Zamarin Shares Updates and Ongoing Research Endeavors in Gynecologic Oncology

Dmitriy Zamarin, MD, PhD

Recent approvals of immunotherapy agents and antibody-drug conjugates (ADCs), along with ongoing research involving novel treatments such as bispecific antibodies and cellular therapies, continue to propel advances across gynecologic oncology, according to Dmitriy Zamarin, MD, PhD.

“What I'm looking forward to is the development of trials to try to understand the best sequencing of these types of therapies,” Zamarin explained in an interview with OncLive^®.

In the interview, Zamarin highlighted key changes and ongoing research across the endometrial, ovarian, and cervical cancer realms; discussed areas of unmet need in these treatment spaces; and previewed key updates to watch for in 2024 across gynecologic oncology.

Zamarin is the section head of Gynecologic Medical Oncology and a member of the Icahn Genomics Institute and the Precision Immunology Institute at the Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai in New York, New York.

OncLive: Could you please provide some insights into what your new role involves? Additionally, what are your expectations in terms of the main responsibilities and areas of focus that you'll be delving into?

Zamarin: In my new role, I lead the gynecologic medical oncology team [at Mount Sinai]. We work very closely in conjunction with gynecologic oncology surgeons, as well as radiation oncologists, to provide this seamless transition in care for patients with gynecologic malignancies such as ovarian, endometrial, and cervical [cancer,] so we are nicely integrated into the team here. I predominantly provide the medical oncology input into the care of these patients.

Reflecting on the most recent advances in gynecologic cancer treatment, particularly those within the last six months, which developments do you consider to be the most significant in terms of impacting clinical practice?

I'll start with endometrial cancer because we have seen a lot of excitement in the past year. [We can] start with the reports of the combinations of PD-1 inhibitors, namely pembrolizumab [Keytruda] and dostarlimab-gxly [Jemperli], with up-front chemotherapy in patients with advanced endometrial cancer. These therapies have created new standards for the treatment of our patients, in particular patients with mismatch repair–[deficient (dMMR)] endometrial cancers, and we now use these therapies routinely for these patients.

For patients with the more common subtype of endometrial cancer, which is mismatch repair–proficient [pMMR], there is still a lot of work to be done. It seems like some incorporation of these immunotherapy agents may benefit some patients, but we have no way of understanding of which patients are benefiting vs not [benefitting]. The work that has already been published does create a lot of opportunities for further biomarker work in this population. Fortunately, since we do have samples that have been collected from these patients, we hopefully will be able to answer these questions in the coming years.

There has also been some exciting work in endometrial cancer in the field of ADCs. [Although these agents] have not been approved by the FDA for the treatment of endometrial cancer, we have seen exciting activity with the drugs targeting various targets on the surface of endometrial cancer cells. The most advanced in development is fam-trastuzumab deruxtecan-nxki [Enhertu], a HER2-targeted ADC that has shown dramatic activity in high-grade endometrial cancer, such as carcinosarcoma, that otherwise has no treatment options. Trastuzumab deruxtecan is already listed by the National Comprehensive Cancer Network [Guidelines] as an option for these patients, and we look forward to the emerging data from other ADCs targeting HER2 and other targets such as B7-H4, TROP2, and others.

Could you elaborate on the development of ADCs and other therapies in ovarian cancer?

Staying on track with the ADCs, these are relevant to other gynecologic cancer subtypes, including ovarian cancer, and we have seen data with the same HER2 ADCs such as trastuzumab deruxtecan, [demonstrating efficacy] in ovarian cancer. That's quite exciting, and we look forward to seeing more of that data.

We already have an approved ADC in ovarian cancer at targeting folate receptor α, which is mirvetuximab soravtansine-gynx [Elahere].¹ We saw confirmatory results of that [ADC in the phase 3 MIRASOL study (Study 0416; NCT04209855)] in the past year that have validated the use of this drug in patients who have recurrent ovarian cancer.

The immunotherapies, namely immune checkpoint inhibitors, unfortunately, have not been very successful in ovarian cancer thus far, although there may be some newer [generation] agents that are coming out that may be used in combinations and have shown some preliminary activity, including some of the agents that we have explored in the past such as the ones targeting CTLA-4.

