Clinical, Molecular Factors Correlate With pCR for Durvalumab/Trastuzumab/Pertuzumab in Early HER2+ Breast Cancer

A multifactor analysis from the single-arm phase 2 DTP study (NCT03820141) evaluating a chemotherapy-free regimen of durvalumab (Imfinzi) plus trastuzumab (Herceptin) and pertuzumab (Perjeta) in patients with HER2-enriched early breast cancer demonstrated a correlation between pathologic complete response (pCR) and several clinical, pathologic, and molecular factors.1

These findings could help inform patient selection for future research with this regimen, according to Polly Niravath, MD.

In a presentation at the 2024 San Antonio Breast Cancer Symposium (SABCS), data demonstrated that with smaller tumor size (P = .007), earlier stages (P = .018), a higher tumor-infiltrating lymphocyte (TIL) percentage (P = .02), and a higher PD-L1 combined positive score (CPS; P = .038) were all associated with higher pCR rates. Molecular analyses identified a high score on the HER2Dx assay; a larger population of plasma cells and B cells; and a lower population of SPP1-positive tumor-associated macrophages were also predictors of pCR.

“[By identifying] which patients were most likely to have a pCR, [it could allow us] to focus only on those patients and get an even higher pCR rate [in future trials],” Niravath said.

In an interview with OncLive®, Niravath discussed the prior efficacy data from the DTP trials, elaborated on the markers found to be predictive of pCR, and explained how these analyses could inform future research and patient selection.

Niravath serves as the Lois E. and Carl A. Davis Centennial Chair in Cancer Research at the Dr. Mary and Ron Neal Cancer Center and an associate professor of clinical medicine at the Academic Institute, Department of Medicine, Houston Methodist Hospital, in Texas.

OncLive: What was the rationale for evaluating the chemotherapy-free combination of durvalumab, trastuzumab, and pertuzumab for the treatment of patients with early HER2-enriched breast cancer?

Niravath: The basic idea was that we know [within] the HER2-positive breast cancer [population], there is a subset of patients who are exquisitely responsive to anti-HER2 therapy [alone] and probably don't need chemotherapy at all. The entire basis of this trial was to identify those patients and treat them with only targeted therapy, which is far less toxic than chemotherapy. Ideally, [we wanted to] achieve the same results, which is cure, without using chemotherapy at all.

What were the prior efficacy and safety data reported from this study?

We previously presented the initial results of this study at the 2024 AACR Annual Meeting, which [showed] that by using a chemotherapy-free regimen with only 6 cycles of durvalumab—an immunotherapy—plus trastuzumab and pertuzumab, which are anti-HER2 antibodies, we were able to achieve a pCR rate of [48.6%].2 If we include patients who had a residual cancer burden [RCB] of 0 or 1, we had a [67.6% pathologic response rate].

The safety outcomes have been excellent. Those data were presented at AACR, and we primarily saw grade 1 and 2 adverse effects [AEs]. The most significant immune-related AE was thyroiditis, which is very common. We had a thyroiditis rate of approximately 30% to 35%. In general, everything was mostly grade 1 and 2, [and durvalumab plus trastuzumab and pertuzumab] was very well tolerated.

What were the key findings regarding clinical, pathologic, and molecular factors that were correlated with pCR?

[At the 2024 SABCS], we presented [findings on] how we can help identify which patients were most likely to have a pCR, [which could allow us] to focus only on those patients and get an even higher pCR rate [in future trials].

We found that patients who had higher [levels of] TILs, a higher PD-L1 CPS, and lower stages [of disease] were more likely to have a pCR. Interestingly, those patients who had higher immune cell [counts] in their tumor milieu did much better with treatment and were more likely to achieve pCR. Those patients had more plasma cells and B cells, meaning that they were more ripe for immune activity.

Finally, there's a genomic assay called the HER2Dx assay, and scoring highly on that HER2Dx assay was also predictive for pCR.

What are the future directions for this research?

We are looking at doing the next iteration of this trial, which is going to use durvalumab plus trastuzumab and pertuzumab in a highly selected group of patients who have HER2-enriched [breast cancer], have high immune markers, and are positive on the HER2Dx assay. We will give them that same regimen of durvalumab plus trastuzumab and pertuzumab.

For those patients who aren't responding in this next iteration [of the study], we're hoping to rescue them with another drug, such as fam-trastuzumab deruxtecan-nxki [Enhertu].

What are the potential clinical implications of this study?

The implications could be quite revolutionary. If this method turns out to be successful on a larger scale—we're looking at doing a larger phase 2 trial next—then the hope is that some women who have HER2-positive breast cancer, especially this HER2-enriched, very sensitive type of breast cancer, may potentially be cured without ever having to use chemotherapy, which would revolutionize the entire treatment of breast cancer.

References

1. Niravath P, Li M, Guan J, et al. Multifactor analysis for pathologic complete response (pCR) in a chemotherapy-free regimen of durvalumab, trastuzumab, and pertuzumab (DTP Trial) in HER2-enriched early breast cancer. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract RF1-07.
2. Guan J, Sun K, Jain, D et al. Chemotherapy-free neoadjuvant regimen with durvalumab, trastuzumab and pertuzumab (DTP) in HER2-enriched early breast cancer: A prospective, open-label phase II trial. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT029.