Recent Approvals Support Continued Research on New and Emerging ADCs Across Breast Cancer Subtypes

Stephanie L. Graff, MD

As indications for novel antibody-drug conjugates (ADCs) continue to expand in both triple-negative breast cancer (TNBC) and hormone receptor (HR)-positive, HER2-negative breast cancer, researchers continue attempts to move these agents into earlier treatment lines alongside the development of datopotamab deruxtecan (Dato-DXd) in both breast cancer subtypes.

Additionally, the optimal sequencing of CDK4/6 inhibitors in the first-line metastatic and curative settings for patients with high-risk, HR-positive, HER2-negative disease remains a topic of debate, according to Stephanie L. Graff, MD.

On August 5, 2022, the FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for the treatment of patients with unresectable or metastatic HER2-low breast cancer according to findings from the phase 3 DESTINY-Breast04 trial (NCT03734029).¹

In the HR-positive space, sacituzumab govitecan-hziy (Trodelvy) gained FDA approval on February 3, 2023, for patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer based on results from the phase 3 TROPiCS-02 trial (NCT03901339).² This is the second indication for this agent in breast cancer, as it was previously approved for patients with unresectable locally advanced or metastatic TNBC on April 7, 2021.³

“I’m excited to see how new and developing ADCs are going to [perform] in both TNBC and HR-positive metastatic breast cancer,” ​​Graff said following an OncLive® Institutional Perspectives in Cancer webinar on breast cancer, which she chaired. “Hopefully, [these] novel compounds will continue to shape the landscape. I’m excited to see where the future of breast oncology is going.”

In an interview with OncLive, Graff highlighted key topics discussed at the meeting, including an overview of recently approved ADCs in TNBC and HR-positive, HER2-negative breast cancer, as well as the importance of continued research with these agents in the first-line setting. Graff also discussed the investigation of datopotamab deruxtecan, the role of CDK4/6 inhibitors in high-risk HR-positive, HER2-negative breast cancer, and the efficacy of tucatinib (Tukysa)-based treatments in treating patients with brain metastases according to the phase 2 HER2CLIMB study (NCT02614794). 

Graff is the director of Breast Oncology, at Lifespan Cancer Institute, assistant professor of medicine at the Warren Alpert Medical School, and co-leader of the Breast Cancer Translational Research Disease Group atBrown University’s Legorreta Cancer Center in Providence, Rhode Island.

OncLive: Could you briefly discuss what data from the TROPiCS-02 trial led to the FDA approval of sacituzumab govitecan in metastatic HR-positive, HER2-negative breast cancer, as well as the significance of this approval?

Graff: In the ADC space, we've had a new approval for sacituzumab govitecan in HR-positive metastatic breast cancer. Of course, we've been using sacituzumab govitecan to treat [patients with] metastatic TNBC for a while now, based on [data from] the phase 3 ASCENT trial [NCT02574455]. We've now seen results from the TROPiCS-02 trial, which randomized patients with metastatic HR-positive breast cancer to sacituzumab govitecan vs physician's choice of treatment and followed them for the primary end point of progression-free survival [PFS]. Patients were randomized [to treatment] after at least 2 prior lines of chemotherapy and 1 prior endocrine therapy. We saw that sacituzumab govitecan did significantly improve median PFS from 4 months in the physician's choice group to 5.5 months in the sacituzumab govitecan arm. [The trial was] followed for overall survival [OS], which has also now been met.

We are excited to have [an approval] in the HR-positive, heavily pretreated population. [However], it'd be interesting to see how sacituzumab govitecan [performs] in earlier lines of therapy.

What data supported the recent approval of T-DXd in HER2-low metastatic breast cancer?

Another new approval for ADCs [that] everybody's very excited about [is] T-DXd. [This was approved] for HER2-low metastatic breast cancer. We all know the DESTINY-Breast04 trial, [which was] presented at the 2022 ASCO Annual Meeting and synchronously published in the New England Journal of Medicine.

