New targets, treatment strategies create ‘exciting time’ in triple-negative breast cancer

By Gregory A. Vidal, MD, PhD; Rana Muhammad Usman, MD; and Janice Mullins, DO

Although breast cancer mortality has declined by 40% over the past several decades, more than 40,000 women will die of the disease this year, according to SEER data.

This is partly due to the lack of targeted therapeutic options for patients with triple-negative breast cancer (TNBC).

TNBC is best characterized as a diagnosis of exclusion, as these cancers lack receptors for estrogen and progesterone, and have normal expression of the HER2 protein. Molecularly, however, TNBC may comprise as many as six different subtypes. This heterogeneity is, in part, responsible for the lack of targeted therapies.

Despite accounting for only about 10% to 20% of all breast cancers, TNBC carries a poorer prognosis due to higher distant recurrence rates. It occurs more frequently among young women of African or Hispanic descent, and it usually exhibits unfavorable characteristics, such as larger tumor size and nodal involvement. TNBC also often is associated with germline BRCA mutations.

Chemotherapy remains the only systemic therapeutic option for women with curable disease and was the only option for metastatic TNBC until March, when the FDA approved atezolizumab (Tecentriq, Genentech) — an immune checkpoint inhibitor — in combination with taxane chemotherapy for patients with PD-L1-positive disease. This article will address current and future therapeutic options for metastatic TNBC.

Current strategies

Treatment of TNBC can be challenging. Drug selection is dependent on factors such as tumor burden, ECOG performance status and presence of comorbidities.

Anthracycline/taxane-based chemotherapy remains the preferred therapeutic partner for treatment of early TNBC. The standard approach in the metastatic setting has been to utilize single-agent chemotherapies sequentially unless rapid response is desired. Despite improvement in overall response rates and PFS, most doublet therapies did not confer OS benefit and had questionable tolerability.

Importantly, chemotherapy approvals for treatment of metastatic TNBC were based on subgroup analysis of larger all-comer clinical trials. For metastatic breast cancer, taxanes (paclitaxel, docetaxel and albumin-bound paclitaxel), anthracyclines (doxorubicin, pegylated liposomal doxorubicin and epirubicin), anti-metabolites (capecitabine and gemcitabine), and nontaxane microtubule inhibitors (eribulin and vinorelbine) are preferred single-agent options based on National Comprehensive Cancer Network guidelines. Other agents with activity are platinum salts (carboplatin and cisplatin) and other microtubule inhibitors, such as ixabepilone (Ixempra, Bristol-Myers Squibb). Some of these agents may appear to induce more favorable activity in TNBC populations.

Kaufman and colleagues conducted a phase 3 trial that compared capecitabine with eribulin (Halaven, Eisai) for patients with metastatic breast cancer. Results, published in 2015 in Journal of Clinical Oncology, showed no survival difference; however, subgroup analysis demonstrated a significant survival advantage for eribulin over capecitabine among those with metastatic TNBC.

Similarly, in the TNT trial conducted by Tutt and colleagues, carboplatin induced a higher ORR than docetaxel as first-line treatment for patients with metastatic TNBC who had BRCA mutations. Carboplatin added to chemotherapy in the neoadjuvant setting also has increased complete pathologic response rates (pCR) among patients with TNBC.

The effect of the addition of neoadjuvant carboplatin on survival is inconclusive. A randomized phase 2 study of first-line therapy for metastatic TNBC demonstrated superior survival with nab-paclitaxel and carboplatin compared with gemcitabine and carboplatin among patients previously treated with an anthracycline and a taxane.

Prior to this year, bevacizumab (Avastin, Genentech) — a humanized monoclonal antibody — was the only noncytotoxic agent approved for use in metastatic TNBC. The E2100 trial — which combined bevacizumab with paclitaxel — had shown a PFS benefit and ORR activity among patients with metastatic breast cancer, but it lacked an OS benefit and had concerning toxicity. The FDA granted fast-track approval for its use in first line metastatic breast cancer.

However, the RIBBON-1 and AVADO confirmatory studies resulted in modest survival benefit along with notable safety concerns, and the FDA withdrew its approval in 2011. Later, subgroup analysis of RIBBON-2 hinted toward a survival benefit in the TNBC population. The NCCN upholds the combination of paclitaxel and bevacizumab as a treatment option for first-line metastatic breast cancer in the right clinical scenario.

Targeted agents and immunotherapy

Over the past several years, efforts have been made to develop new and effective targeted therapies to improve survival outcomes in TNBC.

