De-escalated Neoadjuvant Trastuzumab/Pertuzumab Induced Sufficient Responses in HER2+/HR– Breast Cancer

Results of the WSG-ADAPT trial (NCT01779206) indicate that de-escalation of trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without weekly paclitaxel for 12 weeks as neoadjuvant treatment of HER2-positive, hormone receptor–negative early breast cancer is safe and feasible, based on response rate and survival data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Additionally, the use of treatment without chemotherapy in the neoadjuvant setting was considered possible in select patients, such as those with high HER2 expression.

“We have for the first time in a prospective, multicenter trial both excellent pCR [pathologic complete response] and survival in patients treated by de-escalated 12-week neoadjuvant weekly paclitaxel and dual HER2 blockade irrespective of additional chemotherapy use,” Nadia Harbeck, MD, PhD, said during a presentation of the results. “Early pCR after only 12 weeks of neoadjuvant paclitaxel plus pertuzumab plus trastuzumab was strongly associated with improved outcome and may thus serve as a predictive clinical marker for further treatment de-escalation.”

The multicenter, prospective phase2/3 trial is being performed within the ADAPT umbrella trial protocol that enrolled 134 patients with HER2-positive, estrogen receptor–negative and progesterone receptor–negative early breast cancer that had not metastasized. Patients had an ECOG performance status of 0 or 1 or a Karnofsky performance status of 80% or higher. Participants were randomized 5:2 to either receive trastuzumab and pertuzumab alone in arm A or with added paclitaxel in arm B. In arm A, patients (n = 92) received a loading dose of 8 mg/kg trastuzumab and 840 pertuzumab followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks for a total of 12 weeks. In arm B (n= 42), paclitaxel was added at 80 mg/m2 every week for 12 weeks.

Surgery was to be completed within 3 weeks of treatment. If the patient did not achieve pCR, standard neoadjuvant therapy could be added followed by surgery. Additional chemotherapy use in patients who did achieve pCR was up to the investigator’s discretion. All patients received adjuvant therapy in accordance with national guidelines.

Patients were biopsied at 3 weeks for assessment of early response, which was defined as Ki-67 decrease of at least 30% from baseline or low cellularity (<500 invasive tumor cells).

The primary end point was pCR rate and secondary end points included invasive disease-free survival (iDFS) rate, overall survival (OS), safety, and translational research.

Patients were followed for a median of 59.9 months (range, 0.2-75.3).

At baseline, patients had a median age of 54 (range, 28-74) in arm A and 51.5 (range, 30-78) in arm B. More than half of patients in both arms had tumors larger than 2 cm and node-negative disease. Eighty-eight percent of patients in each arm had grade 3 disease. HER2 expression was 3+ in 85.9% of patients in arm A and 90.5% of patients in arm B. Median Ki-67 was 50% in both arms.

Data about pCR rates in the trial were previously released and showed that the pCR rate in patients treated with pertuzumab and trastuzumab alone was 34.4% compared with 90.5% in patients who also received paclitaxel chemotherapy.² In patients without ductal carcinoma in situ, the pCR rates were 24.4% and 78.6% in arms A and B, respectively. Twenty-nine percent of patients in arm A and 79.0% in arm B did not require further chemotherapy after achieving pCR.

According to updated findings presented during ASCO, the iDFS rate at 5 years was 87% (95% CI, 78%-96%) in arm A and 98% (95% CI, 84%-100%) in arm B (HR, 0.32; 95% CI, 0.07-1.47; P = .144).1 Harbeck, head of the Breast Center and chair for conservative oncology, Department of Obstetrics and Gynecology, University of Munich, Germany, noted that in univariate analysis, pCR was significantly associated with iDFS.

The distant DFS rate at 5 years was 92% (95% CI, 83%-96%) in the pertuzumab/trastuzumab alone arm and 98% (95% CI, 84%-100%) in the added paclitaxel arm (HR, 0.34; 95% CI, 0.04-2.80; P = .313). Harbeck noted that there were only 7 distant DFS events between the 2 arms.

