Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study.

There is limited knowledge on the benefit of the α-subunit-specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor-positive (ER+) HER2- and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083-0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078-0.60, P = 0.003). SIGNIFICANCE: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007.

Targeting immune pathways in breast cancer: review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC).

Breast cancer has been one of the last tumor types to see benefit from immunotherapies. Yet, immune infiltrates have been noticed for decades in primary breast cancers. Lately, quantity of tumor infiltrating lymphocytes (TILs) have been reported to have strong prognostic value in improving estimates of distant recurrence-free survival, disease-free and overall survival in early-stage triple negative BC (TNBC) treated with standard adjuvant/neoadjuvant chemotherapy (Level 1B evidence). Quantity, as a percentage of tumor stromal infiltration, is based on an evaluation by pathologists using light microscopy on H&E stained glass slides (see method at www.tilsinbreastcancer.org) [1,2] at time of diagnosis (pre-treatment and in the residual disease post neoadjuvant chemotherapy). Whilst TILs are currently not used for treatment allocation, this is an active area of investigation. Combination of atezolizumab with nab-paclitaxel in a phase III study has recently seen success in terms of improved progression free and overall survival for the PD-L1 -positive population of metastatic TNBC in the first line/newly relapsed setting [3]. This has led to approval of atezolizumab for use in this setting. However, this population was only 41% of the trial population. Data in advanced breast cancer currently suggest requirement for enrichment of the population for preexisting anti-tumor immunity for benefit to PD(L)1 inhibition. Checkpoint inhibitors are currently being investigated in the early-stage setting in a number of phase II/III trials in TNBC with various different anti- PD-1, PD-L1 and CTLA-4 agents. In this context, we will face issues of the best chemotherapy backbone, the possible detrimental role of steroids and growth factor support, risk of overtreatment, differences between PD-1 and PD-L1 inhibition and if we can use a biomarker to effectively escalate or de-escalate chemotherapy and/or use checkpoint inhibition in this setting.