Poly(ADP-ribose) polymerases (PARP) have been a promising target among patients with germline BRCA mutations. PARP inhibitors cause the accumulation of double-stranded breaks in cells that lack repair protein — BRCA1 or BRCA2 — resulting in apoptosis.

The FDA approved olaparib (Lynparza, AstraZeneca) and talazoparib (Talzenna, Pfizer) for patients with previously treated metastatic breast cancer who harbor germline BRCA mutations. The prevalence of BRCA mutations in TNBC is approximately 15% to 30%, and it is dependent on age at diagnosis.

The approvals of these agents were based on two randomized phase 3 trials — OlympiAD and EMBRACA — that compared PARP inhibitors with physician’s choice of chemotherapy. In these studies, 45% to 50% of patients had metastatic or locally advanced TNBC with BRCA1/BRCA2 germline mutations. Results of both trials showed statistically significant improvement in median PFS of approximately 3 months with PARP inhibitors — 7 months vs. 4.2 months in favor of olaparib in OlympiAD, and 8.6 months vs. 5.6 months in favor of talazoparib in EMBRACA. Subgroup analysis showed patients with metastatic TNBC appeared to fare slightly better on olaparib, whereas they did equally well in the talazoparib study.

In March, the FDA granted accelerated approval to atezolizumab plus nab-paclitaxel (Abraxane, Celgene) as first-line therapy for unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 of 1% or greater. This was groundbreaking, as it represented the first approval of immunotherapy for breast cancer and the first biomarker-driven treatment for TNBC. Moreover, it is the first drug combination approved specifically for a group of patients with metastatic TNBC in desperate need of more effective targeted therapies. Median OS for metastatic TNBC is approximately 12 months.

Atezolizumab is a monoclonal antibody that targets and blocks recognition of PD-L1 on cancer cells by T cells. This prevents binding of PD-1 on the T-cell to the PD-L1 receptor on the cancer cell and, therefore, releases the brakes on the T cell to allow for attack and killing of the cancer cells.

The FDA based the approval on the randomized phase 3 IMpassion130 trial, in which Schmid and colleagues compared atezolizumab plus nab-paclitaxel to placebo plus nab-paclitaxel. After median follow-up of 12.9 months, the results — published last year in The New England Journal of Medicine — showed a statistically significant improvement in median PFS (7.5 months vs. 5 months; HR = 0.62; P < .0001) in the PD-L1-positive population. Researchers observed no statistically significant PFS improvement in the PD-L1-negative subgroup.

After median follow-up of 18 months, a second interim analysis showed a compelling 7-month median OS advantage in the PD-L1-positive population, (25 months vs. 18 months; HR = 0.71). Significance could not be concluded for OS as per the study design, which stated that statistical significance must be achieved in the intent-to-treat population (this was not significant) before it could be concluded in the PD-L1-positive subgroup. Importantly, PD-L1 positivity was defined as PD-L1 expression on at least 1% of immune cells based on the Ventana PD-L1 (SP142) Assay. A higher percentage of patients with PD-L1-positive disease achieved 24-month OS (51% vs. 37%), and a numerically superior ORR was observed in the PD-L1-positive population (59% vs. 49%).

Despite enthusiasm for checkpoint inhibitors in metastatic TNBC, their activity is not ubiquitous. The randomized phase 3 KEYNOTE-119 trial — which compared physician’s choice of chemotherapy vs. single-agent pembrolizumab (Keytruda, Merck), a PD-1 checkpoint inhibitor — in the late-line setting proved negative, according to a company-issued press release.

Questions remain

Several questions remain unanswered, such as:

• Is a chemotherapy backbone essential in metastatic TNBC?

• Are all chemotherapy backbones created equal?

• How much concordance is there between PD-L1 assays?

• Are these targets only active in the earlier treatment settings for TNBC?

As more study results become available, we may slowly be able to answer these questions.

In a topline data announcement, Merck stated that a trial evaluating pembrolizumab in the neoadjuvant setting met its primary endpoint of increased pCR. We also are anxiously awaiting the maturation of several phase 3 trials that evaluated the combination of checkpoint inhibitors and chemotherapies for first-line metastatic TNBC. These include KEYNOTE-355, which combined pembrolizumab with nab-paclitaxel or paclitaxel, or gemcitabine and carboplatin; IMpassion132, which combined atezolizumab with carboplatin and gemcitabine or capecitabine for patients with early relapsing recurrent TNBC; and IMpassion131, which combined atezolizumab with paclitaxel.

