Atezolizumab Combo Numerically Improves pCR in HER2+ Operable Breast Cancer

“An exploratory analysis shows a statistically significant higher rate of pCR with atezolizumab added to AC followed by HPTC compared with control HPCT, suggesting either a direct anthracycline effect or a mechanistic enhancement of AC with atezolizumab,” according to Luca Gianni, MD.

Treatment with atezolizumab (Tecentriq) plus neoadjuvant trastuzumab (Herceptin), pertuzumab (Perjeta; HP) and chemotherapy improved pathologic complete response (pCR), although this improvement did not reach statistical significance, according to results from the phase 3 APTneo Michelangelo trial (NCT03595592) presented during the 2023 San Antonio Breast Cancer Symposium (SABCS).

In the intention-to-treat (ITT) population, the pCR achieved with HP plus carboplatin and paclitaxel (HPCT; arm A; n = 223) was 52.0% vs 57.8% with atezolizumab plus HPCT with or without anthracyclines (arm B; n = 438; P = .091). pCR was defined as the absence of invasive cells in the breast and lymph nodes. 

The pCR achieved in those who received doxorubicin and cyclophosphamide (AC) and atezolizumab followed by HPCT (arm B1; n = 218) was significantly higher than that achieved with HPCT alone, at 61.9% vs 52.0%, respectively (P = .022). No significant difference in pCR was observed in those who received atezolizumab plus HPCT without anthracyclines (arm B2; n = 220) vs those given HPCT alone, at 53.6% vs 52.0%, respectively (P = .526).

“An exploratory analysis shows a statistically significant higher rate of pCR with atezolizumab added to AC followed by HPTC compared with control HPCT, suggesting either a direct anthracycline effect or a mechanistic enhancement of AC with atezolizumab,” Luca Gianni, MD, study investigator and chair of the International Breast Cancer Research Committee at Fondazione Michelangelo in Milano, Italy, said in a presentation of the data.

For patients with high-risk HER2-positive breast cancer, neoadjuvant dual targeting of HER2 with HP and chemotherapy serves as the standard of care. Prior findings have indicated that the immune system plays a central role in prognosis and response achieved with HER2-directed approaches, and this has led to the exploration of pairing immune checkpoint inhibitors with HER2-directed antibodies, according to Gianni.

The open-label phase 3 APTneo trial enrolled 661 patients with operable or locally advanced HER2-positive breast cancer who had not previously been exposed to chemotherapy. These patients were randomized to 1 of 3 arms:

• Those in arm A received trastuzumab at an initial dose of 8 mg/kg and 6 mg/kg thereafter plus pertuzumab at an initial dose of 840 mg and 420 mg thereafter plus carboplatin at area under the curve of 2 on days 1 and 8 every 21 days and paclitaxel at 90 mg/m2 on days 1 and 8 every 21 days for 6 cycles. No later than 4 weeks after the last dose of neoadjuvant treatment, patients underwent definite surgery. They went on to receive adjuvant HP for another 12 cycles.
• Those in arm B1 received doxorubicin at 60 mg/m2 every 21 days plus cyclophosphamide at 600 mg/m2 every 21 days for 3 cycles followed by HPCT for 3 cycles plus atezolizumab at 1200 mg every 3 weeks. They went on to receive surgery and adjuvant HP and atezolizumab for an additional 12 cycles.
• Those in arm B2 were given HPCT plus atezolizumab for 6 cycles followed by surgery and adjuvant HP and atezolizumab for an additional 12 cycles.

The primary end point of the trial is focused on comparing event-free survival (EFS) between arm A and arm B at 5 years after the last patient is randomized.1 pCR serves as an important secondary end point, Gianni noted. Investigators will also examine the tolerability of the different regimens and conduct molecular analyses to identify predictive markers of benefit and/or resistance to the approaches.

The main patient characteristics at the time of randomization in the ITT population were “very well balanced,” Gianni said. The median patient age in arm A was 50 years (range, 29-79); in arms B1 and B2, the median patient ages were 50 years (range, 21-81) and 49 years (range, 24-78), respectively. He highlighted that greater than 44% of patients across arms A, B1, and B2 had locally advanced disease (45.3%; 45.0%; 44.1%) and approximately 30% (30.5%; 29.8%; 30.9%) had PD-L1 positivity. Moreover, 39.0%, 34.9%, and 30.9% of patients, respectively, had estrogen receptor negativity.

