Studies presented at the 2024 annual meeting of the European Society for Medical Oncology (ESMO), held in Barcelona, Spain, September 13 – 17, 2024, show that new groups of women with early-stage endometrial [1] and cervical cancers [2] may gain clinically meaningful benefit from adding immunotherapy to current standard-of-care treatments, while a first-in-human study found promising antitumor activity with a novel antibody-drug conjugate (ADC) targeting claudin-6 (CLDN6) in heavily pretreated patients with ovarian and endometrial cancers. [3]
Gynecological cancers, including endometrial and cervical cancers, remain a leading cause of cancer deaths and a major challenge to women’s health worldwide. [4] Immunotherapy has greatly improved survival in many people with different cancers such as melanoma, but results have been more variable in those with gynecological cancers, so there is a lot of interest in determining how best to use immunotherapy in these patients.
Improved survival
Results from the randomized double-blind phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial (NCT04221945) in adult patients (age ≥18 years) at 176 medical centers in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer showed that pembrolizumab (Keytruda®; Merck & Co/MSD) plus concurrent chemoradiotherapy achieved a significant and clinically meaningful improvement in overall survival. [2] The 3-year overall survival rate was 82.6% in patients randomized to pembrolizumab compared to 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,” noted Professor 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, not involved in the study.
“Immunotherapy plus chemoradiotherapy provides a new standard of care for patients with high-risk locally advanced cervical cancer,” Ray-Coquard added.
“In the initial setting, current treatments such as radiochemotherapy can cure this disease but with considerable side effects for patients,” Ray-Coquard explained.
“We need to increase the chances to be cured with new treatment options that are better tolerated,” she added:
“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,” she concluded.
High-risk endometrial
Another phase 3 randomized study, the ENGOT-en11/GOG-3053/KEYNOTE-B21 trial (NCT04634877) in women newly diagnosed with high-risk endometrial cancer found that adding the immune checkpoint inhibitor pembrolizumab to chemotherapy (carboplatin-paclitaxel) after surgery did not improve disease-free survival (DFS). [1] However, subgroup analysis revealed that patients with deficient mismatch repair (dMMR) tumors showed clinically meaningful improvements in disease-free survival with immunotherapy.
The study randomized 1095 patients to receive either pembrolizumab (n = 545) 200 mg or placebo, (n = 550) every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per assigned treatment.
The interim analysis showed 119 (22%) DFS events in the pembrolizumab group and 121 (22%) in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Following Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). The study included patients with histologically confirmed high-risk stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, without prior radiotherapy or systemic therapy.
“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, at the Todua Clinic in Tbilisi, Georgia and president of the Georgian School of Oncology, who was not involved in the study either.
She suggested that the results will guide future research with immunotherapy in early-stage endometrial cancer.
While acknowledging immunotherapy is beneficial in some gynecological cancers, Ray-Coquard agrees that it is not necessarily true for all patients.
“We need to focus on which subgroups of patients with particular gynecological 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,” Mariamidze added.
“New treatment options for women with gynecological cancers to improve outcomes are key,” 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, underscoring the need to develop new therapies that are both more effective and also with lower toxicity,” she said.
Good tolerability and antitumor activity
Updated results from the first-in-human phase 1 TORL123-001 (TRIO-049) trial (NCT05103683) investigating TOTL-1-23 (see: ADC Drugmap) in patients diagnosed with advanced or metastatic cancer, showed good tolerability and antitumor activity in heavily pretreated patients with ovarian and endometrial cancers that expressed claudin-6 (CLDN6). [3]
Claudin-6 (CLDN6) is a tumor-specific transmembrane protein of tight junctions important for cell-to-cell connectivity. Overexpression of Claudin-6 (CLDN6) is implicated in the initiation, progression, and metastasis of certain cancers, including ovarian, non-small cell lung, endometrial, testicular, and others. High expression correlates with shortened survival outcomes for patients with ovarian cancer.
TORL-1-23 is an antibody-drug conjugate (ADC) that consists of a fully humanized IgG1 (TORL-1-23-MAb) linked to monomethyl auristatin E (MMAE) through a cathepsin hydrolyzable dipeptide VC linker (vc-MMAE) and targets claudin-6 (CLDN6).
TORL-1-23 binds to claudin-6 (CLDN6) with a high affinity and specificity with rapid ADC-CLND6 complex internalization and release of an MMAE payload which disrupts the microtubule network leading to cell cycle arrest and apoptosis.
The results of the ongoing phase 1 study of heavily pretreated claudin-6 positive (CLDN6) platinum-resistant/refractory ovarian cancer (PROC) patients showed encouraging antitumor activity with ‘deep and durable confirmed responses’ at doses of 2.4 mg/kg and 3.0 mg/kg every 3 weeks (Q3W) in 45% of participating patients (9/20). The median duration of response exceeded 6 months at both dose levels.
The researchers reported that the study, which also included patients with testicular cancer and non-small cell lung cancer, showed promising preliminary antitumor activity.
“The emerging Phase 1 profile of TORL-1-23 suggests that this ADC may achieve that goal for patients with platinum-resistant ovarian cancer, a serious unmet medical need,” noted Dennis Slamon, MD, PhD, Professor of Medicine, and Chief of the Division of Hematology/Oncology at UCLA’s David Geffen School of Medicine.*
“Although at an initial stage, this study is very interesting for several reasons,” Ray-Coquard, explained
“Firstly, it paves the way for a new target for antibody-drug conjugates in gynecological cancers, where we currently have very few validated ones. Secondly, the findings suggest potential efficacy in ovarian cancer, a disease for which we currently have very few treatment options,” she added.
Ray-Coquard considered that claudin-6 (CLDN6) is of particular interest as a treatment target because its expression is very low in healthy cells. This means that targeting claudin-6 (CLDN6) in cancer cells can 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 (PFS) in a larger group of patients with ovarian cancer and to test the safety and efficacy in a phase 3 randomized clinical trial,” Ray-Coquard added.
Future development
“I think combination therapies will be the future in gynecological 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,” Mariamidze said.
“The studies presented at ESMO 2024 mark important progress in gynecological 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 early-stage gynecological cancer patients and potentially with new ADCs to prolong overall survival,” Ray-Coquard concluded.
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Note: * Through a strategic partnership with the Slamon Research Lab at UCLA, TORL Biotherapeutics has exclusive development and commercial rights to a large program of biologics-based drugs for new, promising, and novel cancer targets. Dennis Slamon, MD, PhD, Professor of Medicine, and Chief of the Division of Hematology/Oncology at UCLA’s David Geffen School of Medicine is the Scientific Co-founder of the company.
Clinical trials
Study of Chemoradiotherapy With or Without Pembrolizumab (MK-3475) For The Treatment of Locally Advanced Cervical Cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11/GOG-3047) – ClinicalTrials.gov ID NCT04221945
Study of Pembrolizumab (MK-3475) in Combination With Adjuvant Chemotherapy With or Without Radiotherapy in Participants With Newly Diagnosed Endometrial Cancer After Surgery With Curative Intent (MK-3475-B21 / KEYNOTE-B21 / ENGOT-en11 / GOG-3053) – ClinicalTrials.gov ID NCT04634877
First in Human Study of TORL-1-23 in Participants With Advanced Cancer – ClinicalTrials.gov ID NCT05103683
Highlights of Prescribing Information
Pembrolizumab (Keytruda®; Merck & Co/MSD) [Prescribing Information]
References
[1] 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. LBA28 presented at the ESMO Congress 2024 (13-17 September), Proffered Paper Session on Sunday, 15 September, 14:45 – 16:15 (CEST) in the Sevilla Auditorium – Hall 2.
[2] 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. Abstract 709O presented at the ESMO Congress 2024 (13-17 September), Presidential Symposium 1 on Saturday, 14 September, 16:30-18:15 (CEST) in the Barcelona Auditorium – Hall 2.
[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 (ADC) in patient with advanced solid tumors. Abstract 721MO presented at the ESMO Congress 2024 (13-17 September), Mini Oral Session on Sunday, 15 September, 14:45 – 16:15 (CEST) in the Santander Auditorium – Hall 5.
[4] Jiang G, Wu Q and Li B. Evaluation of immunotherapy efficacy in gynecologic cancer. Frontiers in Immunology. 2023. DOI 10.3389/fimmu.2023.1061761
Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.
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