Studies reported at the European Society for Medical Oncology (ESMO) Congress 2024 reveal new groups of women with early-stage cervical1 and endometrial cancers2 who gain clinically meaningful benefit from adding immunotherapy to current standard treatments, and a first-in-human study found “promising” antitumor activity with a novel antibody-drug conjugate targeting the protein claudin 6 in heavily pretreated patients with ovarian and endometrial cancers.3
Addition of Immunotherapy
Results from a phase III randomized double-blind study in high-risk locally advanced cervical cancer showed that the immune checkpoint inhibitor pembrolizumab plus concurrent chemoradiotherapy achieved a significant and clinically meaningful improvement in overall survival.1 The 3-year overall survival rate was 82.6% in patients randomly assigned to pembrolizumab compared with 74.8% in the placebo group (P = .0040); all patients also received chemoradiotherapy.
Isabelle Ray-Coquard, MD, PhD
“The benefit in terms of improved overall survival should change our practice as soon as possible,” said Isabelle Ray-Coquard, MD, PhD, President of the Group d’Investigateurs National Evaluation des Cancers de l’Ovaire (GINECO), Centre Leon Bérard, Université Claude Bernard, Lyon, France. “Immunotherapy plus chemoradiotherapy provides a new standard of care for patients with high-risk locally advanced cervical cancer,” she stated. “In the initial setting, current treatments such as radiochemotherapy are able to cure this disease but with considerable side effects for patients. We need to increase the chances to be cured with new treatment options that are better tolerated. Further research should pinpoint subgroups of patients with localized disease who particularly benefit from immunotherapy, as well as determine the best treatments to combine with immunotherapy in the future to optimize outcomes.”
In this regard, another phase III randomized study in women newly diagnosed with high-risk endometrial cancer found that adding pembrolizumab to chemotherapy after surgery did not improve disease-free survival.2 However, subgroup analysis revealed that patients with deficient mismatch–repair (dMMR) tumors showed clinically meaningful improvements in disease-free survival with immunotherapy.
Elene Mariamidze, MD
“Although this trial is not positive in the study population as a whole, it gives us important information indicating that patients with endometrial dMMR tumors are more sensitive and reactive to immunotherapy,” said Elene Mariamidze, MD, a medical oncologist, Todua Clinic, Tbilisi, Georgia, and President of the Georgian School of Oncology. She suggested that the results will guide future research with immunotherapy in early-stage endometrial cancer.
While acknowledging immunotherapy is beneficial in some gynecologic cancers, Dr. Ray-Coquard agrees that it is not for all patients. “We need to focus on which subgroups of patients with particular gynecologic cancers benefit from immunotherapy. Findings on the subgroup with newly diagnosed endometrial dMMR tumors offer a powerful example that identifying a good biomarker enables us to change a patient’s story definitively,” she added.
Antibody-Drug Conjugate
A first-in-human phase I study of TORL-1-23, an antibody-drug conjugate targeting the protein claudin 6, showed good tolerability and antitumor activity in heavily pretreated patients with ovarian and endometrial cancers that expressed the protein.3 Claudin 6 is aberrantly expressed in many cancers, including ovarian and endometrial cancers. The researchers reported that the study, which also included patients with testicular cancer and non–small cell lung cancer, showed “promising preliminary antitumor activity.”
“Although at an initial stage, this study is very interesting for several reasons,” said Dr. Ray-Coquard. “First, it paves the way for a new target for antibody-drug conjugates in gynecologic cancers, where we currently have very few validated ones. Second, the findings suggest potential efficacy in ovarian cancer, a disease for which we currently have very few treatment options.” She considered that claudin 6 is of particular interest as a treatment target because its expression is very low in healthy cells. This means that targeting claudin 6 in cancer cells may reduce the risk of harming the healthy ones, thereby limiting the treatment’s toxicity. “The next step will be to confirm the response and the duration of response and assess the effect on progression-free survival in a larger group of patients with ovarian cancer and to test the safety and efficacy in a phase III randomized clinical trial,” Dr. Ray-Coquard added.
Looking to the future, Dr. Mariamidze said: “I think combination therapies will be the future in gynecologic cancers, potentially involving combinations of immunotherapy with chemotherapy or radiotherapy and targeted agents. There is also significant room for growth in developing personalized medicines, such as neoantigen vaccines and personalized immunotherapy-based on tumor type and molecular characteristics.”
“The studies presented at ESMO 2024 mark important progress in gynecologic cancer research, suggesting that several new treatment options may soon be available, which is very good for our patients. The development of new therapies such as immune therapy will offer the chance to cure more [patients with] early-stage gynecologic cancer and potentially with new [antibody-drug conjugates] to prolong overall survival,” Dr. Ray-Coquard concluded.
DISCLOSURE: For full disclosures of all study authors, visit cslide.ctimeetingtech.com/esmo2024/attendee/confcal/session.
REFERENCES
1. Lorusso D, Xiang Y, Hasegawa K, et al: Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: Overall survival results from the randomized, double-blind phase 3 ENGOT-CX11/GOG-3047/KEYNOTE-A18 study. ESMO Congress 2024. Abstract 709O. Presented September 15, 2024.
2. Van Gorp T, Rob L, Lu W, et al: ENGOT-EN11/GOG-3052/KEYNOTE-B21: A phase 3 study of pembrolizumab or placebo in combination with adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. ESMO Congress 2024. Abstract LBA28. Presented September 15, 2024.
3. Konecny GE, Wahner Hendrickson AE, Winterhoff B, et al: Phase I, two-part, multicenter, first-in-human (FIH) study of TORL-1-23, a novel claudin 6 (CLDN6) targeting antibody drug conjugate in patient with advanced solid tumors. ESMO Congress 2024. Abstract 721MO. Presented September 15, 2024.