“In a multivariate analysis, treatment with anthracyclines, PD-L1–positive expression, negative expression of the estrogen receptor, and the presence of 30% [or higher] stromal tumor-infiltrating lymphocytes [sTILs] were all associated with higher probability of pCR,” Gianni reported.

The odds ratio (OR) for pCR for arm B1 vs arm A was 1.58 (95% CI, 1.07-2.33; P = .022). The OR for pCR in terms of PD-L1 positivity vs negativity was 1.57 (95% CI, 1.10-2.23; P = .012), and the OR for pCR in terms of estrogen receptor negativity vs positivity was 2.16 (95% CI, 1.53-3.06; P < .0001). The OR for pCR with regard to high vs low sTILs in arm B1 vs arm A was 1.58 (95% CI, 1.07-2.34; P = .021).

“Atezolizumab did not cause major tolerability issues,” Gianni said.

Any-grade treatment-related adverse effects (TRAEs) occurring in at least 15% of patients across arms A, B1, and B2, respectively, included anemia (19.6%; 19.9%; 24.5%), asthenia (26.5%; 38.9%; 29.6%), constipation (6.8%; 16.2%; 8.8%), diarrhea (64.8%; 52.8%; 64.8%), fatigue (21.5%; 22.2%; 19.4%), mucosal inflammation (13.7%; 17.1%; 20.4%), nausea (42.9%; 53.7%; 44.9%), neutropenia (23.7%; 25.9%; 24.5%), decreased neutrophil count (18.3%; 15.7%; 18.5%), rash (12.3%; 5.1%; 15.3%), and vomiting (16.0%; 22.7%; 18.5%).

The most common grade 3 or higher TRAEs reported in arm A were decreased neutrophil count (12.3%), neutropenia (11.9%), diarrhea (3.2%), anemia (1.4%), asthenia (0.9%), fatigue (0.5%), and mucosal inflammation (0.5%). In arm B1, the most common grade 3 or higher TRAEs comprised neutropenia (16.2%), decreased neutrophil count (10.6%), diarrhea (6.9%), anemia (3.7%), asthenia (3.7%), vomiting (0.9%), fatigue (0.9%), mucosal inflammation (0.5%), and nausea (0.5%). In arm B2, the most common grade 3 or higher TRAE was neutropenia (14.8%), followed by decreased neutrophil count (10.6%), diarrhea (6.4%), anemia (2.3%), asthenia (2.3%), vomiting (1.9%), mucosal inflammation (0.9%), rash (0.6%), and fatigue (0.5%).

There was 1 episode of sudden death during neoadjuvant treatment in the control arm.

“We also looked very carefully at immune-mediated adverse effects (AEs) and infusion reactions given the characteristics of the drugs we’re using in the trial,” Gianni said. “Mostly, the AEs associated with atezolizumab were hyperthyroidism and hypothyroidism. But overall, if you look at grade 3 [or higher] immune-mediated AEs, they were not very frequent, and all of them could be effectively treated and controlled clinically.”

The study will continue follow-up until analysis of the primary end point of EFS, he concluded.

Editor’s Note: Gianni disclosed that he serves on advisory boards for Artemida Pharma Ltd, AstraZeneca, Daiichi-Sankyo, Pfizer, Roche, and Zymeworks. He has consulting roles for selected programs with Amgen, Biomedical Insights Inc, Denali Therapeutics Inc, Menarini Ricerche, Revolution Medicines, Synaffix, and Zymeworks. He also noted being a co-inventor of European Patent Application N. 12195182.6 and 12196177.5 titled “PDL-1 expression in anti-HER2 therapy” with Roche but no compensation was provided.

Reference

Gianni L, Munzone E, Mansutti M, et al. Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2 positive, early high risk and locally advanced breast cancer: APTneo Michelangelo randomized trial. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract LBO1-02.