Tecentriq Plus Perjeta, Herceptin, Chemo Does Not Improve pCR in HER2+ Breast Cancer

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A recent phase 3 APTneo Michelangelo trial added Tecentriq to neoadjuvant Herceptin plus Perjeta and chemotherapy which did not lead to a statistically significant improvement in pathologic complete response in patients with HER2-positive operable breast cancer.

The addition of Tecentriq (atezolizumab) to neoadjuvant Herceptin (trastuzumab) plus Perjeta (pertuzumab) and chemotherapy was shown to improve the number of pathologic complete responses (pCR) compared to Perjeta plus chemotherapy in patients with HER2-positive operable breast cancer.

However, there was no statistically significant difference between the two treatment groups, meaning that the researchers could not definitively say that one treatment was better than the other when it came to pCR.

These findings were presented at the 2023 San Antonio Breast Cancer Symposium.

The pCR achieved with Perjeta plus carboplatin and paclitaxel (223 patients) was 52.0% vs 57.8% with Tecentriq plus Herceptin, Perjeta and chemotherapy (HPCT) with or without anthracyclines (438 patients). However, there was an approximate 9.1% likelihood that the difference between these two groups happened by chance, rather than the difference in treatments. pCR was defined as the absence of invasive cells in the breast and lymph nodes.

The pCR achieved in those who received Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide) and Tecentriq followed by HPCT (218 patients) was significantly higher than that achieved with HPCT alone, at 61.9% vs 52.0%, respectively. No significant difference in pCR was observed in those who received Tecentriq plus HPCT without anthracyclines (220 patients) compared with those given HPCT alone, at 53.6% vs 52.0%, respectively, a difference which, once again, was not statistically significant.

“An exploratory analysis shows a statistically significant higher rate of pCR with (Tecentriq) added to (doxorubicin and cyclophosphamide) followed by HPTC compared with control HPCT, suggesting either a direct anthracycline effect or a mechanistic enhancement of (doxorubicin and cyclophosphamide) with Tecentriq,” Dr. Luca Gianni, study investigator and chair of the International Breast Cancer Research Committee at Fondazione Michelangelo in Milano, Italy, stated 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 randomly assigned to one of three arms:

  • Those in arm A received Herceptin at an initial dose of 8 mg/kg and 6 mg/kg thereafter plus Perjeta at an initial dose of 840 mg and 420 mg thereafter plus carboplatin 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 four weeks after the last dose of neoadjuvant treatment, patients underwent definite surgery.They went on to receive adjuvant Perjeta for another 12 cycles.
  • Those in arm B1 received Adriamycin at 60 mg/m2 every 21 days plus cyclophosphamide at 600 mg/m2 every 21 days for three cycles followed by HPCT for three cycles plus Tecentriq at 1200 mg every three weeks. They went on to receive surgery and adjuvant HP and Tecentriq for an additional 12 cycles.
  • Those in arm B2 were given HPCT plus Tecentriq for six cycles followed by surgery and adjuvant Perjeta and Tecentriq for an additional 12 cycles.

The primary end point of the trial is focused on comparing event-free survival (EFS; the measure of time from treatment that a group of people in a clinical trial has not had cancer come back/worsen) between arm A and arm B at five years after the last patient is randomized.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 intent-to-treat population were “very well balanced,” Gianni said. The median patient age in arm A was 50 years in arms B1 and B2, the median patient ages were 50 years and 49 years, respectively. He highlighted that greater than 44% of patients across arms A, B1, and B2 had locally advanced disease and approximately 30% 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.

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

Any-grade treatment-related side effects occurring in at least 15% of patients across arms A, B1 and B2, respectively, included anemia (19.6%; 19.9%; 24.5%), weakness/lack of energy (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 treatment-related side effects reported in arm A were decreased neutrophil count (12.3%), neutropenia (11.9%), diarrhea (3.2%), anemia (1.4%), weakness/lack of energy (0.9%), fatigue (0.5%) and mucosal inflammation (0.5%). In arm B1, the most common grade 3 or higher treatment-related side effects 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 treatment-related side effects 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 one episode of sudden death during neoadjuvant treatment in the control arm.

“We also looked very carefully at immune-mediated side effects and infusion reactions given the characteristics of the drugs we’re using in the trial,” Gianni said. “Mostly, the treatment-related side effects associated with Tecentriq were hyperthyroidism and hypothyroidism. But overall, if you look at grade 3 (or higher) immune-mediated side effects, 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.

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