Emerging ADCs and Immunotherapy Shake Up Triple-Negative Breast Cancer Management

A host of novel agents have emerged for the treatment of patients with triple-negative breast cancer (TNBC), from PARP inhibitors to antibody-drug conjugates (ADCs), enhancing the once-bare treatment paradigm, according to Linda T. Vahdat, MD.

“We’ve made a lot of progress in both the treatment of [patients with] early-stage TNBC and metastatic TNBC,” Vahdat said in an interview with OncLive®.

In the interview, Vahdat discussed the current TNBC treatment paradigm, emerging ADCs for patients with metastatic TNBC, and the potential for neoadjuvant immunotherapy to enhance outcomes for patients with early-stage disease.

Vahdat highlighted findings from the phase 3 OptiTROP-Breast01 trial (NCT05347134), in which the ADC sacituzumab tirumotecan (Sac-TMT; SKB264/MK-2870; n = 130) generated a median progression-free survival (PFS) of 5.7 months (95% CI, 4.3-7.2) vs 2.3 months (95% CI, 1.6-2.7) with chemotherapy (n = 133; HR, 0.31; 95% CI, 0.22-0.45; P < .00001) in patients with previously treated, locally recurrent or metastatic TNBC.¹

She also shared insights from the phase 2 NeoPACT trial (NCT03639948), which showed that neoadjuvant pembrolizumab (Keytruda) plus carboplatin and docetaxel elicited a pathologic complete response (pCR) rate of 58% (95% CI, 48%-67%) among patients with residual cancer burden (RCB)–0 TNBC, and 69% (95% CI, 60%-78%) among those with RCB-1 disease.²

Vahdat is the section chief of Medical Oncology, interim section chief of Hematology, and a professor of medicine at the Geisel School of Medicine at Dartmouth Health in Lebanon, New Hampshire.

OncLive: How has the development of targeted therapies driven the evolution of TNBC management approaches?

Vahdat: Eight years ago, we didn’t have any targeted therapies. We were just starting to understand the biology of the disease, and when we started to investigate treatment for metastatic TNBC, the median overall survival [OS] was less than 1 year. Today, we’re not where we need to be, but we’ve made a lot of progress.

For example, we’ve been able to stratify risk for [patients with] early-stage breast cancer. We’ve been able to demonstrate that neoadjuvant pembrolizumab increases the pCR rate, which subsequently increases both event-free survival [EFS] and OS. Olaparib increases EFS and OS in germline BRCA mutation carriers. Adjuvant capecitabine is a standard of care for patients with residual disease.

In the metastatic setting, we understand the biology a lot better [than we used to]. We know that there are multiple subtypes of TNBC, and they all have different pathways that are activated. We know [which patients should and should not receive] immunotherapy. PARP inhibitors work [for] both germline and somatic BRCA mutations. Then we have a spate of ADCs for TNBC—sacituzumab govitecan-hziy [Trodelvy] and fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu]—with good results and improvements in survival. This has translated into [improved survival outcomes compared with] where we were 8 years ago, but there’s still a lot of work to do.

Regarding where are we for managing metastatic TNBC, we have an evolving roadmap. Clinical trials are still the best options for patients. We stratify [patients] by [whether their] tumors are PD-L1 positive or [whether they have a] combined positive score of greater than 10, because those are the patients for whom we will begin to use immunotherapy. If they have a germline BRCA mutation, we’ll use a PARP inhibitor. After that, we’ll start using the ADCs, either sacituzumab govitecan or T-DXd, and we will start with standard treatments. [However], clinical trials are the best option.

What are some emerging ADCs of interest for patients with metastatic TNBC?

Regarding recent data with drugs that have some activity in metastatic TNBC, there are 2 drugs I’d keep an eye on. One is a drug called sac-TMT. The antibody part of it is TROP2, and the drug part of it is belotecan, a novel topoisomerase I inhibitor.

This [ADC] was evaluated in the randomized [OptiTROP-Breast01] study, in which patients [with TNBC] were heavily pretreated and had received at least 2 regimens in the metastatic setting. [Patients] were [randomly assigned to receive] to sac-TMT vs treatment of physician’s choice. The [median] PFS was almost double [with sac-TMT vs treatment of physician’s choice]. Investigators noted that OS was also increased in the sac-TMT group. Keep an eye on this drug to see where it pans out. There’s a lot of competition in that space.

The second ADC that is interesting is enfortumab vedotin. The antibody part of this drug targets Nectin-4, an adhesion molecule that is highly expressed in solid tumors. The payload is one we’ve seen before called MMAE, an antimicrotubule agent.

The [phase 2 EV-202 trial (NCT04225117)] was also in a heavily pretreated group of patients [with TNBC] who had received at least 1 regimen in the metastatic setting. All patients got enfortumab vedotin. The overall response rate was 19.0%. You might say that we can do better than that. However, the disease control rate was 57.1%, so [this drug is] worth investigating. At a median follow-up of 11.20 months, the median OS was what we’ve seen in some of the other trials, at 12.91 months. This drug needs a lot more work, but it’s interesting, so we should keep an eye on it. 

What research may shift the standard of care for patients with early-stage TNBC?

Regarding updates in early TNBC, when we look at guidelines and think about treating patients, for patients in the node-negative setting [with tumors] up to 2 centimeters [in size], we can consider surgery first. [For patients with tumors that are] 1.5 to 2 centimeters, [optimal treatments are] a bit of a gray area where you might consider neoadjuvant treatment.

Most patients with TNBC these days receive neoadjuvant chemoimmunotherapy. The study that supports that [approach] best is [the phase 3] KEYNOTE-522 trial [(NCT03036488), which evaluated pembrolizumab plus chemotherapy [in patients with early TNBC]. We’ve seen many updates through the years of KEYNOTE-522. One of the findings that has continued to be solid and prominent is the fact that the pCR rate was 64.8%, which is good.

In the most recent analysis, the difference in EFS between the immunotherapy arm and the non-immunotherapy arm was 7.7%. [There was also] an improvement in OS [with pembrolizumab vs placebo]. Considering the summary of first events by RCB category, not unexpectedly, RCB category increased as distant metastases increased. That’s where [pembrolizumab’s] main impact is.

Another study, which was published by Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City], and colleagues in JAMA Oncology in 2024, was the NeoPACT study, [which investigated] an anthracycline-free regimen. If you have a patient who is not a candidate for an anthracycline, this is a good [regimen] for them. That trial enrolled 115 patients with stage I to III TNBC, who received docetaxel, carboplatin, and pembrolizumab every 3 weeks for 6 cycles.

The pCR rate was 58%, which isn’t so bad because in KEYNOTE-522, it was 64.8%. [The rate of] patients with RCB-0 and RCB-1 disease was 69%. Those patients will hopefully do well [with this regimen]. [The rate of] any immune-related adverse effects was 26.1%; [the rate of] those that were grade 3 was 3.5%. At a median follow-up of 21 months, the median 2-year EFS for the [patients who did not achieve] pCR was 82%. One of the strong aspects of this study is that these results were seen with no adjuvant pembrolizumab. Patients got 18 weeks of treatment, and then they were good to go.

References

1. Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): results from the phase III OptiTROP-Breast01 study. J Clin Oncol.2024;42(suppl 16):104. doi:10.1200/JCO.2024.42.16_suppl.104
2. Sharma P, Stecklein SR, Yoder R, et al. Clinical and biomarker findings of neoadjuvant pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer: NeoPACT phase 2 clinical trial. JAMA Oncol. 2024;10(2):227-235. doi:10.1001/jamaoncol.2023.5033