Preoperative Treatment with Atezolizumab/Epirubicin Plus Trastuzumab/Pertuzumab Elicits High pCR Rate in Patients With Early HER2+ Positive Breast Cancer

Gabriel Rinnerthaler, MD

A combination of atezolizumab (Tecentriq), epirubicin (Ellence), trastuzumab (Herceptin), and pertuzumab (Perjeta) led to high pathologic complete response (pCR) rates when delivered in the neoadjuvant setting to patients with early-stage HER2-positive breast cancer, according to findings from the randomized phase 2 ATHENE trial (EudraCT2019-002364-27).

Results presented at the 2023 ESMO Breast Annual Congress showed that the overall pCR rate was 60.3% (n = 35/58; 95% CI, 47.5%-71.9%). In an exploratory analysis breaking down responses by treatment arm, investigations showed that with the addition of atezolizumab, the pCR rate increased to 65.5% (n = 19/29; 95% CI, 47.3%-80.1%), and without dropped to 55.2% (n = 16/29; 95% CI, 37.5%-71.6%), reflecting an absolute difference of 10.3% (95% CI, -15% to 35%).

“In an univariable logistic regression model, the response rates were lower in hormone receptor–positive patients, in peri- or premenopausal patients, and in histologies other than NST [no special type],” Gabriel Rinnerthaler, lead study author and associate professor in the Department of Internal Medicine III at the University Hospital Salzburg in Austria, said in a presentation of the data. “The response rates were high in patients with an increased body mass index. Probably due to small numbers in each subgroup there was no statistical significance in this data, only hypothesis-generating [findings].”

Standard therapy for most patients with early HER2-positive breast cancer consists of neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab plus chemotherapy. However, toxicity remains an issue with standard therapy, prompting investigators to evaluate potential chemotherapy de-escalation approaches.

Atezolizumab is a PD-L1 monoclonal antibody approved for the treatment of patients with immune cell–positive triple-negative breast cancer. The addition of atezolizumab to standard chemotherapy and dual HER2 blockade failed to improve outcomes in patients with HER2-positive early breast cancer enrolled in the phase 3 IMpassion050 trial (NCT03726879). However, doxorubicin, epirubicin, and idarubicin have been shown to result in immunogenic cell death. As such, investigators hypothesized that the addition of an anthracycline to checkpoint inhibition could promote synergistic activity.

The study enrolled 58 treatment-naïve patients with early HER2-positive breast cancer according to ASCO and CAP guidelines, measuring as at least cT1c disease with 0 to 3 involved nodes. Patients also had to have an ECOG performance status of 0 or 1 and left ventricular ejection fraction greater than or equal to 55%.

The open-label, two-arm, single-stage study consisted of 2 parts. In part 1, patients were randomly assigned 1:1 to 2 cycles of atezolizumab, pertuzumab, and trastuzumab (n = 29), or 2 cycles of pertuzumab and trastuzumab alone (n = 29). In part 2, all patients received 4 cycles of atezolizumab, pertuzumab, trastuzumab, and epirubicin before undergoing surgery. After surgical recovery, all patients received standard anti–HER2 therapy, and endocrine therapy if hormone receptor positive. Adjuvant taxane-based chemotherapy was also recommended for patients who did not achieve a pCR.

pCR, defined as ypT0/is or ypN0, served as the primary end point. Secondary end points that were also presented included safety and RCB.

Per the statistical plan, pCR of at least 40% had to be achieved to be considered a positive trial. Results were analyzed among 3 populations: the intention-to-treat population (all randomized, n = 58), the safety population (all randomized and received at least 1 dose of study treatment, n = 58), and the efficacy assessment population (all randomized, received at least 2 cycles of study treatment, and underwent pCR evaluation, n = 56).

A total of 70 patients were screened, resulting in a screen failure fate of 17%. One patient each was excluded from the final efficacy assessment in the atezolizumab and control arms due to informed consent withdrawal and absence of end of study visit, respectively.

Overall (n = 58), the median patient age was 57 years (range, 33-82). Most patients were postmenopausal at randomization (59%), had T2 (60%), N0 (60%), and grade 2 (48%) disease. Additionally, most patients had tumor-infiltrating lymphocytes amounting to at least 5% (90%), hormone receptor positivity at the time of randomization (72%), and stage IIA or below disease (78%).

A total of 55 patients were evaluable for RCB assessment. Overall, the RCB rate was 80.0% (n = 44/55; 95% CI, 67.6%-88.4%). Divided by treatment arm, the RCB rate was 85.7% (n = 24/28; 95% CI, 68.5%-94.3%) with atezolizumab vs 74.1% (n = 20/27; 95% CI, 55.3%-86.6%) without, reflecting an absolute difference of 11.6% (95% CI, -9.4% to 32.6%).

Further stratified, the rates of RCB 0, I, II, and III overall (n = 55) were 63.6%, 16.4%, 16.4%, and 3.6%, respectively. With atezolizumab (n = 28), these rates were 67.9%, 17.9%, 14.3%, and 0%, respectively. With trastuzumab and pertuzumab alone (n = 27), these rates were 59.3%, 14.8%, 18.5%, and 7.4%, respectively.

Further exploratory analyses by PD-L1 status indicated that the pCR rates in the PD-L1–negative (immune cell <1%) and PD-L1–positive (immune cell ≥1%) populations were 69.2% (95% CI, 50.0%-83.5%) and 55.2% (95% CI, 37.5%-71.6%), respectively. In the atezolizumab arm, the pCR rates in the PD-L1–negative and–positive populations were 73.3% (95% CI, 48.0%-89.1%) and 58.3% (95% CI, 32.0%-80.7%), respectively. With trastuzumab and pertuzumab alone, the pCR rates were 63.6% (95% CI, 35.4%-84.8%) and 52.9% (95% CI, 31.0%-73.8%), respectively.

Regarding safety, no new signals were identified, Rinnerthaler said. Treatment-emergent adverse effects (AEs) that occurred in at least 15% of patients listed in order of frequency included nausea, diarrhea, fatigue, alopecia, headache, chills, decreased appetite, neutropenia, constipation, pyrexia, infusion-related reaction, mucosal inflammation, arthralgia, dry skin, dyspepsia, and nasopharyngitis.

Grade 3 or greater AEs occurred in 29.3% of patients: 31.0% in the atezolizumab arm and 27.6% in the trastuzumab/pertuzumab arm.

No grade 3 or greater AEs of special interest, defined as immune-related AEs, cardiac disorders, or infusion-related reactions, were reported.

“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” Rinnerthaler concluded.

Disclosures: Dr Rinnerthaler declared honoraria from Amgen, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Roche, and Seagen; consulting or advisory roles for Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Merck, MSD, Novartis, Pfizer, Pierre Fabre, and Roche; and travel accommodations from Amgen, Daiichi Sankyo, Eli Lilly, Gilead, Merck, Pfizer, and Roche.

Reference

Rinnerthaler G, Egle D, Bartsch R, et al. Randomized phase II trial of neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in early HER2-positive breast cancer (ABCSG-52 / ATHENE). Presented at: 2023 ESMO Breast Cancer Congress; May 11-13, 2023; Berlin, Germany. Abstract 123O.