B7-H4–Directed ADCs May Broaden Breast and Gynecologic Cancer Armamentariums

The future trajectory of antibody-drug conjugates (ADCs) in the treatment of patients with breast and gynecologic cancers will be shaped by findings from ongoing and upcoming tumor-agnostic trials that are investigating ADCs with various targets, according to Bradley J. Monk, MD, FACOG, FACS, and Paolo Tarantino, MD. 

The ongoing phase 1 SGNB7H4V-001 trial (NCT05194072) is investigating the B7-H4 vedotin ADC SGN-B7H4V in patients with advanced solid tumors. Preliminary findings from this study revealed objective responses in 7 of 28 patients with breast cancer and 4 of 20 patients with ovarian cancer. Additionally, of 16 patients with endometrial cancer, 1 achieved a complete response (CR).¹

Another phase 1 trial (NCT05263479) is investigating the B7-H4–directed ADC HS-20089 in patients with advanced solid tumors.² Of 28 evaluable patients with triple-negative breast cancer (TNBC), this agent elicited an overall response rate (ORR) of 28.6% (95% CI, 13.2%-48.7%). In the cohort of patients with ovarian cancer, the ORR was 66.7% (95% CI, 9.4%-99.2%).

“Generally, late-phase [drug] development is done in later lines [of therapy], but ultimately, earlier line combinations, and several tumor types is how the life cycle [of ADCs] needs to be managed to help the most patients we can,” Monk said in an interview with OncLive^®.

“It will be important to understand the mechanisms of resistance to optimize the use of these ADCs in sequence and develop the new generation of ADCs,” Tarantino stated in another interview.

In the interviews, Monk and Tarantino discussed key data with B7-H4–directed ADCs across solid tumor types, the evolving role of developmental ADCs in gynecologic cancers, and the importance of determining optimal ADC sequencing in breast cancer.

Monk is the director of GOG Partners and the GOG Foundation and a professor at the University of Arizona College of Medicine and Creighton University Health Sciences Campus in Phoenix.

Tarantino is a researcher at the European Institute of Oncology in Milan, Italy, as well as a clinical research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts.

OncLive: What is the rationale for investigating B7-H4–directed vedotin ADCs, and what unmet needs could they address for patients with gynecologic cancers?

Monk: One target I’m interested in [has been] shown to be effective. Tisotumab vedotin-tftv [Tivdak] is approved for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. [Another vedotin-based ADC is] SGN-B7H4V. The vedotin is the combination of the linker and the ligand.

[Findings from SGNB7H4V-001 investigating SGN-B7H4V in patients with advanced solid tumors were] presented at [the 2023 ESMO Congress] by Cesar Perez, MD , who’s part of the Sarah Cannon Research Institute at Florida Cancer Specialists and works at the Lake Nona [location of Florida Cancer Specialists & Research Institute] in Orlando, Florida. [These findings were] exciting because [the drug] was active. We’re trying to help patients who have serious diseases. [SGN-B7H4V demonstrated] activity in 7 of 28 patients [with breast cancer who] were treated at many different doses, and 4 of 20 patients with ovarian cancer. [The investigators] saw a CR [in 1 patient with] endometrial cancer and some activity in lung and biliary tract cancers. These were early, deep, and durable responses. The AEs have been well documented for vedotin [ADCs, and include] fatigue, neuropathy, and bone marrow suppression, with low levels of diarrhea. Interestingly, alopecia is rare, and pneumonitis is rare. 

The key point of this abstract presented by Dr Perez was to investigate the dosing schedule [of SGN-B7H4V]. The 2 schedules [the investigators evaluated] were [administering SGN-B7H4V on days] 1 and 8 of a 21-day cycle and [administering the agent] every other week on a 4-week cycle. This abstract told us, preliminarily, the activity [of the agent] and supported the safety profile we’ve seen. [Additionally], [administering SGN-B7H4V] every other week in 4-week [cycles is probably the dosing schedule that will] move forward, although [the agent was active in] both schedules.

How might the findings from the phase 1 study investigating HS-20089, another B7-H4–directed ADC, further inform the future use of ADCs targeting this ligand?

Monk: HS-20089 is not the only B7-H4–directed vedotin [under investigation]. At least 3 others [are under investigation]. [These agents are] generating similar results, but they’re not the same. It’s too early to compare HS-20089 [with SGN-B7H4V] as a second [agent in this class], but I’m excited about the target. I’m excited about the [potential opportunity for vedotin ADCs to come to the clinic] because that linker and payload is established and FDA approved for several tumor types, so we have confidence about its activity and safety profile.

If data with SGN-B7H4V continue to be positive, what is the potential future role for this agent within gynecologic oncology?

