Abstract P4-16-06: Incidence of interstitial lung disease in patients with HER2-positive advanced breast cancer treated with everolimus and trastuzumab: A combined analysis of two phase 3 randomized controlled trials
Authors: Thein KZ , Swarup S , Sultan A , Tijani L , D'Cunha N , Hardwicke FT , Awasthi S , Jones C 
Published: May 2019

Abstract
Background: The human epidermal growth factor receptor 2 (HER2) protein is overexpressed in approximately one fourth of breast tumors. Trastuzumab resistance has been demonstrated via aberrant PI3K/AKT/mTOR signaling due to PTEN loss. To circumvent this resistance mechanism, everolimus, an oral mTOR inhibitor, has been employed in treatment of HER2-positive advanced breast cancer (ABC). Lung toxicity due to everolimus is well established and has been reported with trastuzumab. Yet, the incidence of interstitial lung disease (ILD), when everolimus was added to trastuzumab, has never been reported. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the incidence of ILD in patients with HER2-positive ABC treated with both everolimus and trastuzumab.
Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through January 2018. Phase 3 RCTs that mention ILD as an adverse effect were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI).
Results: A total of 1272 patients with HER-2 positive ABC from two phase 3 RCTs were eligible. Studies compared everolimus + paclitaxel + trastuzumab vs paclitaxel + trastuzumab and everolimus + vinorelbine + trastuzumab vs vinorelbine + trastuzumab. The initial dose of everolimus in BOLERO-1 was 10mg per day and in BOLERO-3, 5mg per day was used. The median relative dose intensity of everolimus was reduced to 0.54 in BOLERO-1 due to toxicity related dose reductions and dose interruptions. The randomization ratio of everolimus to placebo was 2 to 1 in BOLERO-1 and 1 to 1 in BOLERO-3. Everolimus was utilized in trastuzumab-resistant ABC after prior taxane therapy in the BOLERO-3 study (n= 562) and as first-line treatment in the BOLERO-1 study (n= 710). The I2 statistic for heterogeneity was 0, and the heterogeneity X2 (Cochran's Q) was 1 (P= 0), suggesting homogeneity among RCT. The incidence of all-grade ILD was 31 (4.122%) in the everolimus group vs 3 (0.577%) in control group and of high-grade ILD was 11 (1.463%) in everolimus arm vs 0 (0%) in the control arm. The pooled RR for all-grade ILD was significant at 7.258 (95% CI: 2.130 – 24.733, p = 0.002) and the absolute RD was 0.035 (95% CI: 0.019 – 0.050, P &lt; 0.001). The pooled RR for high-grade ILD was noted at 7.930 (95% CI: 0.997 – 63.044, p = 0.050) and the absolute RD was 0.014 (95% CI: 0.004 – 0.024, P = 0.004).
Conclusions: Approximately 0.46 and 0.61% of patients on trastuzumab alone have been reported to develop ILD in previous studies. Our study showed that the addition of reduced dose of everolimus to trastuzumab, significantly contributed a higher incidence in all grades of ILD with a relative risk of 7.93 for grade 3 and 4 ILD. More randomized trials are required to determine the definitive incidence and actual relation of ILD as well as the optimal dose of everolimus, when combined with trastuzumab or other chemotherapy.
Citation Format: Thein KZ, Swarup S, Sultan A, Tijani L, D'Cunha N, Hardwicke FT, Awasthi S, Jones C. Incidence of interstitial lung disease in patients with HER2-positive advanced breast cancer treated with everolimus and trastuzumab: A combined analysis of two phase 3 randomized controlled trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-06.