Excitingly, therapies that are targeting surface antigens on ovarian cancer cells, such as bi-specifics and some CAR T-cell therapies, have also shown promising activity, and for some of the targets that have had data presented, for example, claudin 6 [CLDN6], there was a small [phase 1] study [NCT04503278] with [the CAR T-cell therapy BNT211] that was conducted in a number of solid tumors, including ovarian cancer, and it showed promising activity, according to data most recently reported at the 2023 ESMO Congress.2 [These early data have] certainly validated [CLDN6] as a potential target, and we look forward to more studies in this area.

Are there any key updates in cervical cancer that you would like to highlight?

Cervical cancer is still unfortunately a cancer of highly unmet needs, particularly since it's mostly prevalent in underserved populations. In cervical cancer, we have not necessarily had as many advances as we would have liked. We have seen activity with ADCs in HER2-positive cervical cancer, and again, the HER2-targeted ADCs are potential options for this population.

Immunotherapies such as pembrolizumab are approved for cervical cancer in the later-line setting. Recently, a number of trials have been conducted to incorporate pembrolizumab or other immune checkpoint inhibitors into therapy in an earlier-line setting, such as in combination with chemoradiation. [The phase 3] KEYNOTE-A18 trial [NCT04221945] which [investigated] the combination of pembrolizumab with chemoradiation for advanced cervical cancer, was reported to be positive at the 2023 ESMO Congress,³ and this eventually led to the recent FDA approval of [pembrolizumab] in combination with chemoradiation for patients with [FIGO] stage III to IVA cervical cancer.⁴

These are exciting findings for us because the management of locally advanced cervical cancer has not changed in the past 20 years, and this is the first new drug that we have. Unfortunately, even with the addition of this drug, approximately 30% to 40% of patients with locally advanced cervical cancer will develop disease recurrence, highlighting that this remains an unmet need, and further work needs to be done in that area.

Could you elaborate more on the current strategies being employed with CAR T-cell therapies in gynecologic cancers?

Until recently, CAR T-cell therapies—or adoptive cell therapies in general—have not shown that much efficacy in solid tumors. Most of these [therapies] have been approved predominantly in [hematologic] malignancies and have shown tremendous activity with [potential] cures against leukemias, CD19-positive lymphomas, and multiple myeloma. We have not seen that much activity in solid tumors. However, advances in CAR T-cell engineering, as well as the identification of appropriate targets, have led to the revolution of CAR T cell therapies over the past few years.

Emerging studies in solid tumors seem to indicate that these therapies can be effective. They are effective in mouse models of solid tumors, and there is no reason to expect why mouse solid tumors would not somehow be related to the human solid tumors. We are starting to see some of the evidence of that efficacy. [In 2023] there was a CAR T-cell trial with a specific type of CAR called [the T-cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel)] targeting mesothelin that was reported in Nature Medicine, demonstrating activity against mesothelin-expressing cancers such as malignant pleural mesothelioma and ovarian cancer.⁵

Again, this is validating CAR T cells as a proof of concept for therapy in solid tumors. I [previously] highlighted CLDN6-targeted CAR T cells; this study of [the mesothelin-targeted] CAR T-cell therapy predominantly enrolled patients with germ cell tumors and ovarian cancer. And in both cancers, responses of over 50% were reported. These are still small, early studies, but nevertheless, they're indicating that we can harness the power of the T cells to fight solid malignancies. These trials are not very easy to implement, and [if these types of therapies] become approved, they may generate some challenges as well. CAR T-cell therapy does require manufacturing, which can be logistically challenging as patients have to wait for the T cells to be made. Additionally, treatment of these patients [with CAR T-cell therapy] can be probably only applied right now in specialized centers that know how to deliver the CAR T cells and then manage of the potential toxicities, such as neurologic toxicities and cytokine release syndrome.

However, these strategies are being implemented. We are hopeful that the use of CAR T cells, as well as methods to implement them, will continue to advance and make these types of therapies more broadly applicable.

Notably, for the first time, in [February 2024,] we saw the approval of, not a CAR T-cell therapy, but another adoptive cell therapy for solid tumors, namely the tumor infiltrating lymphocyte [TIL] therapy [lifileucel (Amtagvi)] for [select patients with pretreated] unresectable or metastatic melanoma.⁶ TIL therapy was the first type of adoptive cell therapy and was on the back burner for a while, and we're excited to see that it made it to the approval stage. And again, based on some of the data in other cancers, including gynecologic cancer such as cervical cancer, demonstrating promising activity of such agents, we are hopeful that this will be the first product that paves its way for additional [adoptive cell therapies] that will be applicable to our patients.

