TNBC Heterogeneity Opens Door for Emerging Targeted Therapies

As a greater understanding of triple-negative breast cancer (TNBC) heterogeneity develops over time, combinations of PD-1/PD-L1 plus PARP inhibitors, androgen receptor (AR) targeted agents, and PI3K/AKT/mTOR pathway inhibitors are undergoing evaluation by investigators in the field.

“We’ve learned that triple-negative breast cancer has multiple different subtypes,” Kari B. Wisinski, MD, said during a presentation at the 22nd Annual Lynn Sage Breast Cancer Symposium, a virtual event.¹ “There are targeted therapies that can be used based on the biomarkers that we identify for each patient.”

Wisinski, associate professor in the Department of Medicine at the University of Wisconsin–Madison, reviewed studies in support of emerging treatment strategies for metastatic TNBC, which was traditionally treated with chemotherapy.

About 80% of TNBCs fall within the basal-like cluster on the PAM50 assay,² Wisinski said. Those basal and nonbasal subtypes that do not fall within this cluster reflect different prognoses and chemotherapy response, as well as different molecular targets that can individualize treatment.

In the PI3K/AKT/mTOR pathway—important for cell proliferation, invasion, and survival— multiple agents have been developed. Buparl-isib (BKM120), a pan-class PI3K inhibitor, was evaluated in a randomized phase 2/3 BELLE-4 study in first-line HER2-negative breast cancer (NCT01572727). Patients were stratified by hormone receptor status and PI3K pathway activation. At the interim analysis, the study was stopped for futility because the treatment arm had a progression-free survival (PFS) of 8.0 months compared with 9.2 months for the placebo arm (HR, 1.18; 95% CI, 0.82-1.68).³

The phase 2 LOTUS study (NCT02162719) produced more encouraging results, Wisinski said.⁴ This randomized study in first-line TNBC evaluated paclitaxel alone or combined with ipatasertib, an investigational AKT inhibitor. PFS improved not only in the intention-to-treat cohort, at 6.2 months versus 4.9 months (HR, 0.60; 95% CI, 0.37-0.98; P = .037), but also in patients with PI3K pathway alterations, at 9.0 versus 4.9 months (HR, 0.44; 95% CI, 0.20-0.99; P = .041).

Further, encouraging overall survival (OS) results were seen in the treatment arm, demonstrating a median OS of 25.8 months compared with 16.9 months in the placebo arm and a trend toward benefit in the biomarker cohorts.⁵ “This is now being studied in an ongoing phase 3 study,” Wisinski said.

Results of the PAKT study (NCT02423603) hold further promise, said Wisinski.⁶ This randomized phase 2 study in first-line TNBC looked at another AKT inhibitor, capivasertib, in combination with paclitaxel or paclitaxel alone. PFS was improved in the intention-to-treat cohort, but benefits were also observed in the PI3K-pathway altered cohort, with the treatment arm having a median PFS of 9.3 months versus the control arm having a median PFS of 3.7 months (HR, 0.30; 95% CI, 0.11-0.79; 2-sided P = .01). OS was also improved in the intention-to-treat cohort, at 19.1 months in the capivasertib treatment arm versus 12.6 months in the placebo arm (HR, 0.61; 95% CI, 0.37-0.99; P = .04).

PARP Inhibitor Combinations

Another interesting future direction for TNBC involves combinations that include PARP and checkpoint inhibitors. Preclinical study findings have shown PARP inhibitors upregulate PD-L1 expression in breast cancer cell lines in animal models and that the combination increases therapeutic efficacy.⁷

Two studies evaluated this combination in TNBC. TOPACIO (NCT02657889) looked at 47 patients treated with niraparib (Zejula) plus pembrolizumab (Keytruda).⁸ At a median follow-up of 14.8 months, the primary end point of objective response rate was 21%. Five patients each had a partial or complete response. The median duration of response was not met. The second study, MEDIOLA (NCT02734004), was a basket study in which 1 arm included germline BRCA1/2 mutation carriers who had HER2-negative metastatic breast cancer.⁹ Of these, 57% had TNBC. Olaparib was given with nivolumab (Opdivo), and the primary end point was disease control at 12 weeks; of the 30 patients evaluable for this end point, the rate of disease control was 80%.

