Immunotherapy enables the body’s immune system to recognize and destroy cancer cells and improves long-term overall survival in patients with advanced melanoma as reported in results from large international studies presented at the 2024 annual meeting of the European Society for Medical Oncology (ESMO), held in Barcelona, Spain, September 13 – 17, 2024. [1][2]
Researchers leading the longest follow-up study to date suggest that immunotherapy offers the potential for cure in patients who respond to this treatment. [1] Further clinical trials reported at ESMO 2024 showed improved long-term survival with immunotherapy given before and after surgery in women with early-stage, hard-to-treat triple-negative breast cancer (TNBC) and in patients with muscle-invasive bladder cancer. [3][4]
“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,” noted Alessandra Curioni-Fontecedro, MD, professor of oncology at the University of Fribourg and director of oncology at the Hospital of Fribourg, Switzerland, who was 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,” she added.
Results of a phase 3 trial of immunotherapy with an anti-programmed death (PD)-1-based therapy showed continued long-term survival benefits in patients with advanced melanoma. [1] After a follow-up of at least 10 years, the median overall survival was 71.9 months (about 6 years) in patients randomized to combination immunotherapy with nivolumab (Opdivo®; Bristol-Myers Squibb) plus ipilimumab (Yervoy®; Bristol-Myers Squibb) in the CheckMate 067 trial (NCT01844505). Very few of the patients showing good initial response to anti-PD-1-based immunotherapy, with no disease progression for at least 3 years, had died of melanoma at 10 years (10-year melanoma-specific survival rate 96%). The researchers suggested that there is now a potential for cure in patients responsive to these treatments.
“The results from this trial do confirm the potential for cure with immunotherapy in patients with advanced melanoma,” agreed Marco Donia, MD, PhD, associate professor of clinical oncology at the National Center for Cancer Immune Therapy of Denmark, Copenhagen University Hospital Herlev, Denmark, who was not a study author either.
“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,” Donia added.
“Importantly, the long-term survival benefit with immunotherapy is also seen in routine clinical practice, outside clinical trials,” 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 said.
Donia considered that 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.”
Triple-negative breast cancer
Improved overall survival with immunotherapy was also reported in early-stage TNBC and muscle-invasive bladder cancer. Triple-negative breast cancers are particularly difficult to treat because they do not have estrogen or progesterone receptors or raised HER2 levels, so fail to respond to commonly used breast cancer treatments. 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% in patients given immunotherapy and 81.2% in the placebo group. [3]
“This study shows improvements with immunotherapy in patients with the most aggressive subtype of breast cancer, where previously we could only offer chemotherapy,” Curioni-Fontecedro explained.
“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 sensitization of TNBC to immunotherapy,” she added.
Neoadjuvant treatment of bladder cancer
A similar improvement in overall survival with neoadjuvant immunotherapy (i.e. before surgery) was seen in a study of patients with muscle-invasive bladder cancer. The global open-label, multi-center phase-3 NIAGARA study (NCT03732677) randomized patients to immunotherapy with durvalumab (Imfinzi®; AstraZeneca), which binds to B7H1 antigen and blocks B7H1 signaling that may activate the immune system to attack tumor cells, plus chemotherapy before radical cystectomy followed by continued immunotherapy or to only chemotherapy before surgery.
Patients treated with immunotherapy showed significantly longer event-free survival (hazard ratio 0.68 [95% confidence interval 0.56-0.82] p<0.001) and overall survival (hazard ratio 0.75 [95% CI 0.59-0.93] p=0.0106) compared to those receiving chemotherapy alone. [4] The researchers noted that giving immunotherapy before surgery did not compromise the ability to perform radical cystectomy, which was completed in 88% of the immunotherapy group and 83% of the comparator arm.
Future approach
“We still have some major unanswered questions. 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,” Curioni-Fontecedro said.
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,” she concluded.
__
Note: * In October 2023, the European Society for Medical Oncology (ESMO) called for all European member states to adopt final the EU Consumer Credits Directive and guarantee cancer survivors seeking financial credit the so-called right to be forgotten after five years following the end of their treatment. The five-year mark constitutes a pragmatic, reasonable threshold supported by scientific evidence, for omitting cancer-related health data from assessments of creditworthiness.
Clinical trials
Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate 067) – ClinicalTrials.gov ID NCT01844505 (CheckMate 067 trial)
Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Participants With Advanced Melanoma (MK-3475-006/KEYNOTE-006) – ClinicalTrials.gov ID NCT01866319
Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-522/KEYNOTE-522) – ClinicalTrials.gov ID NCT03036488
Durvalumab+ Gemcitabine/Cisplatin (Neoadjuvant Treatment) and Durvalumab (Adjuvant Treatment) in Patients With MIBC (NIAGARA) – ClinicalTrials.gov ID NCT03732677
Highlights of prescribing information
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]
Ipilimumab (Yervoy®; Bristol-Myers Squibb) [Prescribing Information]
Durvalumab (Imfinzi®; AstraZeneca)[Prescribing Information]
References
[1] Larkin J, Chiarion Sileni V, Gaudy Marqueste C et al. 10-y survival outcomes from the phase 3 CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma. LBA43, presented at the ESMO Congress 2024 (13-17 September), Mini Oral Session on Sunday, 15 September, 14:45-16:25 (CEST) in the Oviedo Auditorium – Hall 3.
[2] Robert C, Carlino MS, McNeil C et al. Pembrolizumab vs ipilimumab in advanced melanoma: 10-year follow-up of the phase 3 KEYNOTE-006 study. LBA44, presented at the ESMO Congress 2024 (13-17 September), Mini Oral Session on Sunday, 15 September, 14:45-16:25 (CEST) in the Oviedo Auditorium – Hall 3.
[3] Schmid P, Cortes J, Dent RA et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: overall survival results from the phase 3 KEYNOTE-522 study. LBA4, presented at the ESMO Congress 2024 (13-17 September), Presidential Symposium 2 on Sunday, 15 September, 16:30-17:50 (CEST) in the Barcelona Auditorium – Hall 2.
[4] Powles TB, van der Heijden MS, Galsky MD. A randomized phase 3 trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). LBA5, presented at the ESMO Congress 2024 (13-17 September), Presidential Symposium 2 on Sunday, 15 September, 16:30-17:50 (CEST) in the Barcelona Auditorium – Hall 2.
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.
DOI
