Trastuzumab Deruxtecan Approval for HER2-Low Breast Cancer Sparks Bright Future for ADCs

Shanu Modi, MD

The approval of fam-trastuzumab deruxtecan-nxki (Enhertu) for patients with HER2-low breast cancer has opened conversations regarding the classification of HER2 mutant disease and the role that antibody-drug conjugates (ADCs) will play in the space.

On August 5, 2022, trastuzumab deruxtecan was approved for patients who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy and who have disease that is classified as immunohistochemistry (IHC) 1+ or IHC 2+/ in situ hybridization–negative.

The approval was supported by data from the phase 3 DESTINY-Breast04 trial (NCT03734029) in which trastuzumab deruxtecan resulted in a median progression-free survival (PFS) of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) with chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; P < .0001). Median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) vs 17.5 months (95% CI, 15.2-22.4), respectively (HR, 0.64; 95% CI, 0.40-0.86; P = .003).

“Trastuzumab deruxtecan is the first HER2-targeted therapy that has been active for [the] population of patients with HER2-low level expressing breast cancers and not only is it active, it’s much more active than what we normally treat these patients with,” Shanu Modi, MD, said.

In an interview with OncLive®, Modi, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, discussed the significance of the approval.

Please discuss the shift observed in HER2 classification.

We normally classify breast cancers in a binary way: HER2-positive or HER2-negative. If cancer is HER2-positive, it means it has high levels of the HER2 protein [and], generally, a worse prognosis clinically. We have a lot of very active HER2-targeted therapies for HER2-positive breast cancer. Everything else we call HER2-negative but that’s a real oversimplification because there are tumors within the HER2-negative population that also express the HER2 protein just at lower levels.

It’s been a frustration that none of our current HER2-targeted therapies have been effective for those with cancers with low levels of that HER2 target.

What have been the notable outcomes of the approval?

I was impressed that the NCCN [National Comprehensive Cancer Network] guidelines committee moved very quickly [to add the agent to practice guidelines]. Trastuzumab deruxtecan [being regarded] as an option, as the only option for HER2-low breast cancer, almost within weeks of the data of being released [is significant].

Similarly, the FDA moved very quickly to review the data and approve trastuzumab deruxtecan. There is a lot of eagerness among clinicians to be able to offer this treatment to our patients. As you can see from the control arm in [DESTINY-Breast04], standard therapies are not very effective. It’s great that we now have access to this drug for a large group of our patients with metastatic disease.

Please discuss the pivotal efficacy data from the DESTINY-Breast04 trial.

DESTINY-Breast04 was a randomized study open to patients with HER2-low advanced stage breast cancer. HER2 low was defined as tumors that had IHC 1+ or 2+ expression without gene amplification. To be eligible patients had to have received at least 1 line of chemotherapy, but no more than 2 lines. Furthermore, patients who had hormone receptor–positive HER2-low breast cancer also had to have received and have exhausted endocrine options.

This was a group of patients [who were] a little more heavily pretreated and the study [randomly assigned] them to either standard of care—there was the option to use 4 or 5 different standard regular chemotherapy drugs, which they would normally [receive]—vs trastuzumab deruxtecan. The primary end point of the trial was PFS, and in this study trastuzumab deruxtecan was able to double the duration of time that cancers were under control.

The median PFS period was [approximately] 5 months with standard chemotherapy and [was] 10 months for the patients who got trastuzumab deruxtecan. Looking at OS there was the same trend with standard chemotherapy. On average patients had an OS of 17 months and with trastuzumab deruxtecan that improved to almost 2 years, so [approximately] one-third prolongation in survival for the patients who got trastuzumab deruxtecan.

These are clinically impactful results for a population of patients where we normally don’t see these kinds of improvements in survival when we introduce new agents in a later-line setting.

What toxicities are associated with this agent?

The toxicity is the important counterpoint to the efficacy of this drug, and we’ve been using trastuzumab deruxtecan in HER2-positive patients for a couple of years. We have a lot of experience with it.

The most common single toxicity is nausea and thankfully it is a low-grade nausea. If you give your patients antinausea medications up front, you can control it. The other main category of the day-to-day toxicities is bone marrow suppression. This is something we’re familiar with managing as oncologists and we can manage well with trastuzumab deruxtecan.

There is one important toxicity and it’s important, not because it’s frequent or common, but because [of the] potential for it to be serious and that’s lung toxicity. On average, we see lung toxicity reported with trastuzumab deruxtecan between 10% and 15% in different trials. For most patients, it’s a low-grade toxicity, you can stop therapy, it’s reversible, but there’s a small group of patients where it becomes a high-grade toxicity. We’ve seen fatalities from lung toxicity with trastuzumab deruxtecan; in [DESTINY-Breast04] it was less than 1% [at] 0.8%, so there were 3 reported cases of lung toxicity that were fatal.

It is a reminder for everyone, not only the physicians, but patients, that this is a toxicity that we must be aware of [and] the key to managing it is to…have a high threshold of suspicion and stop therapy if you suspect lung toxicity. [Detection] should launch an investigation into other causes, and if it really is trastuzumab deruxtecan–related lung toxicity, start steroids early. Overall, this is a drug that really improves and prolongs survival for patients with an advanced-stage, incurable cancer. The risk-benefit balance still favors [trastuzumab deruxtecan] as an important option for refractory patients.

What do these data signal about the future of ADCs and the future direction of research for trastuzumab deruxtecan?

These results from DESTINY-Breast04 are [about] much more than just breast cancer and this drug specifically. They are about progress in cancer therapy. [With] the technological evolution of an ADC, we’re now able to treat cancer so much more effectively [with] this strategy. The bystander effect [and] linker-payload technologies have evolved to a point that we’re able to see activity with a drug where we’ve never been able to before. I think this can apply to other cancers, and it can apply to other low-level targets; this is a real [step] forward in cancer therapy in general.

We are excited about the potential of trastuzumab deruxtecan for our high-risk early-stage patients. We’ve been using this drug for [patients with] high-risk HER2-positive [disease] for a couple of years and now we’re going to be using it in the in the HER2-low population.

There's also a population of patients with early-stage disease for whom our current therapies are just not effective enough and these are patients who have high risk of recurrence and we have started to move trastuzumab deruxtecan into the high-risk, HER2-positive population. We’ve opened a neoadjuvant trial [at Memorial Sloan Kettering] and I am very excited about that [NCT05113251]. We hope to open a similar type of study [soon] for the HER2-low population.

In addition, we’re doing a lot of work and trying to understand how we can enhance the effectiveness of trastuzumab deruxtecan for patients who don’t seem to derive the same benefit. [My colleagues are conducting] translational work, looking at combinations to enhance the effectiveness of trastuzumab deruxtecan for all patients.

Reference

FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed August 29, 2022. bit.ly/3zGfOPt