My colleague Mary Ann Fenton, MD, FACP, of Lifespan Cancer Institute, presented [these data] at our OncLive State of the Science Summit. [The trial] randomized patients with HER2-low breast cancer, which is breast cancer that is either immunohistochemistry [IHC] 1+ or 2+ and in situ hybridization [ISH] negative, to either T-DXd or physician's choice of treatment. Again, the patient population was predominantly HR-positive, [but] a smaller cohort was HR-negative. We saw that those patients had a striking improvement in median PFS from 5.5 months to 10.1 months [with T-DXd]. Then we saw a significant improvement in OS in the total patient population from 16.8 months to 23.4 months. [This trial] met both primary and secondary end points, leading to a new approval.

How has the approval of sacituzumab govitecan inspired its current investigation as a first-line treatment option in TNBC?

Sacituzumab govitecan is now being studied in numerous settings. [These studies aim to determine] whether it will have a role in earlier lines of therapy [for] both TNBC [and HR-positive breast cancer]. Sacituzumab govitecan is being explored [as a] first-line therapy for metastatic TNBC either in combination with immunotherapy for patients that express PD-L1, or as a single agent for patients that do not express PD-L1. This is an important question, especially now that we're treating patients with the [phase 3] KEYNOTE-522 [(NCT03036488) regimen of pembrolizumab (Keytruda) plus neoadjuvant] chemotherapy in the curative setting. If [patient's] don't have a pathologic complete response, maybe they're also getting capecitabine [Xeloda], a PARP inhibitor, [or] pembrolizumab. We have so [many] adjuvant and neoadjuvant therapies [in this space]. When a patient has a metastatic recurrence, the question is: What now? [Therefore], the [use of] ADCs in that first-line setting is an exciting clinical research question in metastatic TNBC.

With the latest approval for trastuzumab deruxtecan heightening the focus on HER2-low classifications in breast cancer, how might the DESTINYBreast-06 trial (NCT04494425) further clarify the agent’s utility in this space?

The same story is going to unfold in the metastatic HR-positive space with T-DXd. In the [phase 3] DESTINY-Breast06 trial, T-DXd [is being] explored in patients [in] earlier lines of therapy. [The trial] included patients with advanced HR-positive disease in the first-line setting who had progressed on prior endocrine therapy, and randomized them to T-DXd vs investigator's choice of chemotherapy. [The trial] also looked to accrue a small population of patients that were HER2-zero, [which is] the lowest possible definition of HER2-low [provided] we continue to [group these together]. There's already some data that the HER2-zero population may respond to trastuzumab deruxtecan. [This trial] continues to see how trastuzumab deruxtecan does in earlier lines of therapy, and [to define] how much, if any, [HER2] expression is needed for [the agent] to hit its target.

What activity has been seen with the emerging ADC datopotamab deruxtecan in both the HR-positive and TNBC cohorts from the TROPION-PanTumor01 trial (NCT03401385)?

Dato-DXd is an emerging Trop-2 targeting ADC with that same deruxtecan payload. It's like a marriage of sacituzumab govitecan and T-DXd. We saw [data with] dato-DXd in the [phase 1] TROPION-PanTumor01 trial, and we've seen [some] in non–small cell [lung cancer] as well as some other cancer types. In breast cancer, we have seen [data with this agent in] TNBC and HR-positive breast cancer. Again, these ADCs cross our typical drug classes, and we're seeing activity across different groups. For that TNBC population, the waterfall plots are beautiful, and we still saw [responses] regardless of [whether] patients had been previously exposed to a topoisomerase-1 inhibitor. [The agent produced] an objective response rate [ORR] of 44% in this heavily pretreated population with TNBC, which is meaningful in a phase 1 study. Dato-DXd is going to be moving forward in the [phase 3] TROPION-Breast02 [NCT05374512] study.

