Two neoadjuvant treatment regimens can improve pathologic complete response (pCR) rates over standard care in patients with HER2-positive breast cancer, according to phase 2 results published in Nature Communications.

Both ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and combination paclitaxel, trastuzumab, and pertuzumab (THP) improved pCR rates, when compared with paclitaxel plus trastuzumab (TH), in the adaptively randomized I-SPY2 trial (ClinicalTrials.gov Identifier: NCT01042379).

The trial included 128 patients with stage II/III, HER2-positive breast cancer who had tumors larger than 2.5 cm. The patients were randomly assigned to receive neoadjuvant treatment with T-DM1/P (52 patients), THP (45 patients), or TH (31 patients). After neoadjuvant therapy, patients went on to receive doxorubicin/cyclophosphamide, followed by surgery.


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The 3 treatment arms had similar baseline characteristics overall. However, the T-DM1/P arm had more patients with Mammaprint ultra-high tumors when compared with the control arm (44% vs 16%; P =.01).

Response Rates

Response to treatment was examined in the overall group as well as the hormone receptor (HR)-positive and HR-negative groups.

For the overall group, the estimated pCR rate was higher with T-DM1/P than with TH — 55% and 25%, respectively. This corresponded to a 99.9% probability that T-DM1/P was superior to TH and a 96% predictive probability of superiority in a 300-patient phase 3 trial.

In the HR-positive group, the probability that the pCR rate would be higher with T-DM1/P than with TH was 99.7%. The probability was 98.8% in the HR-negative group.

In the overall group, the estimated pCR rate was higher with THP than with TH — 56% and 25%, respectively. This corresponded to a 99.9% probability that THP was superior to TH and a 97% predictive probability of superiority in a 300-patient phase 3 trial.

In the HR-positive group, the probability that the pCR rate would be higher with THP than with TH was 99.5%. The probability was 99.9% in the HR-negative group.

Survival and Safety

The 3-year event-free survival rate was 88% in the T-DM1/P arm, 92% in the THP arm, and 87% in the TH arm. At a median follow-up of 4.1 years, there were 7 events in the T-DM1/P arm, 3 in the THP arm, and 7 in the TH arm.

Adverse events were largely grade 1/2 in nature. Grade 3 or higher adverse events occurred in 5.8% of patients in the T-DM1/P arm, 11% of those in the THP arm, and 9.7% of those in the TH arm.

One patient in the THP arm died due to respiratory failure, but this was deemed unrelated to therapy.

Biomarkers

The researchers also evaluated whether 10 biomarkers are predictors of response to TDM1/P and THP.

They found that proliferation markers showed the largest predictive performance differences between the treatment arms. All 3 proliferation markers analyzed were significantly associated with response to TDM1/P but not THP in the HR-positive group.

All 5 HER2 pathway biomarkers analyzed were significantly associated with pCR in the TDM1/P and THP arms (P <.05). In contrast, higher estrogen receptor signaling levels were associated with nonresponse to TDM1/P and THP in the population as a whole and in the HR-positive subsets within both arms.

“These findings are critically important to the design of the next generation of HER2+ trials in which these biomarkers can be utilized to assess which patients can potentially de-escalate therapy (by dropping toxic anthracycline or platinum agents) from those who could benefit from treatment escalation with new and more intensive treatment approaches,” the researchers wrote.

Disclosures: The I-SPY2 trial is sponsored by QuantumLeap Healthcare Collaborative. Additional support was provided by several companies, foundations, and private individuals. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Clark AS, Yau C, Wolf DM, et al. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial. Nat Comm. Published online November 5, 2021. doi:10.1038/s41467-021-26019-y