We also await with anticipation the potential approval of the antibody-drug conjugate sacituzumab govitecan (IMMU-132, Immunomedics), an anti-trop antibody conjugated to SN-38 chemotherapy. A single-arm phase 2 study revealed an ORR of greater than 30% as late-line therapy for metastatic TNBC. The FDA granted breakthrough therapy designation and priority review to the agent for this indication, but it has not been approved due to issues with manufacturing. A follow-up FDA review is planned. A randomized phase 3 trial of sacituzumab govitecan vs. physician’s choice of chemotherapy in the second-line or later setting is completed and awaiting maturation.

This is an exciting time for TNBC as new targets, combination therapies, other novel treatment strategies and biomarkers are being investigated. Our hope is that, in our lifetimes, the survival outcomes of TNBC will match those of other breast cancer subtypes.

References:

Bardia A, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.70.8297.

Blum JL, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.71.4147.

Brufsky AM, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2010.34.1255.

Brufsky A, et al. Breast Cancer Res Treat. 2012;doi:10.1007/s10549-012-2008-6.

Diana A, et al. Curr Oncol Rep. 2018;doi:10.1007/s11912-018-0726-6.

Engel C, et al. BMC Cancer. 2018;doi:10.1186/s12885-018-4029-y.

Foulkes WD, et al. N Engl J Med. 2010;doi:10.1056/NEJMra1001389.

Kassam F, et al. Clin Breast Cancer. 2009;doi:10.3816/CBC.2009.n.005.

Kaufman PA, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2013.52.4892.

Lehmann BD, et al. J Clin Invest. 2011;doi:10.1172/JCI45014.

Litton JK, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1802905.

Merck. Merck provides update on phase 3 KEYNOTE-119 study of Keytruda (pembrolizumab) monotherapy in previously treated patients with metastatic triple-negative breast cancer. Available at: investors.merck.com/news/press-release-details/2019/Merck-Provides-Update-on-Phase-3-KEYNOTE-119-Study-of-KEYTRUDA-pembrolizumab-Monotherapy-in-Previously-Treated-Patients-with-Metastatic-Triple-Negative-Breast-Cancer/default.aspx. Accessed Aug. 12, 2019.

Merck. Merck’s Keytruda (pembrolizumab) in combination with chemotherapy met primary endpoint of pathological complete response (pCR) in pivotal phase 3 KEYNOTE-522 trial in patients with triple-negative breast cancer. Available at: investors.merck.com/news/press-release-details/2019/Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Chemotherapy-Met-Primary-Endpoint-of-Pathological-Complete-Response-pCR-in-Pivotal-Phase-3-KEYNOTE-522-Trial-in-Patients-with-Triple-Negative-Breast-Cancer-TNBC/default.aspx. Accessed Aug. 12, 2019.

Miles DW, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2008.21.6457.

Miller K, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa072113.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Breast Cancer. 2013.

Rhiem K, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.34.15_suppl.1090.

Robert NJ, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2010.28.0982.

Robson M, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1706450.

Schmid P, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809615.

Schmid P, et al. J Clin Oncol. 2019;doi:10.1200/JCO.2019.37.15_suppl.1003.

Sikov WM, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.57.0572.

Tutt A, et al. Nat Med. 2018;doi:10.1038/s41591-018-0009-7.

Xu HB, et al. J Cancer Res Clin Oncol. 2011;doi:10.1007/s00432-010-0967-8.

Von Minckwitz G, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70160-3.

Yardley DA, et al. Ann Oncol. 2018;doi:10.1093/annonc/mdy201.

For more information:

Gregory A. Vidal, MD, PhD, is medical oncologist at West Cancer Center and Research Institute and assistant professor in the department of hematology/oncology at The University of Tennessee Health Science Center. He can be reached at West Cancer Center and Research Institute, 7945 Wolf River Blvd., Germantown, TN 38138; email: gvidal@westclinic.com.

Rana Muhammad Usman, MD, is an internal medicine resident at The University of Tennessee Health Science Center.

Janice Mullins, DO, is a hematologist/medical oncologist at West Cancer Center and Research Institute.

Disclosures: Vidal reports consultant/advisory roles with Eli Lilly, Genentech, Immunomedics, Novartis, Pfizer and Puma Biotechnology; speakers roles with Eli Lilly, Novartis, Pfizer and Puma Biotechnology; and research funding from Bristol-Myers Squibb, Calithera, Celcuity, Eli Lilly, Genentech, Merck, Puma Biotechnology and Tesaro. Usman and Mullins report no relevant financial disclosures.