Similarly, the data that we saw from the HR-positive cohort in the TROPION-PanTumor01 trial [included] beautiful waterfall plots and a great ORR. Responses [were] durable, with a median PFS of about 8.3 months. [Investigators] have designed the [phase 3] TROPION-Breast01 study [(NCT05104866) to] explore dato-DXd vs physician's choice of treatment for patients with metastatic HR-positive breast cancer who have progressed on prior endocrine therapy, and 1 or 2 prior lines of chemotherapy. Dato-DXd does cause some mucositis, and oral [adverse effects (AEs)]. [We will] watch for strategies to mitigate that AE as [dato-DXd] continues to advance through clinical trials.

Do any questions remain regarding the use of these recently approved and emerging ADCs in clinical practice?

As these 3 ADCs move forward, [there] will be questions about sequencing and mechanisms of resistance. What matters [more]: the payload, the class of chemotherapy, [or] the target? [Should the primary target] be HER2 or TROP-2? How do those things factor into how these drugs are used in sequence? Do patients respond in sequence, and is there an optimal sequence? None of the patients that we [currently] have data [for] have seen all [these ADCs]. [We] still need to answer these questions and figure out how to implement this new class of drugs into clinical practice.

How do you generally approach the sequencing of CDK4/6 inhibitors in the first line, and what patient factors influence this treatment decision-making?

A bunch of [factors] come into play for patients with metastatic HR-positive breast cancer. At this point, we have data [showing] that there is improved OS with ribociclib [Kisqali] from the [phase 3] MONALEESA-2 [NCT01958021] and MONALEESA-3 [NCT02422615] trials. My preferred first agent does tend to be ribociclib, but it has some unique AEs [such as] QT prolongation. If a patient [is on an] antidepressant [or] cardiac therapy that's important to their health [but] also causes QT prolongation, we might not choose that medicine for them.

OS data from the [phase 3] MONARCH 3 trial [NCT02246621] is trending [positively] but has not yet [reached] maturity. [Conversely, the phase 3] PALOMA-2 [trial (NCT01740427) of] palbociclib [Ibrance] did not meet its OS end point. There's lots of controversy [regarding] the reasons for that. [Researchers question] if it's [because of a] different drug, if there were data collection barriers, or if it was a statistical design issue. All of those [points] are so nuanced that I find them hard to discuss with the patient. [Therefore], I find myself going to palbociclib less often in my day to day practice, but there are times when palbociclib and abemaciclib [Verzenio] may be a better first-line option for patients based on things like financial barriers or AE profiles.

What is the potential role for CDK4/6 inhibitors alongside adjuvant endocrine therapy in high-risk patients with early-stage HR-positive, HER2-negative breast cancer, based on data presented by William M. Sikov, MD, of Lifespan Cancer Institute?

We already have an approval for abemaciclib for patients with early-stage, high-risk, estrogen-receptor [ER]-positive breast cancer [in] the curative [setting] based on the [phase 3] monarchE study [NCT03155997]. I am using abemaciclib in this population. It's nice to see that the indication around Ki-67 has evaporated as those data matured. That just [reduces] the confusion about who we will or won't [treat with abemaciclib]. Larger tumor size and positive lymph nodes [are specific] considerations, [but] it looks like everybody in those higher-stage, higher-risk tumors benefit from the addition of abemaciclib. When we look at data on long-term outcomes, patients that are 10 or 20 years out from HR-positive breast cancer still have an increased risk of recurrence. If taking a CDK4/6 inhibitor [like] abemaciclib for those first 2 years can start to widen those curves and give us long-term differences in outcomes, that [would] be amazing.

[Although] we're still waiting for OS data [from monarchE] to mature, we've seen that the depth of response has continued to increase. [Recently], we've also seen the press release that the [phase 3] NATALEE trial [NCT03701334] has met its primary end point. NATALEE is a similar trial to monarchE, [but it] had some important differences. NATALEE used ribociclib, accrued a slightly lower-risk patient population, and [was] more generous in the inclusion of stage II patients. It [also had] a longer duration of CDK4/6 inhibitor [treatment], [administering] ribociclib for 3 years. Ultimately, it will be interesting to see what these data show [as we] follow it for maturity, [which may potentially lead to] an approval. Figuring out how all these CDK4/6 inhibitors [can be used] in the curative space [will] end up shaping what happens in the metastatic space.

