Studies reported at ESMO 2024 reveal new cohorts of women with early-stage endometrial and cervical cancer who derive clinically significant benefit from adding immunotherapy to current standard treatments, while a first-in-human study found ‘promising’ anti-cancer activity with a new antibody drug conjugate (ADC) targeting the claudin 6 protein in heavily pretreated ovarian and endometrial cancer patients.
Gynecological cancers, including endometrial and cervical cancers, remain the leading cause of cancer deaths and a major challenge to women’s health worldwide. Immunotherapy has significantly improved survival in many people with different cancers such as melanoma, but results have been more variable in people with gynecological cancers, so there is great interest in determining how best to use immunotherapy in these patients.
The results of a randomized, double-blind, phase 3 study in high-risk locally advanced cervical cancer showed that pembrolizumab and concurrent chemoradiotherapy achieved a significant and clinically meaningful improvement in overall survival. The 3-year overall survival rate was 82.6% in patients randomized to pembrolizumab compared with 74.8% in the placebo group (p=0.0040). all patients also received chemoradiotherapy.
“The benefit in terms of improved overall survival should change our practice as soon as possible,” said Dr. Isabelle Ray-Coquard, President of the Group d’Investigateurs National Evaluation des Cancers de l’Ovaire (GINECO), Center Leon Bérard, Université Claude Bernard, Lyon, France, who was not involved in the study. “Immunotherapy and chemoradiotherapy provide a new standard of care for patients with high-risk locally advanced cervical cancer,” he said.
In the original context, current treatments such as radiochemotherapy are able to treat this disease but with significant side effects for patients. We need to increase the chances of cure with new treatment options that are better tolerated. Further research should identify subgroups of patients with localized disease that particularly benefit from immunotherapy, as well as determine the best treatments to combine with immunotherapy in the future to optimize outcomes.”
Dr. Isabelle Ray-Coquard, President, Group d’Investigateurs National Evaluation des Cancers de l’Ovaire (GINECO), Center Leon Bérard, Université Claude Bernard
In this regard, another randomized phase 3 study in women newly diagnosed with high-risk endometrial cancer found that adding the immune checkpoint inhibitor pembrolizumab to chemotherapy after surgery did not improve disease-free survival. (1) However, subgroup analysis revealed that patients with mismatch repair-deficient (dMMR) tumors showed clinically significant improvements in disease-free survival with immunotherapy.
“Although this test 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 responsive to immunotherapy,” said Dr. Elene Mariamidze, medical oncologist, Todua Clinic , Tbilisi, Georgia. and president of the Georgian School of Oncology, who was not involved in the study either. He suggested that the results will guide future research with immunotherapy in early-stage endometrial cancer.
While she acknowledges that immunotherapy is beneficial in some gynecological cancers, Ray-Coquard agrees that it is not for all patients. “We need to focus on which subgroups of patients with specific gynecologic cancers benefit from immunotherapy. The findings for the subgroup with newly diagnosed dMMR endometrial tumors offer a strong example that identifying a good biomarker gives us the ability to permanently change a patient’s story,” he added.
“New treatment options for women with gynecological cancers to improve outcomes are essential,” Mariamidze emphasized. “Fewer treatment options are available for gynecological cancers compared to other cancers, such as breast cancer. Many gynecological cancers have high rates of recurrence even after initial successful treatment, highlighting the need to develop new treatments that are both more effective and with lower toxicity.”
A first-in-human phase I study of TORL-1-23, an antibody drug conjugate (ADC) targeting the protein claudin 6, demonstrated good tolerability and antitumor activity in heavily pretreated ovarian and endometrial cancer patients expressing the protein. (3) Claudin 6 is aberrantly expressed in many cancers, including ovarian and endometrial cancers. The researchers said the study, which also included patients with testicular cancer and non-small cell lung cancer, showed “promising preliminary antitumor activity.”
“Although at an early stage, this study is very interesting for several reasons,” said Ray-Coquard. “First, it paves the way for a new target for antibody-drug conjugates in gynecological cancers, where we currently have very few validated. Second, the findings suggest potential efficacy in ovarian cancer, a disease for which we currently have very few treatment options.” He considered claudin 6 to be of particular interest as a therapeutic target because its expression is very low in healthy cells. This means that targeting claudin 6 in cancer cells can reduce the risk of harming healthy ones, thus limiting the toxicity of the treatment. “The next step will be to confirm the response and the duration of the response and to evaluate the effect on progression-free survival in a larger group of ovarian cancer patients and to test the safety and efficacy in a randomized phase 3 clinical trial,” Ray stated- Coquard added.
Looking ahead, Mariamidze said: “I believe that combination therapies will be the future in gynecological cancers, potentially involving combinations of immunotherapy with chemotherapy or radiation therapy and targeted agents. There is also significant room for growth in the development of personalized medicines such as neoantigen vaccines and personalized immunotherapy based on tumor type and molecular characteristics.”
“The studies presented at ESMO 2024 mark significant progress in gynecological cancer research, indicating that many new treatment options may soon be available, which is very good for our patients. The development of new treatments such as immunotherapy will provide the opportunity to treat more patients with early-stage gynecologic cancer and potentially with new ADCs to prolong overall survival,” concluded Ray-Coquard.
