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Immunotherapy Strategies Explored in HER2+ Breast Cancer

Gina Columbus @ginacolumbusonc
Published: Friday, Oct 26, 2018

Sherene Loi, MD, PhD
Sherene Loi, MD, PhD
Although the first steps have been taken with immunotherapy in breast cancer, Sherene Loi, MBBS, FRACP, PhD, FAHMS, said development is still lagging in HER2-positive disease because of effective anti-HER2 therapies available.

“Certainly, for HER2-positive breast cancer, we are not quite there yet, but there is certainly strong rationale to move forward,” said Loi, a medical oncologist and the head of the Breast Cancer Trials Unit at Peter MacCallum Cancer Centre in Victoria, Australia, in a presentation during the 2018 European Society for Medical Oncology Congress. “Ultimately, immunotherapy could help us achieve no evidence of disease [long-term] in the metastatic and locally advanced setting.”

HER2-positive breast cancers are immunogenic, she explained. On average, HER2-positive breast cancers have high levels of tumor-infiltrating lymphocytes (TILs) compared with other breast cancer subtypes, such as estrogen receptor (ER)–negative, HER2-positive subsets, and nearly similar levels as triple-negative breast cancer (TNBC).

Evidence also suggests that immunotherapy is already being used quite effectively in HER2-positive breast cancer; preclinical data suggest that the dominant mechanism of action with trastuzumab is immune mediated.

Correlative findings from the FinHER trial evaluated the addition of adjuvant treatment with trastuzumab to 9 weeks of chemotherapy. Results showed a greater magnitude of benefit in patients with more than 10% increments of TILs who received trastuzumab (HR, 0.82; 95% CI, 0.58-1.16) versus those who did not receive the agent (HR, 1.22; 95% CI, 1.0-1.47).1

Similar data were seen in the NeoALTTO trial, which looked at the combination of trastuzumab with lapatinib (Tykerb) and either agent alone. Findings suggested that an increase in immune quantity will increase pathologic complete response (pCR) rates to the combination in patients with HER2-positive breast cancer.2 Therefore, Loi said, TILs are a biomarker to prognostic information for a pCR endpoint.

“The TIL biomarker adds prognostic information to a prognostic model in HER2-[positive] breast cancer, including a pCR endpoint, so it’s independent,” she explained.

These conclusions have led the path for combining checkpoint inhibitor and HER2-directed therapies. Data suggest enhanced immune effects of HER2-directed therapy in combination with checkpoint inhibition, effects that are leading to intriguing therapeutic strategies being explored in HER2-positive breast cancer clinical trials.

For example, the phase Ib JAVELIN Solid Tumor study evaluated single-agent avelumab (Bavencio) in previously treated patients with PD-L1–unselected metastatic breast cancer (n = 168). Results showed that the overall response rate (ORR) was 3.0%; the ORR was 5.2% in patients with TNBC and 2.8% in those with ER-positive disease. There was a 0% ORR in patients with HER2-positive breast cancer (n = 26).3

“We know now that the previously treated setting is not the place to evaluate anti–PD-1 therapy in HER2-positive breast cancer,” Loi said.

The phase Ib/II proof-of-concept PANACEA study, however, looked at the combination of pembrolizumab (Keytruda) with trastuzumab in heavily pretreated, trastuzumab-resistant, advanced HER2-positive breast cancer to determine whether a PD-1 inhibitor can have an impact on trastuzumab resistance. Patients had confirmed PD-L1 status on metastatic lesions and were treated with the combination until disease progression; cohorts were divided into PD-L1 positive (≥1% on cells) and negative. The primary endpoint was ORR.

In the PD-L1–positive cohort (n = 44), the ORR was 20%, and there were no responses in the PD-L1–negative cohort.4 Moreover, the median progression-free survival (PFS) was 2.7 months versus 2.5 months in the PD-L1–positive and –negative cohorts, respectively. Additionally, the 12-month PFS rates were 13% and 0%.

The PD-L1–positive cohort had a median overall survival (OS) of 16.1 months compared with 7.0 months for those who were PD-L1 negative. The 1-year OS rates were 65% versus 12%.

The stromal TILs (sTILs) were examined in these patients by PD-L1 status and site of biopsy. Although the average is 20% to 25% in primary HER2-positive breast cancer, the median sTILs was 1% in this study. Moreover, the baseline sTILs by PD-L1 status were higher than in the PD-L1–negative cohort (P = .0004) and in the lymph nodes or lung (P = .0003). In the PD-L1–positive cohort with sTILs ≥5 (41%), the ORR was 39% and the disease control rate was 47%.

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