From Targetless to Targetable, Breakthroughs Push Forward in TNBC Treatment Landscape

Significant advancements have been made targeting the once "targetless" subtype of breast cancer—triple-negative breast cancer (TNBC)—as identifiable targets are being exploited to improve patient outcomes, according to Sara M. Tolaney, MD, MPH.

Notably, combining checkpoint inhibitors with chemotherapy has shown promise, especially in patients with PD-L1–positive metastatic TNBC, as demonstrated by findings from the phase 3 KEYNOTE-355 trial (NCT02819518), which revealed pembrolizumab (Keytruda) plus chemotherapy improved progression-free survival (PFS) and overall survival (OS) vs placebo plus chemotherapy. However, no benefit was observed in patients with PD-L1–negative tumors.¹ Additionally, recent data presented at the 2024 American Society of Clinical Oncology Annual Meeting showed that PARP inhibitors may be a promising strategy in TNBC. An expansion cohort of the phase 3 OlympiA trial (NCT0203282324) included 24 patients with breast cancer and germline PALB2 mutations, and among the 2 patients with TNBC, both experienced a response to treatment with olaparib (Lynparza) monotherapy.²

“We’ve defined TNBC, unfortunately, by what it isn’t rather than what it is. TNBC has been defined as being negative for the estrogen receptor, progesterone receptor, and HER2, whereas there are targets that are present [for] triple-negative disease,” Tolaney said in an interview with OncLive® following an OncLive State of the Science Summit, which she chaired. “We’ve come a long way from a subtype of breast cancer that was once thought to be targetless, to one that has multiple targets. We are now taking advantage of that and using that to improve outcomes for our patients.”

In the interview, Tolaney discussed the transformation of treatments for TNBC and expanded on her interpretation of data from the KEYNOTE-355 trial. Tolaney is chief of the Division of Breast Oncology and associate director of the Susan F. Smith Center for Women’s Cancers; she also serves as a senior physician at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, all in Boston, Massachusetts.

OncLive: What is the rationale for combining checkpoint inhibitors with chemotherapy?

Tolaney: We were initially disappointed by the efficacy of immunotherapy in triple-negative disease; we tried using checkpoint inhibitors as monotherapy and saw that only a small subset of patients derived benefit from a checkpoint inhibitor given alone. There was a lot of interest in seeing what we could do to make immunotherapy more effective, and one thought was that combining a checkpoint inhibitor with chemotherapy could make [treatment] more effective.

The rationale was that the chemotherapy is going to kill the cancer cells, release antigens, and then allow the immune system to recognize the cancer and work synergistically with the chemotherapy. It turns out that was true because when you use chemotherapy with checkpoint inhibition, [the doublet] does much better than chemotherapy alone. However, it only does [better in terms of efficacy] in patients who have PD-L1–positive metastatic triple-negative disease. If the tumor does not express PD-L1, then the checkpoint inhibitor is not adding additional benefit. In that sense, we are a little bit limited [with options as] approximately 40% of patients who have metastatic TNBC will have tumors that are PD-L1–positive, so [the doublet] is not benefiting all patients with triple-negative metastatic disease.

What key data should be noted on checkpoint inhibitor combinations in TNBC?

The KEYNOTE-355 trial randomly assigned patients with metastatic TNBC who had not received any therapy in the metastatic setting for triple-negative disease to chemotherapy of physician’s choice which could be a taxane or carboplatin and gemcitabine vs chemotherapy of physician’s choice with pembrolizumab.

At the time the trial was conducted, we didn’t know that checkpoint inhibitors were only going to add benefit in the metastatic setting for patients who had PD-L1–positive tumors. Therefore, the trial was designed to look not just at patients who had tumors that were PD-L1–positive, but also to look at the overall patient population. Data showed that there was an improvement in both PFS as well as OS in patients with PD-L1–positive tumors, but no benefit in those with PD-L1–negative tumors.

The cut-off that was used to define positivity for PD-L1 was using a [PD-L1 IHC] 22C3 assay and a combined positive score [CPS] that was greater than or equal to 10. We’re always looking to see if the CPS score is 10 or higher to know if a patient is a candidate for pembrolizumab with chemotherapy.

What is important to know about targeting DNA repair?

In breast cancer, the drugs that have been approved for targeting DNA repair are PARP inhibitors and they are only currently approved in the metastatic setting for patients who have a germline BRCA mutation. If patients have a germline BRCA mutation either talazoparib [Talzenna] or olaparib are very effective in this setting. When these agents have been compared head-to-head with chemotherapy, [they] win in terms of improving PFS. However, I was a little disappointed because when PARP [inhibitors are] compared with chemotherapy, they are not superior in terms of OS. There is still room for improvement.

We do know, however, that it’s not just patients with germline BRCA mutations who benefit [from these agents]. Emerging data that came out from the olaparib expanded trial showed that patients who have germline PALB2 mutations as well as patients who have somatic BRCA alterations also derive benefit from PARP inhibition. In my practice, I will use a PARP inhibitor in a patient who has germline PALB2, somatic BRCA, or germline BRCA [mutations]. There are other agents in development, such as PARP1 selective inhibitors, so we will see more about where those agents move [in the treatment landscape].

References

1. Cortes J, Rugo HS, Cescon DW, et al; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387(3):217-226. doi:10.1056/NEJMoa2202809
2. Tung NM, Robson ME, Nanda R, et al. TBCRC 048 (olaparib expanded) expansion cohorts: Phase 2 study of olaparib monotherapy in patients (pts) with metastatic breast cancer (MBC) with germline (g) mutations in PALB2 or somatic (s) mutations in BRCA1 or BRCA2. J Clin Oncol. 2024;42(suppl 16):1021. doi:10.1200/JCO.2024.42.16_suppl.1021