Regarding the presentation given by Mary Ann Fenton, MD, of Lifespan Cancer Institute, how do updated results from the exploratory analysis of patients with brain metastases in HER2CLIMB help clarify the real-world use of tucatinib-based treatments?

[Research on] HER2-positive brain metastases is this continually emerging landscape. HER2CLIMB is a fantastically well-designed study, and you will be hard pressed to find an expert in the field who doesn't [agree]. HER2CLIMB accrued patients that had previously untreated brain metastasis, and we can see what happened to brain metastases that were exposed to tucatinib. Patients had a great central nervous system [CNS] response [with tucatinib]. Their systemic disease was also well controlled and did meet its primary end point of OS, but that CNS disease [was particularly] well controlled. [Other] meaningful end points that you would want to see in a population with brain metastases, [including] the rate of new disease developing in the brain, unfolded. Historically, this has been a population that drug developers and researchers [were] afraid to include in clinical research because they are high risk and [could] complicate the interpretation and analysis [of results]. [This trial] is proof that it is important to [obtain data on brain metastasis] when it's common in the disease itself.

HER2CLIMB gives us a lot of information about how powerful tucatinib can [for] patients with brain metastases. That being said, patients that have small or new brain metastasis [are] often a little uncomfortable [with receiving tucatinib] in clinical practice. [It is difficult] for a patient to trust that the drug is going to work when it comes to their brain. [Accordingly, both] the American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines still say that the standard of care is stereotactic radiosurgery or CyberKnife [robotic radiotherapy] for targeted brain metastasis. If you have a brain lesion that's amenable to local therapy, we still typically offer [that first] in clinical practice. There's also a significant volume of emerging [data] from trials like the [phase 2] TUXEDO-1 trial [(NCT04752059), showing] that T-DXd likely has great penetrance and activity in the CNS. [However, it's not] prospective, randomized, phase 3 data like we have with HER2CLIMB.

This is an area to watch. [It will be interesting] to see how those data continue to mature across the full landscape, [and how it could] help tailor approaches for patients with HER2-positive brain metastasis.

Please discuss one or two trials in the breast cancer space that are being conducted at your institution that you’re excited about.

Right now, [Brown University’s Legorreta Cancer Center is] doing the [phase 3] postMONARCH [NCT05169567] study, which [aims] to answer the question about second-line CDK4/6 inhibitor use. We have data from the [phase 2] PACE study [NCT03147287], which took patients after progression on palbociclib and continued them on palbociclib [plus endocrine therapy]. That ended up being a negative trial, suggesting that this strategy was not [the way] forward. Conversely, we have the [phase 2] MAINTAIN trial [NCT02632045] that took patients who had progressed on any prior CDK4/6 inhibitor and randomized them to ribociclib. Most [patients progressed on] palbociclib. We did see improved PFS [with ribociclib], suggesting that switching CDK4/6 inhibitors may be an effective [second-line] strategy.

The postMONARCH study is taking patients who progressed on any prior CDK4/6 inhibitor and randomizing them to abemaciclib plus fulvestrant [Faslodex] vs fulvestrant alone. There are also lots of ongoing questions about the optimal utilization of the ADCs, and we do have several of the TROPION-PanTumor trials looking at dato-DXd.

Editor’s Note: Dr Graff reports serving in a consultory or advisory role for AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, Novartis, Pfizer, and Seattle Genetics.

References

1. FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed April 3, 2023. https://www.fda.gov/news-events/press-announcements
2. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. News release. FDA. February 3, 2023. Accessed March 31, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs
3. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. News release. FDA. April 7, 2021. Accessed April 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs