Kalinsky Sees Growing Excitement Over ADCs in HER2-Negative Breast Cancer

Kevin Kalinsky, MD, MS

The FDA's accelerated approval of sacituzumab govitecan-hziy (Trodelvy) in April 2020, filled a previously undefined role for antibody-drug conjugates (ADCs) in patients with triple-negative breast cancer (TNBC), said Kevin Kalinsky, MD, MS.

Additionally, early data with other ADCs, such as fam-trastuzumab deruxtecan-nxki (Enhertu) and ladiratuzumab vedotin, have demonstrated the growing utility of this therapeutic approach in patients with HER2-low and HER2-negative disease, as well.

“What has been nice is that [ADCs] are moving into other subtypes of breast cancer,” said Kalinsky. “Of course, we will need larger studies to see how this will ultimately play out, but this is an increasingly important class of drugs for patients [with HER2-low or HER2-negative disease].”

In an interview with OncLive^® during the 38th Annual Miami Breast Cancer Conference^®, Kalinsky, director of the Glenn Family Breast Center and Breast Medical Oncology at Winship Cancer Institute, and acting associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, discussed ADCs in HER2-low and HER2-negative breast cancer, key takeaways from breast cancer advances in 2020, and anticipated data in the field.

OncLive^®: How did sacituzumab govitecan open the door for ADCs in HER2-negative disease?

Kalinsky: Sacituzumab govitecan is a Trop-2–directed ADC that has SN-38 as its payload. The drug was approved based on [data from] a phase 1/2 study of a little more than 100 patients. We saw a significant response rate in about one-third of patients with pretreated TNBC. Those data also led to the phase 3 ASCENT trial (NCT02574455), which randomized patients to sacituzumab govitecan versus physician’s choice of chemotherapy. These patients had at least 2 prior lines of treatment.

What was really notable about the data [from the ASCENT trial] is that we saw the same sort of response rate [in about one-third of patients], but also a significant improvement in progression-free survival and, most importantly, overall survival.

[These data] led to [sacituzumab govitecan] being a standard-of-care treatment for patients with metastatic TNBC.

Adverse effects that we can see with the drug include diarrhea, neutropenia, and alopecia. However, this is definitely an important drug that is now being evaluated even earlier on and in combination with other therapies, such as immunotherapy.

What is known about the utility of sacituzumab govitecan in hormone receptor–positive, HER2-negative breast cancer?

When we look at the phase 1/2 basket study of sacituzumab govitecan, the TNBC cohort that I mentioned [was evaluated], but there was also a hormone receptor–positive, HER2-negative cohort of about 50 patients. The notable [finding] was that we saw the same sort of response rate in this population [as in the TNBC cohort]. These data have been published in the Annals of Oncology.

Those data led to the TROPICS-02 trial [NCT03901339], which is a study of sacituzumab govitecan vs physician’s choice of chemotherapy in patients with endocrine-resistant disease.

We are awaiting the results of that study to see whether we can also utilize sacituzumab govitecan in this population of patients with breast cancer.

If the ADC is approved in hormone receptor– positive, HER2-negative disease, how do you anticipate sacituzumab govitecan fitting into the landscape? Does it have the potential to fulfill an existing unmet need?

If sacituzumab govitecan is approved for patients with hormone receptor–positive, HER2-negative disease, this will be another agent in our armamentarium. [Its utility] will depend on how significant [the patient’s] disease burden is. Sometimes, for instance, if patients have bone-only disease and have progressed on hormonal therapy and various targeted therapies, oftentimes we use capecitabine and ramp up to intravenous chemotherapies afterward.

However, the kinds of responses that we are seeing with sacituzumab govitecan are really quite notable. If this is recapitulated in the phase 3 trial, I do think there will be a role for this agent [in hormone receptor–positive, HER2-negative patients].

This particular population [represents] an unmet need because these are patients who have endocrine-resistant disease who may also have tumors that have progressed on various chemotherapies. This is definitely an area that requires additional investigation with other ADCs as well.

What activity has been observed with trastuzumab deruxtecan in patients with HER2-low breast cancer?

When we look at patients in the phase 1 study [of trastuzumab deruxtecan] who were classically defined as being HER2-positive by 3+ or FISH [fluorescence in situ hybridization, we saw] incredibly impressive waterfall plots.

If we look at the HER2-low population, meaning patients who have tumors that are not amplified or are HER2 1+ or 2+, we see really nice waterfall plots as well. This led to randomized studies that we are also awaiting data from to see [the utility of trastuzumab deruxtecan] in this population. When we have a comparative study of trastuzumab deruxtecan vs physician’s choice of chemotherapy, [we will see] whether [the ADC] leads to an improvement in outcomes.

If this is a positive study, [trastuzumab deruxtecan] will be yet another ADC that we could give our patients who have either hormone receptor–positive or hormone receptor–negative breast cancer that is HER2 low that could potentially offer [benefit].

Which investigational ADCs could make potentially good additions to the HER2-low armamentarium?

Beyond sacituzumab govitecan and trastuzumab deruxtecan, there are other drugs that we should keep our eyes on. For instance, [ladiratuzumab vedotin], a targeted ADC that is attached to a microtubule inhibitor, [is under evaluation]. There are other HER2-targeted agents with different payloads that are also under evaluation, [reporting] different toxicity profiles [compared with sacituzumab govitecan and trastuzumab deruxtecan].

Based on some early-phase data, those [ADCs] look like they are active, even in the HER2-low population.

Do you foresee ADCs being combined with other therapies, such as immunotherapy?

Other questions [that remain] are: Will these ADCs partner [with other therapies], specifically with immunotherapy? Will there be some sort of synergistic activity in terms of T-cell infiltration? There are ongoing studies that have looked at ADCs with immunotherapy, such as sacituzumab govitecan in combination with checkpoint inhibitors. I’m curious to see not only the toxicity [profile that is] identified, but, most importantly, the efficacy that we could see with that sort of combination.

What are some of your key takeaways from 2020 with regard to advances made in breast cancer?

There were a number of really interesting studies [in 2020]. We’ve already mentioned sacituzumab govitecan in patients with metastatic TNBC. We also had the approval of pembrolizumab [Keytruda] for patients [with PD-L1–positive TNBC] in the frontline setting. We will wait to see whether there is a role for checkpoint inhibition in the operable setting with additional data from KEYNOTE-522 [NCT03036488]. We are still awaiting additional data with other neoadjuvant studies with checkpoint inhibition.

Also, for HER2-positive disease, the addition of tucatinib [Tukysa] to our armamentarium has been really nice, as well as trastuzumab deruxtecan.

For patients with hormone receptor– positive, HER2-negative breast cancer, a lot of focus has been on the role of CDK4/6 inhibitors in the operable setting. We have seen some mixed data; we will look to see the long-term follow-up of these data to determine the potential role of ribociclib [Kisqali] for these patients.

Also, the other [important data we saw] were the results of RxPONDER [NCT01272037] for patients with hormone receptor–positive, HER2-negative

breast cancer with 1 to 3 lymph nodes involved. [That study] identified that patients who have an Oncotype DX score of 25 or less have a differential effect [with therapy] based upon menopausal status. In the postmenopausal population, which made up about two-thirds of that study, we did not find a benefit with 5 years of chemotherapy, compared with the premenopausal population [who did derive benefit with chemotherapy].

Increasingly, we are trying to move away from the one-size-fits-all approach and give treatment to patients when their tumors suggest they will benefit.

How could oral selective estrogen receptor modulators (SERDs) and circulating tumor DNA (ctDNA) further the paradigm in the future?

For patients with metastatic hormone receptor–positive, HER2-negative disease, there will be a role for oral SERDs. There are a lot of oral SERDs that are in development. Some of the early-phase trials have reported out, and some have been published. A number of agents are in randomized, registration trials. This is an exciting class of drugs for patients with metastatic disease, as well as potentially for patients with operable disease.

I would also keep your eyes on the potential role for ctDNA [circulating-tumor DNA] or cell-free DNA. We’ve seen the potential utility in patients with metastatic disease, but there are prospective and retrospective studies that suggest there can be a prognostic role for these agents in the early-stage setting across the various tumor subtypes. Then, we will ultimately see whether there is also a predictive role and whether we can see clearance of ctDNA. That could potentially be associated with an improvement in outcomes.

What is your take-home message from this year’s Miami Breast Cancer Conference^®?

Unfortunately, we were not able to all be together for this year’s Miami Breast Cancer Conference^®. We can hope for that next year. However, what is really nice about the program and the agenda is that a lot of [the topics discussed] are very multidisciplinary focused. There were [and will be] some really nice tumors boards [at the meeting] that are [bringing] together physicians from across disciplines. Treating patients with breast cancer is a team sport, and I think the meeting agenda really reflected that.