Dr Zamarin on Recent Updates in Endometrial Cancer

Dmitriy Zamarin, MD, PhD, section head, Gynecologic Medical Oncology, member, the Icahn Genomics Institute, member, the Precision Immunology Institute, the Tisch Cancer Institute at Icahn School of Medicine, Mount Sinai, 

discusses the most recent advances in gynecologic cancer

Reflecting on recent strides in gynecologic cancer treatment, particularly those that have been achieved within the past 6 months, prompts a discussion on the developments deemed most influential in shaping clinical practice, Zamarin begins. Commencing with endometrial cancer, notable excitement has surrounded advancements in the past year. Specifically, the combination of PD-1 inhibitors, including pembrolizumab (Keytruda) and dostarlimab-gxly (Jemperli), alongside upfront chemotherapy in patients with advanced endometrial cancer has set new treatment benchmarks, he elucidates. These therapeutic approaches have become standard practice, particularly for patients with mismatch repair–deficient endometrial cancers, Zamarin states.

However, challenges persist for patients with the more prevalent mismatch repair–proficient subtype of endometrial cancer, according to Zamarin. Although some data indicate the potential benefits of incorporating immunotherapy agents into the treatment armamentarium for this disease subset, discerning which patients derive the most benefit remains challenging, he emphasizes, adding that the existing body of research provides a springboard for further exploration into biomarkers within this patient cohort, leveraging existing patient samples to address these lingering questions in the years ahead.

Moreover, notable strides have been made in endometrial cancer management through the exploration of antibody-drug conjugates (ADCs), Zamarin continues. Although awaiting FDA approval for patients with endometrial cancer, these agents have demonstrated promising results by targeting various surface markers on endometrial cancer cells, he says. Among these, fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), a HER2-targeted ADC, has shown significant activity in high-grade endometrial cancer, such as carcinosarcoma, where treatment options are typically limited, Zamarin says.

T-DXd has already earned recognition in the National Comprehensive Cancer Network Guidelines as a viable treatment option for patients with endometrial cancer. Anticipation mounts for forthcoming data with other ADCs targeting HER2 and other markers, such as B7-H4 and TROP2, heralding a promising frontier in endometrial cancer therapeutics, he concludes.

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Dmitriy Zamarin, MD, PhD, discusses the most recent advances in gynecologic cancer management, particularly in endometrial cancer.

Dmitriy Zamarin, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, discusses ongoing work with immunotherapy in patients with ovarian cancer.

Several studies have attempted to define the role of checkpoint inhibitors in both the newly diagnosed and advanced settings, Zamarin says. Most of these studies have been done in patients with advanced platinum-resistant disease. There was initial excitement with these trials, but single-agent anti—PD-1/PD-L1 has only demonstrated response rates of approximately 10%. Researchers also don’t have an effective biomarker for immune response.

However, even if researchers can tailor immunotherapy to a biomarker-selected patient population, about 90% of patients with ovarian cancer will be left without effective treatment. Thus, ongoing research is combining checkpoint inhibition with chemotherapy, a strategy that has shown particular promise in advanced lung cancer. This strategy is being tested in newly diagnosed and recurrent ovarian cancer.

Dmitriy Zamarin, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, discusses ongoing work with immunotherapy in patients with advanced ovarian cancer.

Dr. Zamarin Discusses Ongoing Work With Immunotherapy in Ovarian Cancer

Dmitriy Zamarin, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, discusses priming strategies in ovarian cancer.

Priming strategies aim to induce an immune response, explains Zamarin. Traditionally, priming has been considered in terms of vaccines, in which administering an antigen was thought to induce an immune response that would cross-react with a patient’s tumor. Now, there are a variety of strategies that are being explored in gynecologic cancers, starting with peptide vaccines or whole proteins vaccines, primarily targeting antigens that are known to be overexpressed in ovarian cancer, such as NY-ESO-1, says Zamarin. Although these vaccines have not been effective as single agents, combination strategies with immune checkpoint inhibitors may prove to be effective.

Many other ongoing studies are aiming to address this question in the advanced setting, and occasionally, in patients with minimal or no residual disease after completing upfront chemotherapy, or chemotherapy in the recurrent setting. Investigators are hopeful that the introduction of some of the newer vaccination strategies, such as neoantigen-based vaccines, may show greater efficacy than what has been observed to date, adds Zamarin.

Dr. Zamarin on Priming Strategies in Ovarian Cancer

Dmitriy Zamarin, MD, PhD, a medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the role of pembrolizumab (Keytruda) for patients with endometrial cancer.

Ovarian cancer is not the only cancer that we treat with immunotherapy, explains Zamarin. Immunotherapy has been shown to be effective in endometrial cancer. Pembrolizumab has been FDA approved for microsatellite instability-high (MSI-H) endometrial cancers or for any MSI-H tumor. There is preliminary evidence that was presented, demonstrating that even in a non-MSI-H population, these immune checkpoint inhibitors can work.  