Monk: Ultimately, it’s tough, so you have to optimize the dose. However, there are techniques, [which we use] within the GOG Foundation, [that we can use to] identify the optimized dose and ultimately do an assessment to get accelerated approval and then carry the study forward, generally in a randomized fashion, to gain full approval.

There are so many ADCs. Folate receptor α [FRα] is another target. We’re studying it in ovarian cancer. [In November 2022 , mirvetuximab soravtansine-gynx (Elahere)] received accelerated approval [for patients with FRα-positive, platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer]. [The data that supported this regulatory decision were confirmed] at [the 2023 ASCO Annual Meeting] in a phase 3 trial called MIRASOL [NCT04209855], which is yet to be published and may ultimately flip [the FDA] label from an accelerated approval to a full approval. DS-6000 is another ADC presented at [the 2023 ESMO Congress] with sensational activity and tolerability. The sponsors suddenly have multiple assets, and they have to prioritize them.

What is the potential role for SGN-B7H4V in the breast cancer armamentarium?

Tarantino: An interesting agent was presented at [the 2023 ESMO Congress] in a first-in-human [SGNB7H4V-001] trial. SGN-B7H4V is an ADC comprising a B7-H4–directed monoclonal antibody conjugated to auristatin E via a protease-cleavable linker. We’ve seen [success with] other ADCs with the vedotin payload, such as enfortumab vedotin-ejfv [Padcev] for the treatment of [patients with advanced bladder cancer] and tisotumab vedotin [for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy]. Now, this other vedotin ADC is showing promising activity.

In the phase 1 presentation at [the 2023 ESMO Congress], 86 patients were included in 2 different courts, 1 that included day 1 and day 8 dosing in 21-day cycles, and 1 that included day 1 and day 15 dosing in 28-day cycles. In general, across both cohorts, the most common AEs that were observed were fatigue, peripheral sensory neuropathy, and cytopenias, similar to [the AEs associated with] other vedotin ADCs. However, the cohort receiving [SGN-B7H4V] every 3 weeks experienced more toxicity and 2 grade 5 toxicities, 1 because of hyperglycemia and neutropenia, and the other related to febrile neutropenia. Therefore, all patients in the trial are being transitioned to the 4-week dosing schedule.

Regarding activity, responses were observed in different tumor types. Most of the patients included this trial had ovarian cancer, hormone receptor [HR]–positive breast cancer, or TNBC, but [patients with] other tumor types [were also included]. Seven of the 28 patients with advanced breast cancer responded to the drug, as well as 4 out of 20 patients with advanced ovarian cancer. [Responses were also observed in patients with] endometrial, lung, and biliary tract cancers, among others. We need to see more from this agent, but these first-in-human results are promising.

How significant is the choice of ADC target or payload regarding treatment efficacy, resistance, and patient outcomes?

Monk: The [target generating the] most excitement, at least in gynecologic cancers, is HER2. fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] has breakthrough therapy designation in several tumor types for [tumors that are] HER2 [2+ or 3+ by immunohistochemistry], and as of September 20th, 2023, T-DXd is recommended at level 2A by the National Comprehensive Cancer Network guidelines for patients with cervical and endometrial cancers. DB-1303, [another HER2-directed ADC with findings] presented by Kathleen Moore, MD, MS, [of Stephenson Cancer Center in Oklahoma City] at the [2023 ESMO Congress], is exciting. We will need to sort out which [ADC targets are most effective in which patient populations]. [These targets include] B7-H3, HER2, and TROP2. There are several TROP2-directed ADCs, [of which] sacituzumab govitecan-hziy [Trodelvy] is the furthest ahead and is FDA approved for patients with breast cancer.

Tarantino: In general, choosing the antibody and target is important, and the payload is also critical. We’re starting to see data showing that the mechanism of resistance to ADCs can be related to both the target and the payload. We need to see ADCs broadly. We need to understand that each part of the ADC is extremely important. The linker determines the stability of the component where the payload is released.

In drug development, when we think of developing new ADCs, we have to think of expanding the range of targets we’re investigating, expanding the range of payloads, and probably also refining the linking technology. For instance, the DXd platform, [which consists of] T-DXd, datopotamab deruxtecan [Dato-DXd; DS-1062a], and patritumab deruxtecan [HER3-DXd], is successful thanks to an interesting linker that allows intermediate stability, where some of the target and payload reach the tumor and some of [the payload] spills and has broader activity, even in heterogeneous tumors. Each part of the ADC is extremely important, and we’re learning this day by day.

What further research is needed to clarify second-line sequencing with ADCs in breast cancer?

Tarantino: Sequencing may be 1 of the most complex topics in breast oncology, particularly ADC sequencing, because increasingly more ADCs are approved or [expected to be approved] soon. Several of these ADCs share either targeted antigens or payloads. For instance, both T-DXd and ado-trastuzumab emtansine [T-DM1; Kadcyla] target HER2, and they can work one after the other.