Multiple other ongoing studies have evaluated the combination of PARP inhibitors and immunotherapies.

PARP inhibitors could have a role beyond germline BRCA1/2 mutations. At the 2020 American Society of Clinical Oncology Virtual Scientific Program, results of TBCRC 048, a phase 2 study (NCT03344965) evaluating olaparib in metastatic breast cancer, were presented. Study participants had either germline mutations in DNA damage response genes that were not BRCA1/2 or somatic tumor mutations that could include BRCA1/2 or other DNA damage response genes (TABLE).¹⁰

“Of those patients with a germline PALB2 mutation, 82% had a response. Those patients with somatic tumor alterations in BRCA1/2 had a 50% response. No patients with an ATM or CHEK2 mutation in a tumor or germline had a response,” Wisinski said. “The subsequent genes listed on this TABLE were all rarely identified, and so it is too early to make any definitive conclusions.”

Androgen Receptor Pathway

Research focusing on the AR pathway is encouraging, as well. Data evaluating enzalutamide (Xtandi) in AR-positive TNBC cell lines show significant activity in a phase 2 study in patients with AR-positive disease, defined as 1% staining or higher, with a clinical benefit rate as a primary end point (NCT01889238).¹¹

“Notably, the investigators did define a second cohort as an evaluable cohort with AR positivity 10% or higher and at least 1 postbaseline tumor assessment,” Wisinski said. “The clinical benef it rate in the evaluable subgroup was 33%, and there were a few cases of partial or complete responses.” Wisinski cautioned that the PFS in this cohort remained modest.

Preclinical data looking at the combination of PARP inhibitors with PI3K inhibition improves tumor response in both germline BRCA, as well as wild-type TNBC cell models, Wisinski noted. A study (NCT03911973) conducted by the Big Ten Cancer Research Consortium is currently evaluating talazoparib (Talzenna), a PARP inhibitor, plus gedatolisib, a dual PI3K-mTOR inhibitor. This study will evaluate patients with advanced TNBC and patients with a germline BRCA mutation.

“We’ve seen some significant advances in TNBC in the metastatic setting,” Wisinski concluded. Targeted treatment options for first- and second-line settings continue to emerge, and unique combinations offer patients further benefit.

_References:

_{1. Wisinski KB. Management of metastatic triple negative breast cancer. Presented at: 22nd Annual Lynn Sage Breast Cancer Symposium; September 10-12, 2020; virtual.}

_{2. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750-2767. doi:10.1172/ JCI45014}

_{3. Martin M, Chan A, Dirix L, et al. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2-advanced breast cancer (BELLE-4). Ann Oncol. 2017;28(2):313-320. doi:10.1093/annonc/mdw562}

_{4. Kim SB, Dent R, Im SA, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18(10):1360-1372. doi:10.1016/S1470-2045(17)30450-3}

_{5. Dent R, Oliveira M, Isakoff SJ, et al. Final results of the double-blind placebo-controlled randomized phase II LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer. Paper presented at: European Society for Medical Oncology Breast Cancer Virtual Meeting 2020; May 23-24.}

_{6. Schmid P, Abraham J, Chan S, et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38(5):423-433. doi:10.1200/JCO.19.00368}

_{7. Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711-3720. doi:10.1158/1078-0432.CCR-16-3215}

_{8. Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019;5(8):1132-1140. doi:10.1001/jamaoncol.2019.1029}

_{9. Domcheck SM, Postel-Vinay S, Im SA, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 2020;21(9):1155-1164. doi:10.1016/S1470-2045(20)30324-7}

_{10. Tung NM, Robson ME, Ventz S, et al. TBCRC 048: a phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded). J Clin Oncol. 2020;38(suppl 15):1002. doi:10.1200/ JCO.2020.38.15_suppl.1002}

_{11. Traina TA, Miller K, Yardley DA, et al. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol. 2018;36(9):884-890. doi:10.1200/JCO.2016.71.3495}