzumab and pertuzumab. Trastuzumab/pertuzumab was continued for up to 18 cycles, or 1 year. In the experimental arm, patients were given a taxane-sparing combination comprised of T-DM1 plus pertuzumab for up to 18 cycles, or 1 year.

Stratification factors included region, nodal status, centrally assessed hormone receptor status, and type of anthracycline. The co-primary end points of the trial included iDFS in the node-positive and ITT populations. The primary analysis had been planned for after 160 events were reported in the node-positive population and after 171 events occurred in the ITT population; this allowed for the detection of a HR of 0.64 with 80% and 82.5% power, respectively, said Harbeck.

Notably, after the phase 3 MARIANNE trial demonstrated noninferior progression-free survival with T-DM1 in combination with pertuzumab versus trastuzumab plus a taxane treatment in the metastatic setting, the KAITLIN protocol was amended to decrease the sample size from 2,500 to approximately 1,850, while upholding the statistical power of the study to evaluate the primary end points of the trial.

Secondary end points of the trial included overall survival in the node-positive population and the ITT population, iDFS including secondary primary non-breast cancer, disease-free survival, and distant recurrence-free interval; safety; and patient-reported outcomes per the QLQ-C30 and the QLQ-BR23.

Ninety percent of the 1,846 patients enrolled on the trial had node-positive disease. The median duration of follow-up was 57 months for the investigational arm, which was comprised of 928 patients. The clinical data cutoff was November 27, 2019.

Baseline patient and disease characteristics were well balanced between the 2 arms, said Harbeck; however, more than half of the patients, or 60%, were aged 50 years or older. The majority of the population was Caucasian, and 30% was Asian. Ninety percent of patients on the trial had an ECOG performance status of 0 at baseline.

“Only 10% of patients in KAITLIN were node negative ad 90% were node positive,” said Harbeck. “Over 30% of patients had 4 or more involved lymph nodes. So this is, by far, the highest risk population in any of the adjuvant and HER2 phase 3 trials.”

She added that central hormone receptor status was negative in approximately 40% of patients in both arms. Additionally, epirubicin was the choice anthracycline, utilized in approximately 60% of patients. The median left ventricular dysfunction at baseline proved to be identical between the arms at 65.0. The majority of the tumors were over 2 cm.

With regard to treatment exposure in the HER2-targeted phase of the trial, 65% of patients on the AC-KP arm completed 18 cycles of T-DM1. A total of 167 patients switched from KP to HP during the trial, mostly because of laboratory abnormalities. Eighty-one percent of patients completed HER2-targeted therapy. Additionally, 81% of patients who received AC-KP completed 18 cycles of pertuzumab versus 85% of those who received AC-THP.

With regard to safety, grade ≥3 adverse effects (AEs) were reported in 51.8% of patiens on the AC-KP arm versus 55.4% on the AC-THP arm; 21.4% versus 23.3%, respectively, experienced serious events. Seven deaths occurred on the trial, with 5 reported on the AC-KP arm and 2 on the AC-THP arm; however, all of these events were not determined to be related to study treatment. AEs resulting in withdrawal from trastuzumab/T-DM1 was 26.8% on the AC-KP arm versus 4.0% on the AC-THP arm. Toxicities leading to withdrawal from a taxane was 0% versus 6.7% in the AC-KP and AC-THP arms, respectively.

“The types and severity of AEs were similar to the known safety profiles of each treatment,” said Harbeck. “In the AC-KP arm, we see a higher number of high-grade hepatotoxicity and thrombocytopenia. Peripheral neuropathy was low, under 4% in both arms. In the standard taxane-containing arm, we see a higher number of high-grade diarrhea, leukemia, or mucositis.”

A lower risk of deterioration was reported in the AC-KP arm from the start of treatment with HER2-targeted therapy, with differences between the arms during the taxane treatment (stratified HR, 0.71; 95% CI, 0.62-0.80). A similar pattern was reported with regard to physical functioning, role functioning, and cognitive functioning.

“KAITLIN did not meet its primary end point. AC-KP did not demonstrate a statistically significant or clinically meaningful improvement in iDFS compared with AC-THP in the node-positive or ITT populations,” concluded Harbeck. “However, the 3-year iDFS rates of 94% in the AC-THP arm and 93% in the AC-KP arm are excellent in this high-risk population, given the fact that 90% of the KAITLIN population were node positive, and 30% had more than 4 involved lymph nodes.”

Reference

Harbeck N, Im S-A, Barrios CH, et al. Primary analysis of KAITLIN: a phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC). J Clin Oncol. 2020;38(suppl 15):500. doi:10.1200/JCO.2020.38.15_suppl.500