Preliminary data presented at ASCO demonstrated the combination of an immune checkpoint inhibitor with a targeted agent. According to Zamarin, when lenvatinib (Lenvima) was combined with pembrolizumab, the response rate was 50%. 

Dr. Zamarin on the Role of Pembrolizumab in Endometrial Cancer

Dmitriy Zamarin, MD, PhD, a medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the future treatment landscape for patients with gynecologic malignancies.

According to Zamarin, the first drugs that will be approved will be more of the standard off-the-shelf treatments, such as immune checkpoint blockade or vaccines.

The adoptive T-cell therapies will be are more involved and more expensive, states Zamarin. The recent product that was approved from Novartis for the treatment of patients with leukemia is very expensive per treatment, which may become a limitation of choosing some of these therapies. If the therapies resolve in long-term disease stabilization or even cures of these patients, perhaps these types of treatments will justify the costs, explains Zamarin.

Dr. Zamarin on the Future Treatment Landscape of Gynecologic Malignancies

Dmitriy Zamarin, MD, PhD, a medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the role of vaccines for patients with cervical cancer.

Cervical cancer presents itself as a good candidate for a vaccine-type of therapy because the majority of tumors are HPV-driven, explains Zamarin.

There are several vaccines that have been demonstrated to elicit specific immune responses. There is a vaccine from Inovio called VGX-3100 that was effective in the precancerous setting in patients with CIN 2/3, states Zamarin. This could then be effective in advanced settings.

Dr. Zamarin on the Role of Vaccines in Cervical Cancer

Dmitriy Zamarin, MD, PhD, a medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) in endometrial cancer.

This combination has been evaluated in patients with endometrial cancer and renal cell carcinoma, results of which were presented at the 2017 ASCO Annual Meeting and the 2017 EMSO Congress, respectively. Results in both trials demonstrated promising response rates and progression-free survival, Zamarin says.

The rationale for combining these drugs is not completely clear, says Zamarin, but these trials prove how little is known about the potential of drugs not initially developed to target the immune system.

Dr. Zamarin on Lenvatinib Plus Pembrolizumab in Endometrial Cancer

Dmitriy Zamarin, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses some of the novel approaches with immunotherapy that he would like to explore in the future treatment of patients with gynecologic cancers.

According to Zamarin, we are only just beginning to scratch the surface of immunotherapeutic regimens in this space. Combination treatments involving PD-1/PD-L1 blocking antibodies and CTLA inhibitors are commonly investigated at the present time.

Gynecologic cancers specifically offer opportunities to assess locoregional approaches, says Zamarin. For example, locoregional intraperitoneal chemotherapy is a standard chemotherapy approach that is already approved for the treatment of patients with ovarian cancer. Generally speaking, many gynecologic cancers often spread through the peritoneum, thus supporting the rationale to explore the use of these agents directly in the peritoneal cavity. Future treatment approaches should continue to investigate this, he says.

Dr. Zamarin on Novel Immunotherapy Approaches in Gynecologic Cancers

Dmitriy Zamarin, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the ways in which immunotherapy is slated to play a major role in multiple cancer types.

According to Zamarin, once the efficacy of these agents is confidently established in more advanced settings, they will certainly move up into earlier lines of treatment. Oncologists currently strive to enhance the immune response to these cancers in order to prevent the disease from coming back. However, Zamarin speculates that the real value of immunotherapy may lie not necessarily in its ability to prolong survival in patients who already have metastatic disease, but instead in its efficacy in preventing the metastatic disease from developing in the first place.

While checkpoint blockade inhibitors targeting the PD-1/PD-L1 pathway tend to dominate the field, there are several other exciting approaches to anticancer immunotherapy being explored in a range of solid tumors.

For example, anticancer vaccines are rapidly expanding. Vaccines can enhance the recognition of tumor antigens by the immune system through many strategies, including DNA-encoded vaccines and virus-vectored vaccines, as well as through wholly modified tumor cells, tumor-associated antigen or tumor-specific antigen peptides, tumor-associated antigen proteins, dendritic cells loaded with specific antigens, adjuvants, and in situ vaccinations.

With the situ vaccination approach, all of the patient’s antitumor antigens that are present at the tumor site can be exploited. Specifically, in situ vaccination can generate localized tumor lysis and T-cell activation, as well as antigen release and presentation. Treatments in the in situ vaccination category include local ablative therapies (such as radiation and cryotherapy), intratumoral cytokine injections (such as interleukin-2), intratumoral tolllike receptor agonist injections, intratumoral bacteria injections, and intratumoral virus injections.

Dmitriy Zamarin, MD, PhD

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