OS rate at 5 years was 94% (95% CI, 86%-97%) in arm A and 98% (95% CI, 86%-97%) in arm B (HR, 0.41; 95% CI, 0.05-3.55; P = .422); there was only 1 event in arm B.

Patients who achieved a pCR had a 5-year iDFS rate of 98% (95% CI, 90%-100%) compared with 82% (95% CI, 69%-90%) in patients who did not achieve pCR (HR, 0.14; 95% CI, 0.03-0.64; P = .011). Further, in arm A, the iDFS rate was 98% (95% CI, 78%-100%) in those who achieved pCR versus 83% (95% CI, 69%-91%) in those who did not (HR, 0.18; 95% CI, 0.02-1.43; P = .106). “pCR status after de-escalated therapy is deep [and] meaningful regarding outcome in the whole study,” Harbeck commented.

The investigators looked to biomarkers to determine if they could identify who could benefit from dual HER2 blockade alone. Seven patients in the trastuzumab/pertuzumab alone arm had basal subtype by PAM50 gene signatures, and none of these patients achieved a pCR, compared with 36.5% of patients with non-basal cancers in the treatment arm.

Patients with HER2 1+/2+ or fluorescence in situ hybridization (FISH) positivity (n = 13) also did not respond to dual HER2 blockade alone, as was previously presented at the 2019 San Antonio Breast Cancer Symposium.³ Additionally, patients with HER2 3+/FISH positivity who did not show an early response to treatment (n = 17) had a low pCR rate of 12%. This accounted for a total non-sensitive population of 33.7% of patients in arm A.

In the study as a whole, patients with these non-sensitive tumors had an increased risk for both iDFS and distant DFS. The 5-year iDFS rate was 79% (95% CI, 59%-90%) in patients with non-sensitive tumors and 93% (95% CI, 81%-97%) in patients with potentially sensitive tumors (HR, 1.99; 95% CI, 0.61-6.55; P = .255). Harbeck noted that the hazard ratio for distant DFS for those with non-sensitive tumors was about 5.

The impact of RNA signature on pCR and iDFS was also explored. Of note, BRCAness was associated with worse pCR and iDFS in patients treated in arm A. Harbeck noted that the ERBB2 signature was a strong predictor for pCR, which she said was consistent with what was observed in patients with HER2 2+/3+ expression on IHC. Otherwise, most of the signatures showed greater prediction for iDFS than pCR.⁴

Harbeck concluded that future investigation of chemotherapy-free regimens may need to be focused on select patients with sensitive tumors, such as those with HER2 3+, non–basal-like tumors, early responders, and those with predictive RNA signatures such as immune signatures.

The ADAPT umbrella trial and other trials (COMPASS, DECRESCENDO) continue to explore de-escalation strategies in patients with breast cancer.

References

1. Harbeck N, Gluz O, Christgen M, et al. De-escalated neoadjuvant pertuzumab+trastuzumab with or without paclitaxel weekly in HR-/HER2+ early breast cancer: ADAPT-HR-/HER2+ biomarker and survival results. J Clin Oncol. 2021;39(suppl 15):503. doi:10.1200/JCO.2021.39.15_suppl.503

2. Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol. 2017;28(11):2768-2772. doi:10.1093/annonc/mdx494

3. Gluz O, Kolberg-Liedtke C, Biehl C, et al. Predictive value of HER2 expression, early response and tumor infiltrating lymphocytes (TILs) on efficacy of de-escalated pertuzumab+trastuzumab in the neoadjuvant WSG-ADAPT-HER2+/HR- trial. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract P4-10-05.

4. Graeser M, Gluz O, Biehl C, et al. Impact of RNA expression signatures and tumor infiltrating lymphocytes (TILs) for pathological complete response (pCR) and survival after 12 week de-escalated neoadjuvant pertuzumab + trastuzumab +/- paclitaxel in the WSG-ADAPT HER2+/HR- trial. Presented at: 2021ESMO Breast Cancer Virtual Congress; May 5-7, 2021; Virtual. Abstract LAB2.