Immunotherapy Strategies Explored in HER2+ Breast Cancer

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%.

“This has certainly shown promise, but of course, this is only a proof-of-concept study, but it showed that similar to other treatment types, the responses with pembrolizumab and trastuzumab were durable, but only the PD-L1—positive patients responded. It seems that the TILs added to the PD-L1 biomarker,” Loi explained. “What we learned is that advanced disease is poorly immunogenic and immune hostile.”

The next question this led to, Loi said, is how the durability and ORR can be increased, especially in a PD-L1—negative population.

The phase II Australian DIAmOND study (BCT 1703) is looking to answer this by investigating the combination of PD-L1 and CTLA-4 inhibition added to trastuzumab in patients with advanced, incurable HER2-positive breast cancer that has progressed on prior trastuzumab-based therapy.⁵ Patients receive induction durvalumab (Imfinzi) and tremelimumab every 4 weeks; trastuzumab either weekly, biweekly, or every 3 weeks; and estrogen suppression for those who are ER positive, for weeks 1 through 16. In weeks 17 to 52, patients received durvalumab plus trastuzumab every 3 weeks, as well as estrogen suppression if applicable. The primary endpoint is 1-year PFS.

Additionally, the AVIATOR TBCRC045 trial is combining a CD137 agonist with a PD-L1 inhibitor.⁶ The rationale for this, Loi explained, is that CD137 is expressed on activated T cells and natural killer (NK) cells, and trastuzumab upregulates CD137 expression on NK cells. Moreover, CD137 agonists stimulate NK function; therefore, combining a CD137 agonist with trastuzumab is synergistic in nu/nu HER2-positive xenograft models.

Forty patients with advanced HER2-positive breast cancer will be randomized to receive vinorelbine, trastuzumab, and avelumab; vinorelbine and trastuzumab; or vinorelbine, trastuzumab, avelumab, and PF-05082566, a fully human IgG2 agonist monoclonal antibody that binds to the extracellular domain of human 4-1BB/CD137. Those receiving the 2 drugs will then go on to receive the other 3 drugs, while the remaining 2 arms will discontinue therapy. Patients must have received prior trastuzumab and pertuzumab (Perjeta) but no prior immunotherapy; this is a PD-L1—unselected population.

The randomized phase II KATE2 study is evaluating the addition of atezolizumab (Tecentriq) to ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with locally advanced or metastatic HER2-positive locally advanced or metastatic breast cancer who received prior trastuzumab and taxane-based therapy.⁷ The results will be presented at the 2018 San Antonio Breast Cancer Symposium.

For patients with stage IV disease, the setting of “cure” remains a major question, Loi explained. In the United States and Australia, more than 80% of patients have metastatic disease. With reports of long-term survival, 13% of patients achieve no evidence of disease at 10 years. Therefore, the use of checkpoint inhibitors could be a curative strategy for this population.

Moreover, in the adjuvant setting, the presence of TILs could facilitate de-escalation of anthracyclines or determine patients who are suitable for adjuvant trastuzumab, without the addition of pertuzumab or neratinib (Nerlynx), Loi concluded.

An analysis of the ShortHER trial found that patients with stage II disease and a 10% increment of TILs had a higher metastasis-free survival with 6 months of adjuvant trastuzumab than those with stage I or III disease (HR, 0.38; 95% CI, 0.18-0.80; P = .011).⁸

References

1. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544-1550. doi: 10.1093/annonc/mdu112.
2. Salgado R, Denkert C, Campbell C, et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol. 2015;1(4):448-454. doi: 10.1001/jamaoncol.2015.0830. Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2018;167(3):671-686. doi: 10.1007/s10549-017-4537-5.
3. Manikhas A, Pennella EJ, Bondarenko I, et al. Biosimilar MYL-1401O monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 HERITAGE trial. J Clin Oncol. 2018,36 (suppl; abstr 110).
4. Loi S, Giobbie-Hurder A, Gombos A, et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer: results from the PANACEA study (IBCSG 45-13/BIG 4-13/KEYNOTE-014). In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS2-06.
5. Current clinical trials. DIAmOND BCT 1703. Breast Cancer Trials website. breastcancertrials.org.au/current-clinical-trials/diamond. Accessed October 24, 2018.
6. The AVIATOR Study: Trastuzumab and Vinorelbine With Avelumab or Avelumab & Utomilumab in Advanced HER2+ Breast Cancer.
7. A Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Participants With Human Epidermal Growth Factor-2 (HER2) Positive Locally Advanced or Metastatic Breast Cancer (BC) Who Received Prior Trastuzumab and Taxane Based Therapy (KATE2). clinicaltrials.gov/ct2/show/NCT02924883. Updated October 10, 2018. Accessed October 24, 2018.
8. Dieci MV. Tumor-infiltrating lymphocytes (TILs) as an independent prognostic factor for early HER2+ breast cancer patients treated with adjuvant chemotherapy and trastuzumab in the randomized ShortHER trial. In: Proceedings from the 2018 European Society for Medical Oncology Congress; October 19-23, 2018; Munich, Germany. Abstract 186O.