Emerging HER2-Directed Agents May Address Resistance to SOC Regimens in Pretreated HER2+ Breast Cancer

Advances in HER2-directed therapies have the potential to overcome resistance and expand treatment options for pretreated patients with HER2-positive breast cancer, according to Ian Krop, MD, PhD, who added that it is vital to identify predictive markers for antibody-drug conjugate (ADC) resistance to better understand treatment challenges and improve patient outcomes with these emerging agents.

“The outcomes of patients with HER2-positive disease are now much better than they used to be,” Krop stated. “However, there are still patients whose cancer has become resistant to standard therapies, and we’re not good at identifying which patients are going to benefit from which of the different types of drugs. The spotlight session on HER2-positive disease at the 2024 San Antonio Breast Cancer Symposium (SABCS) focused on both those issues.”

In an interview with OncLive®, Krop discussed several emerging agents of interest spotlighted during the SABCS session on novel HER2 therapeutics. These included the class of HER2-directed TKIs, the novel ADC SHR-A1811, and the bispecific antibody zanidatamab-hrii (Ziihera), all of which may address the lack of efficacious treatment options for pretreated patients, particularly those who have progressed on current standards.

Krop is the director of the Clinical Trials Office, chief clinical research officer, and associate director of clinical sciences at Yale Cancer Center, as well as a professor of internal medicine (medical oncology) at Yale School of Medicine in New Haven, Connecticut.

OncLive: What are some novel HER2-targeted TKIs and ADCs in development to potentially overcome treatment resistance and improve outcomes for pretreated patients with HER2-positive breast cancer?

Krop: HER2-positive breast cancer is the subtype of breast cancer that’s benefited the most from the development of targeted therapies, [which has] led to the FDA approval of 8 drugs to treat [patients with] HER2-positive disease, all targeting HER2 in various ways. One [of the main areas of unmet need discussed during the SABCS session] was [whether] we can develop better drugs that may overcome resistance. The 2 areas where that has been seen most significantly was with TKIs targeting HER2, and new ADCs and antibodies.

There were a few TKIs that seemed potent and had activity in patients with pretreated disease. [Although] that was encouraging, they’ve all had the same issue that we’ve seen with some of the more potent TKIs, which is that they cause substantial diarrhea in patients. We’ll have to see how those new TKIs play out in their development. The [HER2-directed TKIs] that were tested in our group of abstracts were [evaluated] in patients who had not necessarily had progressed on our current [standard] TKIs, such as tucatinib [Tukysa]. Whether [HER2-directed TKIs] will provide benefit to patients who’ve already developed resistance to other TKIs is unknown.

Regarding ADCs, we’ve been given a new ADC, SHR-A1811, which targets HER2 with a topoisomerase inhibitor payload. There was an abstract [published in the Journal of Clinical Oncology in 2024 from a phase 1 umbrella trial (NCT04446260)] investigating SHR-A1811, [In patients with HER2-positive breast cancer and other HER2-expressing or -mutated solid tumors]. SHR-A1811 showed remarkable activity with a high overall response rate [ORR] of 76.3% [in patients with HER2-positive breast cancer (n = 118)].1 [Those findings] looked encouraging and were comparable with what’s been seen with some of the other second-generation ADCs like fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd]. This newer ADC also seems to [be associated with a lower incidence of] interstitial lung disease compared with T-DXd. Again, it is not a head-to-head comparison, but [SHR-A1811] looks encouraging.

There was another study, [the phase 2 FASCINATE-N trial (NCT05582499)] presented at SABCS [evaluating] this novel ADC in the neoadjuvant [HER2-positive breast cancer] setting that also looked promising. [In this study, SHR-A1811 produced] a pathologic complete response rate of 63.2%.2 We’re all excited to see how this [ADC] develops in further testing.

How might novel bispecific antibodies, such as zanidatamab, address the lack of effective therapies for patients progressing on standard T-DXd?

[Zanidatamab] is an interesting bispecific antibody that binds to 2 different molecules on 2 different epitopes of HER2. Technically, it’s a biparatopic antibody but by binding to 2 separate epitopes on HER2, it can cause differences in internalization and perhaps immune response. Early data with this drug [indicate that] it has activity in pretreated HER2-positive disease.

What was interesting about [findings from a phase 1/2 trial (NCT05027139) in metastatic HER2-expressing cancers] was that [zanidatamab was administered] in combination with a drug [called evorpacept (ALX148)], which blocks CD47. Blocking that increases the antibody-mediated phagocytosis of HER2-positive cancer cells. The idea was that this combination would be synergistic and have a stronger antitumor effect.

This combination was evaluated in heavily pretreated patients who’d all previously [received] T-DXd. This is a population for whom we don’t have good therapies, or at least therapies that have shown substantial activity. In this population, there was a confirmed ORR of 55.6% [95% CI, 21.1%-86.3%] in patients with centrally-confirmed HER2-positive [disease].3 These are probably the best data we have so far [for this agent in] patients who previously progressed on T-DXd, even though [the study involved a] small number of patients. How much of the activity was due to the zanidatamab vs [evorpacept] is unclear but it looks promising and warrants further investigation.

How do emerging findings regarding predictors of benefit or resistance to ADCs enhance the field’s understanding of treatment challenges in HER2-positive breast cancer?

The last part of [SABCS featured] predictors of benefit or resistance to these various ADCs. There were a couple abstracts investigating predictive markers. One of the more interesting findings was that, as patients progressed on T-DXd, a small fraction [had] upregulation of alterations in topoisomerase I, which is the target of T-DXd and other similar ADCs. That was interesting and perhaps a sign of a potential mechanism of resistance.

Then there was a separate report evaluating HER2 copy number in relation to responsiveness to ADCs and other HER2-directed antibodies, [which] showed that cancers that had a loss of the HER2 gene seemed to experience particularly poor prognosis and a lack of response to these types of therapies. In some ways, this makes sense; if you lose the target, you potentially lose efficacy. However, I don’t think we’ve seen that relationship [demonstrated so clearly] in other studies. That’s another finding that needs to be followed up with to see whether it is clearly a predictor of lack of benefit from these drugs and whether these cancers may need other types of therapy.

References

1. Yao H, Yan M, Tong Z, et al. Safety, efficacy, and pharmacokinetics of SHR-A1811, a human epidermal growth factor receptor 2-directed antibody-drug conjugate, in human epidermal growth factor receptor 2-expressing or mutated advanced solid tumors: a global phase I trial. J Clin Oncol. 2024;42(29):3453-3465. doi:10.1200/JCO.23.02044
2. Li J-J, Wang Z-H, Chen L, et al. HER2-directed antibody-drug conjugate SHR-A1811 in the neoadjuvant treatment of HER2-positive early breast cancer: a prospective, randomized, open-label, phase 2 trial. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. GS1-04.
3. Montero AJ, Wisinski KB, Fang B, et al. Zanidatamab in combination with evorpacept in HER2-positive and HER2-low metastatic breast cancer: results from a phase 1b/2 study. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-14, 2024; San Antonio, TX. Abstract PS8-09.