We also have 2 ADCs, T-DXd and sacituzumab govitecan, that share a topoisomerase-1 payload. We still don’t have much data of the 2 utilized in sequence. Several abstracts, such as one presented at [the 2023 ASCO Annual Meeting], and one that will be presented at the 2023 San Antonio Breast Cancer Symposium, are evaluating the sequencing of [T-DXd and sacituzumab govitecan] and will hopefully clarify whether we can use one after the other.

I hope we can achieve more differentiation in the payload of the ADCs, because many promising topoisomerase-1 ADCs are in the pipeline. We need more than microtubule inhibitors and topoisomerase-1 inhibitors; we need to move to the next generation of payloads. There is also a potential role for payloads that have been shown to work in other diseases, such as alkylators and some microtubule inhibitors.

In general, there’s a lot going on in the field of ADCs. Sequencing will become a critical topic in the future, but this is a good problem to have, because we’re starting to have more treatments available for patients. We’ll figure out the best way to sequence [these agents] to improve their activity in sequence and minimize cross-resistance and toxicity.

What other emerging ADCs in breast cancer were presented at the 2023 ESMO Congress?

Tarantino: It was slightly disappointing to see the final results of the [phase 3] TULIP trial [NCT03262935]. That was a phase 3 trial investigating vic-trastuzumab duocarmazine [SYD985], a novel HER2-directed ADC, [in patients with HER2-positive metastatic breast cancer]. [TULIP] prolonged PFS [with the agent] compared with traditional treatment. [However, trastuzumab duocarmazine] was associated with ocular and pulmonary toxicities, as well as no improvement in overall survival at the final analysis. [There have been some] promising data and some disappointing data, but in general, there’s a lot of movement in the field. I expect to see more [innovations] in the next months and years.

Finally, we need to mention Dato-DXd. Important phase 1 trials [with this agent] have been presented, including in the first-line TNBC setting, where Dato-DXd plus durvalumab [Imfinzi] was associated with an extremely high ORR of 80% and a median PFS that exceeded 1 year, which is remarkable for metastatic TNBC, a highly aggressive disease. We have also seen phase 3 data in the HR-positive population in the [phase 3] TROPION-Breast01 trial [NCT05104866], where Dato-DXd improved PFS compared with traditional chemotherapy. We expect Dato-DXd to become an available treatment option for patients with pretreated, HR-positive metastatic breast cancer.

What unanswered questions remain surrounding the optimal use of ADCs?

Monk: We need to get these medications approved in earlier lines of therapy and in combinations and then pivot to several tumor types. [We have seen that happen] with T-DXd and sacituzumab govitecan. We will see that with mirvetuximab soravtansine. That’s the platform.

Tarantino: One major unmet need [in breast cancer in] which we’re starting to see promising data is brain metastasis. When brain metastases are detected, they signal a worse prognosis. These patients are hard to treat and sometimes require extensive local treatments. We need systemic treatments that work in the brain.

T-DXd has shown promising intracranial activity. Sacituzumab govitecan is also being studied [in patients with] brain metastases. Soon, we will start a trial to see whether Dato-DXd is also active for brain metastasis.

The second major unmet need [in breast cancer] is curing patients with curable disease. [We should take] ADCs to the early-stage setting, where they may have the biggest effect on treatment, because we could [use them to] eradicate minimal residual disease hopefully better than chemotherapy, since we have shown that ADCs outperform chemotherapy in the metastatic setting. If tested appropriately in the early-stage setting, either as neoadjuvant treatment or adjuvant treatment, ADCs may improve outcomes.

Several trials are ongoing. For instance, T-DXd is being tested in the [phase 3] DESTINY-Breast05 [NCT04622319] and DESTINY-Breast11 [NCT05113251] trials. Sacituzumab govitecan [is being investigated] in the [phase 3] SASCIA [NCT04595565] and OptimICE-RD [NCT05633654] trials. Dato-DXd [is under evaluation] in the [phase 3] TROPION-Breast03 trial [NCT05629585]. Many trials are ongoing in the early-stage setting, and they will target a major unmet need in breast oncology and hopefully deliver important benefits for patients.

References

1. Perez CA, Henry JT, Lakhani N, et al. 660MO first-in-human study of SGN-B7H4V, a B7-H4-directed vedotin ADC, in patients with advanced solid tumors: preliminary results of a phase I study (SGNB7H4V-001). Ann Oncol. 2023;34(suppl 2):S464-S465. doi:10.1016/j.annonc.2023.09.1846
2. Wu J, Zhang J, Li H, et al. 381O first-in-human/phase I trial of HS-20089, a B7-H4 ADC, in patients with advanced solid tumors. Ann Oncol. 2023;34(suppl 2)S336. doi:10.1016/j.annonc.2023.09.558