Regarding your current research endeavors, what specific projects or areas would you like to highlight?

As part of my role [at Mount Sinai], my goal is to expand the clinical, translational, and basic research in gynecologic malignancies. For the clinical research, we are opening a number of clinical trials focusing on some of the targets that I have highlighted, as well as some of the treatment methodologies, including ADCs and bispecific antibodies in gynecologic cancers. However, I continue to be strongly involved with the cooperative groups, namely NRG Oncology, where we are continuing our collaboration with regard to both conducting clinical trials through the NRG and correlative translational research—namely, [research on how] to better understand why certain patients may respond to certain therapeutics. My personal area of interest is immune therapeutics.

This is what my laboratory is heavily focusing on, and we take advantage of patient samples that have been collected within the context of standard therapies and clinical trials to try to understand whether there are certain features of patients' tumors or other biospecimens that may distinguish patients who are more or less likely to respond. We are also trying to understand whether there are certain genetic features of tumors that make them more or less likely to be recognized by the immune system. And finally, we use a number of preclinical models such as mouse models to help us better understand the relationship between the tumor genetics and immune recognition [with the goal of developing] novel therapies.

Could you provide some insights into what we can anticipate in the field of gynecological cancers in 2024? Specifically, are there any anticipated approvals or regulatory decisions that the medical community should be aware of?

We are still waiting for some of the approvals based on the studies and endometrial cancer. For example, the [phase 3 NRG-GY018/KEYNOTE-868 trial (NCT03914612)] evaluated pembrolizumab in combination with up-front chemotherapy [in patients with endometrial cancer], and we're still not entirely sure whether that therapy will be applicable only to the patients with dMMR [disease] or also patients with pMMR [disease].

Since we do now have [more] therapies, that also generates some challenges for us in terms of trying to understand how to best sequence these regimens. On the one hand in endometrial cancer, we have immunotherapy and immunotherapy combinations, such as pembrolizumab and lenvatinib [Lenvima], and now we have emerging ADCs or other therapies targeting HER2 that may potentially be used [for these patients]. The best sequence for using all these agents is not [yet] known.

We're trying to devise novel clinical trials to test some questions, [addressing] both clinical and biological [questions] in cervical cancer that still have not been answered. For example, what is the best sequencing of radiation and immunotherapy? We know that some studies seem to suggest that radiation may be bad for the immune response because we could be killing the same immune cells that we're trying to activate. Studies from other cancers, at least with surgery, do suggest that the incorporation of immunotherapy in the neoadjuvant setting may be more beneficial than giving it concurrently or in the adjuvant setting. This is certainly a question that's worth testing in cervical cancer, and we did in a study through NRG called the phase 1 NRG-GY017 trial [NCT03738228], which seems to demonstrate that the neoadjuvant immunotherapy maybe both immunologically and clinically beneficial for patients [with locally advanced cervical cancer].

We would love to validate these findings in a larger study, particularly now since we're have an approval of immunotherapy in cervical cancer. I also look forward to data with other novel agents, such as the bispecifics and ADCs, and hopefully these data will be emerging both at upcoming [medical conferences such as] the 2024 ASCO Annual Meeting and ESMO Congress. These strategies have been shown to be quite promising for our patients, and our patients are always in need of these novel therapies.

References

1. FDA approves mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. FDA. Accessed March 22, 2024. Accessed March 28, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant-epithelial-ovarian
2. Mackensen A, Haanen JBAG, Alsdorf W, et al. BNT211-01: Interim results from a repeat dose escalation study of CLDN6 CAR-T cells manufactured with an automated process ± a CLDN6-encoding CAR-T cell-amplifying RNA Vaccine (CARVac). Ann Oncol. 2023;34(suppl 2):S1274-S1275. doi:10.1016/j.annonc.2023.10.027
3. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer. FDA. January 12, 2024. Accessed March 28, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemoradiotherapy-figo-2014-stage-iii-iva-cervical-cancer
4. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: a randomized, double-blind, phase III ENGOT-cx11/GOG-3047/ KEYNOTE-A18 study. Ann Oncol. 2023;34(S2):S1279-S1280. doi:10.1016/j.annonc.2023.10.032
5. Hassan R, Butler M, O'Cearbhaill RE, et al. Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results. Nat Med. 2023;29(8):2099-2109. doi:10.1038/s41591-023-02452-y
6. FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed March 28, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma