Reference: February 2025 | Issue 2 | Vol 11 | Page 3
The European Society for Medical Oncology (ESMO) Congress 2024, which took place from 13-17 September in Barcelona, Spain, offered a comprehensive view of the current oncology drug development landscape, with existing medicines demonstrating benefit in additional applications and new agents emerging in large numbers as the range of potential molecular targets for therapy continues to expand.
At the opening press conference of ESMO’s flagship annual event, wide-sweeping progress made with novel immunotherapy combinations was highlighted, alongside results that prefigure how cancer diagnosis and treatment could be transformed in the future.
ESMO 2024 Scientific Chair Dr Rebecca Dent underlined the importance of the overall survival data presented from the KEYNOTE-522 study in triple negative breast cancer subtype. Dent similarly highlighted that for bladder cancer, where treatment options were limited in the past, the positive phase 3 NIAGARA trial marks another milestone in a recent surge of research advances already reported at the ESMO Congress 2023.
In anal cancer, a disease usually diagnosed in the advanced stages and where rates of relapse on standard treatment with chemoradiotherapy are high, a combination of immunotherapy and chemotherapy is opening up new, much-needed possibilities for patients.
As ESMO President Dr Andrés Cervantes explained: “POD1UM-303/InterAACT 2 is the first phase 3 randomised controlled trial, not just of immunotherapy, but overall in this tumour type. Though uncommon in the developed world, anal cancer is more prevalent in low- and middle-income countries and, alongside HPV vaccination as an effective means of prevention, this is an important step in treating a disease that is currently still managed with medicines developed 50 years ago.”
Important data was also presented on the long-term outcomes of the first cohort of patients with melanoma treated with immunotherapy, providing novel insights into its survival benefits and toxicities. “The arrival of immune checkpoint inhibitors and combination therapies dramatically changed the situation for melanoma patients, who previously had few treatment options and poor life expectancy.
“Talking about 10-year survival outcomes is outstanding in and of itself, but as clinicians we also need to understand what happens to these patients over time to be able to better differentiate whom to give which treatment to based on the expected benefits,” Dr Dent explained.
With several phase 3 trials reporting positive results, patients with metastatic castration-resistant prostate cancer will benefit from new treatments options going forward. “Prostate cancer is very common, so it is exciting to see research producing a multitude of therapies to help patients beyond castration resistance, including a novel combination of the androgen receptor antagonist enzalutamide with radium 22, combination immunotherapy, and several new compounds,” said Dr Dent.
Research introducing antibody-drug conjugates (ADCs) has been equally prolific, with over 100 agents currently under development. Data presented at ESMO 2024 covered the entire spectrum of phase 1, phase 2, and phase 3/4 trials.
“ADCs are a smart way of delivering chemotherapy as the antibodies it is bound to in a complex molecular structure deliver their payload directly inside the tumour cells they recognise, preserving healthy tissue and thus offering reduced toxicity alongside potentially higher antitumour activity,” said Dr Cervantes.
While many research results presented over the five days of the Congress will change clinical practice in the short-term, the event also provided a perspective on the directions in which oncology will evolve in the future during a dedicated Presidential Symposium. Dr Cervantes highlighted artificial intelligence for its potential to be applied to medical images, not just from radiology devices, but also from pathology slides, to capture information that the human eye cannot and eventually facilitate better diagnosis, treatment, and follow-up.
The ESMO President took the opportunity to announce the launch of a new ESMO AI and Digital Oncology Congress in 2025. “ESMO has a responsibility to keep doctors updated on what is happening in these areas, which are going to transform the way we receive information about cancer and the way we make decisions in oncology,” he said, explaining the rationale for the new event.
The Congress also addressed current issues affecting the profession. Among these, ensuring the resilience and wellbeing of the cancer workforce in the face of increasing pressures from staff shortages and rising workloads was the subject of a dedicated session. A vital message in this regard was conveyed in the recently published ESMO Resilience Task Force recommendations to manage psychosocial risks, optimise well-being, and reduce burnout in oncology, which included a proposal for multi-tiered, concerted action to support and retain oncologists in the field.
“We cannot afford to lose our workforce, so we must raise awareness and tackle burnout as the common problem that it has become,” said Dr Cervantes.
With a wealth of high-quality data selected from over 5,000 submitted abstracts, and 600 experts onsite to present and discuss the latest research results with 33,000 registered attendees, the 2024 ESMO Congress was a record-breaking meeting. “These unprecedented figures illustrate the strength and the global reach of this meeting in delivering new science to the oncology community,” Dr Cervantes concluded.
Expanding indications for immunotherapy – results from CheckMate 067, KEYNOTE-522, and NIAGARA trials
Immunotherapy improves long-term overall survival in patients with advanced melanoma, according to the results of a number of large international studies reported at ESMO 2024.
Researchers leading the longest follow-up study to date suggest that immunotherapy offers the potential for cure in patients who respond to this treatment. Further clinical trials reported at ESMO 2024 show improved long-term survival with immunotherapy given before and after surgery in women with early-stage, triple negative breast cancer, and in patients with muscle-invasive bladder cancer.
“The main message from all of these studies is that immunotherapy continues to keep its promise and hope of long-term survival for many patients with different types of cancer,” said Dr Alessandra Curioni-Fontecedro, Professor of Oncology at the University of Fribourg and director of oncology at the Hospital of Fribourg, Switzerland, not involved in the study. “At ESMO 2024 we are seeing many studies in many different cancers showing that immunotherapy can work for a long time.”
Results of the CheckMate 067 trial of immunotherapy with an anti-programmed death (PD)-1-based therapy showed continued long-term survival benefit in patients with advanced melanoma. After follow-up of at least 10 years, the median overall survival was 71.9 months in patients randomised to combination immunotherapy with nivolumab plus ipilimumab. The researchers suggested that there is now a potential for cure in patients responsive to these treatments.
“The results from this trial confirm the potential for cure with immunotherapy in patients with advanced melanoma,” said Dr Marco Donia, Associate Professor of Clinical Oncology at the National Centre for Cancer Immune Therapy of Denmark, Copenhagen University Hospital Herlev, Denmark, who was not a study author. He added: “For patients who show no disease progression beyond three years, these longer-term results demonstrate that most of them never progress. The melanoma-specific survival is very high in this group of patients.”
Importantly, the long-term survival benefit with immunotherapy is also seen in routine clinical practice, outside clinical trials, Dr Donia continued. “Immunotherapy has transformed advanced melanoma from something that was previously a deadly disease with a median survival of less than one year to what we see today, with half of patients surviving for many years.”
He considered this raises practical questions about how best to follow these patients up, including whether they need long-term check-ups. “It also supports their right ‘to be forgotten’ as former cancer patients after five years of being cancer-free following the end of treatment, so they don’t suffer discrimination compared to the general population when seeking financial credit.”
Improved overall survival with immunotherapy was also reported in early-stage triple negative breast cancer (TNBC). Results showed a statistically significant and clinically meaningful improvement in overall survival with immunotherapy plus chemotherapy before surgery and continued immunotherapy after surgery; the five-year overall survival rate was 86.6 per cent in patients given immunotherapy and 81.2 per cent in the placebo group.
“This study shows improvements with immunotherapy in patients with the most aggressive subtype of breast cancer, where previously we could only offer chemotherapy,” said Dr Curioni-Fontecedro. “We had thought that breast cancer may not be sensitive to immunotherapy alone, but giving it in combination with chemotherapy before surgery and then further afterwards improves overall survival in many patients. The finding suggests the possibility that the combination of treatments might lead to a sensitisation of TNBC to immunotherapy.”
A similar improvement in overall survival was seen with immunotherapy before surgery in a study of patients with muscle-invasive bladder cancer. The phase 3 NIAGARA study randomised patients to immunotherapy with durvalumab plus chemotherapy before radical cystectomy followed by continued immunotherapy or to chemotherapy alone before surgery.
Patients treated with immunotherapy showed significantly longer event-free survival (HR 0.68; 95% CI 0.56-0.82; P<0.001) and overall survival (HR 0.75; 95% CI 0.59-0.93; P=0.0106) compared to those receiving chemotherapy alone. The researchers noted that giving immunotherapy before surgery did not compromise the ability to perform radical cystectomy, which was completed in 88 per cent of the immunotherapy group and 83 per cent of the comparator arm.
Looking to the future, Dr Curioni-Fontecedro said some major questions remain unanswered. “The first is understanding why cancers recur in some patients despite initial response to immunotherapy. We still don’t understand how resistance to immunotherapy can occur in some patients. We need to understand what happens in these patients, what are the mechanisms of resistance and how we can overcome them.”
She suggested that it is important that clinical researchers and pharmaceutical companies all work together to approach the issue of resistance to immunotherapy effectively. “As long as the issue of resistance is investigated in isolation, looking at individual immunotherapy agents, it will not be enough. We should all put our forces together to improve understanding and promote better treatment for the future.”
New treatments for gynaecological cancers on the horizon
Gynaecological cancers, including endometrial and cervical cancers, remain a leading cause of cancer deaths and a major challenge to women’s health worldwide. Immunotherapy has greatly improved survival in many cancers, but results have been more variable in gynaecological cancers.
Results from a phase 3 randomised double-blind study in high-risk locally advanced cervical cancer showed that pembrolizumab plus concurrent chemoradiotherapy achieved a significant and clinically meaningful improvement in overall survival. The three-year overall survival rate was 82.6 per cent in patients randomised to pembrolizumab compared to 74.8 per cent in the placebo group (P=0.004). 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), Centre Leon Bérard, Université Claude Bernard, Lyon, France, who was not involved in the study.
“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,” she added.
“Further research should pinpoint subgroups of patients with localised disease who particularly benefit from immunotherapy, as well as determine the best treatments to combine with immunotherapy in the future to optimise outcomes.”
In this regard, another phase 3 randomised study in women newly diagnosed with high-risk endometrial cancer found that adding the immune checkpoint inhibitor pembrolizumab to chemotherapy post-surgery did not improve disease-free survival. However, subgroup analysis revealed that patients with deficient mismatch repair (dMMR) tumours showed clinically meaningful improvements in disease-free survival with immunotherapy.
“Although this trial is not positive in the study population as a whole, it gives us important information indicating that patients with endometrial dMMR tumours are more sensitive and reactive 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. She suggested that the results will guide future research with immunotherapy in early-stage endometrial cancer.
While acknowledging immunotherapy is beneficial in some gynaecological cancers, Dr Ray-Coquard agreed that it is not for all patients. “We need to focus on which subgroups of patients with particular gynaecological cancers benefit from immunotherapy. Findings on the subgroup with newly diagnosed endometrial dMMR tumours offer a powerful example that identifying a good biomarker enables us to change a patient’s story definitively,” she added.
“New treatment options for women with gynaecological cancers to improve outcomes are key,” emphasised Dr Mariamidze. “Fewer treatment options are available for gynaecological cancers compared to other cancers, such as breast cancer. Many gynaecological 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 a lower toxicity.”
A first-in-human phase I study of TORL-1-23, an antibody drug conjugate (ADC) targeting the protein claudin 6, showed good tolerability and antitumour activity in heavily pre-treated patients with ovarian and endometrial cancers that expressed the protein. The researchers reported that the study, which also included patients with testicular cancer and non-small cell lung cancer, showed “promising preliminary antitumour activity”.
“Although at an initial stage, this study is very interesting for several reasons,” said Dr Ray-Coquard. “Firstly, it paves the way for a new target for antibody-drug conjugates in gynaecological 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 said claudin 6 is of particular interest as a treatment target because its expression is very low in healthy cells, thereby limiting treatment 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 3 randomised clinical trial,” Dr Ray-Coquard added.
Dr Mariamidze said: “I think combination therapies will be the future in gynaecological cancers, potentially involving combinations of immunotherapy with chemotherapy or radiotherapy and targeted agents. There is also significant room for growth in developing personalised medicines, such as neoantigen vaccines and personalised immunotherapy based on tumour type and molecular characteristics.”
The studies presented at ESMO 2024 mark important progress in gynaecological 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 gynaecological cancer patients and potentially with new ADCs to prolong overall survival,” Dr Ray-Coquard concluded.
