A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229)

Abstract

Background Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD‐L1)‐positive, triple‐negative, metastatic breast cancer (MBC). Antibody‐dependent cell‐mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2‐positive MBC previously treated with chemotherapy and anti‐HER2 antibodies to assess safety, efficacy, and correlative endpoints. Patients and Methods Patients with HER2‐positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D. Results Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40–86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab‐emtansine (93%) for MBC. No dose‐limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade ≥3 immune‐related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had <1% PD‐L1 expression on either archival tissue (7/15) or prestudy biopsy (8/15). In the dose expansion cohort, evaluable pretreatment and on‐treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration. Conclusion The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2‐positive PD‐L1‐negative MBC. Implications for Practice This phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2‐positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2‐positive programmed death ligand 1 (PD‐L1)‐negative MBC with evidence of cytotoxic T‐cell exhaustion. Furthermore, all patients had no expression of PD‐L1 in the tumor cells. These data support the importance of PD‐L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the “cold” tumors to be able to combine current immune‐oncology agents.

PIK3CA gene mutations in the helical domain correlate with high tumor mutation burden and poor prognosis in metastatic breast carcinomas with late-line therapies

“…Candidates for metastatic TNBCs might be PD1/PD-L1 inhibitors, anti-VEGFR, etc [25,26]. Novel TKIs and PD-L1 inhibitors might be useful in HER2-positive patients [27,28]. In this study, we found that the conception of HR/HER2 status was gradually obscured in late-line therapy.…”

Bioengineering the Oxygen-Deprived Tumor Microenvironment Within a Three-Dimensional Platform for Studying Tumor-Immune Interactions

“…It is also well established that boosting CD8+ cell infiltration into the tumor niche can reverse immune evasion (Maimela et al, 2019). In this context, a very promising PD-L1 checkpoint inhibitor (Durvalumab) has been well investigated to treat BCa tumors where CD8 infiltration has been challenging (Steele et al, 2018;Chia et al, 2019). Durvalumab is a fully human high affinity immunoglobulin monoclonal antibody that blocks PD-L1 by binding to PD-1 as reflected by its reported IC 50 values (PD-1: 0.1nmol/l) and (CD-80: 0.04nmol/l).…”

Drug combination and repurposing for cancer therapy: the example of breast cancer

“…Recently, there is a crescent concern in the development of immunotherapy and molecularly targeted therapy combinations for breast cancer of metastatic type. Some examples are the combinations of anti-PDL-1 (programmed death ligand-1) antibodies in combination with HER-2 inhibitors and cyclin-dependent kinase inhibitors [ 50 , 51 , 52 ]. In fact, a growing number of clinical trials are studying combinations of immunotherapy and targeted therapy in breast cancer, with promissory results [ 53 ].…”