Hope for patients with Trastuzumab-resistant breast cancer

Patients whose breast cancer tumours were positive for a biomarker for pembrolizumab showed signs of promise on a combination of pembrolizumab (Keytruda) and trastuzumab (tested in patients with trastuzumab-resistant advanced HER2-positive breast cancer).

At the San Antonio Breast Cancer Symposium in Texas this week, data was presented from the phase lb/II PANACEA trial.

Approximately 20% of all invasive breast cancers are thought to be HER2-positive. Some of these patients develop a resistance to trastuzumab (an HER2-specific monoclonal antibody utilised for treatment of breast cancer).

 

 

We wanted to investigate if immunotherapy approaches can work in patients with advanced HER2-positive breast cancer that is resistant to trastuzumab. We believe that immune evasion is a part of the biological resistance to trastuzumab in patients with this disease. Prior studies from our group have shown that antitumor immunity is important for improved outcomes in patients with advanced HER2-positive breast cancer

Sherene Loi, MD, PhD, associate professor at Peter MacCallum Cancer Centre in Melbourne, Australia, working with the International Breast Cancer Study Group (IBCSG)

It had already been proffered by Loi and colleagues the patients with trastuzumab-resistant advanced HER2-positive breast cancer had evidence of poor immune responses, and preclinical studies revealed that anti-PD1 immunotherapy improved the therapeutic activity of trastuzumab.

From the official press release of the San Antonio Breast Cancer Symposium:

In this phase Ib/II clinical trial, Loi and colleagues enrolled 58 patients with advanced breast cancer that had progressed on prior trastuzumab-based therapies. Tumours were assessed centrally for HER2 positivity and PDL1 status, and for quantity of tumour-infiltrating lymphocytes (TILs).

The Phase Ib portion of the trial was a dose-escalation study of pembrolizumab, an anti-PD1 therapy that targets the T-cell checkpoint protein PD1, in conjunction with the standard dose of trastuzumab. No dose-limiting toxicities (DLTs) were observed.

In phase II, the investigators enrolled 40 patients and 12 patients to the PDL1-positive and PDL1-negative cohorts, respectively. Patients received 200mg of pembrolizumab every three weeks in combination with the standard dose of trastuzumab for 24 months or until disease progression.

In the PDL1-positive intent-to-treat population, the trial met its primary endpoint with an objective response rate (ORR) of 15% and disease control rate (DCR) of 25%. In an Immunotherapy Shows Early Promise for Patients With Trastuzumab-resistant Breast Cancer subgroup of PDL1-positive patients with 5 percent or more TILs present in the metastatic lesion, the ORR was 39% and the DCR was 47%, suggesting that quantification of TILs may help identify patients who will most benefit from this treatment. No responses were observed in the PD-L1 negative cohort.

Five (10.8%) patients in the PDL1-positive cohort continued to have no disease progression at the time of reporting, Loi noted. Pembrolizumab with trastuzumab was well tolerated, with grade 1–2 fatigue as the most commonly reported adverse event (21%). Four immune-related adverse events were reported, two of which were in one patient and were completely resolved; the patient remains in remission two years after treatment, according to Loi.

This study was sponsored and managed by the International Breast Cancer Study Group, in collaboration with the Breast International Group, and funded by Merck & Co. through a subsidiary.