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KEYNOTE-522 Trial KEYNOTE-522 is a prospective, randomized, placebo-controlled trial enrolling patients with stage T1cN1-2 or T2-4N0-2 TNBC (2). Participants received pembrolizumab alongside chemotherapy in the pre-operative setting, followed by adjuvant pembrolizumab for up to 9 cycles after surgery. Primary endpoints have been met and discussed at previous EMSO congresses and published in the New England Journal of Medicine, these being an increase in pathologic complete response (pCR) and event-free survival (EFS). Prof. Peter Schmid presented the secondary endpoint results, being the 5-year overall survival (OS), at this last ESMO congress 2024. The addition of pembrolizumab led to a 5% improvement in 5-year OS, corresponding to a hazard ratio of 0.66, indicating a 34% reduction in the risk of death. The correlation between pCR and OS was also confirmed, with improved OS in patients achieving pCR post-chemotherapy. Among patients not achieving pCR, those who completed 18 cycles of pembrolizumab showed a 71.8% 5-year OS, compared to 65.7% in those not receiving immunotherapy. Safety profiles were similar between the groups, with most toxicities being attributable to chemotherapy rather than pembrolizumab. Pembrolizumab has therefore now solidified its role in the treatment of high-risk, early-stage TNBC and is confirmed to be recommended as a standard of care.
NATALEE Trial The NATALEE trial investigates adjuvant ribociclib in hormone receptor-positive early breast cancer patients at high risk of recurrence (3). The trial included patients with stage IIA, node-positive disease or node-negative disease with additional risk factors, as well as patients with stages IIB and III. Patients received as adjuvant treatment either ribociclib, a CDK4/6 inhibitor, at a dose of 400 mg/day, three weeks on - one week off, in association to hormone therapy or hormone therapy alone. The study’s primary endpoint is invasive disease-free survival (iDFS). The 3-year results were discussed at a previous congress, and the 4-year results were discussed at this year’s ESMO. At 4 years, ribociclib showed a 4.9% improvement in iDFS, with survival curves continuing to separate across all evaluated subgroups, including stage II and III disease. The positive trend suggests an ongoing benefit in terms of both DFS and OS, which results are still awaited. As we could expect, ribociclib was associated with an increase rate of adverse events compared to hormone therapy only, including neutropenia, liver-related toxicities, QTc prolongation, and gastrointestinal effects. Such results suggest that ribociclib represents a valuable option in the adjuvant setting for selected high-risk hormone receptorpositive breast cancer patients.
Take-Home-Messages The findings from the HypoG-01, KEYNOTE-522, and NATALEE trials collectively affirm advancements in breast

cancer treatment. Hypofractionated radiotherapy is now recommended as standard for patients requiring nodal irradiation, pembrolizumab is confirmed as the standard of care in early-stage high-risk TNBC, and the addition of ribociclib can be considered for adjuvant treatment in selected hormone receptor-positive breast cancer patients at high risk of recurrence. These results underscore the importance of tailored, evidence-based approaches in the management of breast cancer.
Author: MD Bianca Giacomuzzi Moore, CHUV Centre hospitalier universitaire vaudois Mentor: Prof. Dr. med. Urban Novak, Inselspital Bern
References: 1. Rivera S et al.: 5-year results of the HypoG-01 phase III UNICANCER trial. Ann
Oncol. 2024;35:S309. 2. Schmid P et al.: KEYNOTE-522 Investigators. Overall Survival with Pembrolizu-
mab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med. 2024;391(21):1981-1991. 3. Hortobagyi GN et al.: A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/ HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025;36(2):149-157.
mRNAbased cancer vaccine in patients with MGMT unmethylated glioblastoma (GBM): first results from the dose escalation phase
This study presents the findings of the first-in-human investigation of the mRNA-based cancer vaccine CVGBM in patients with newly diagnosed, surgically resected, and MGMT-unmethylated glioblastoma, (GBM), a group historically characterized by poor prognosis and limited treatment options (1). The CVGBM construct encoded 8 epitopes derived from 4 GBM-relevant antigens. The primary objectives were to assess safety, tolerability, and determine the recommended dose for further evaluation. Notable secondary endpoints included time to relapse and immunogenicity. Eligible patients were newly diagnosed, MGMT-unmethylated, and HLA-A*02:01-positive, having completed post-surgical radiotherapy, irrespective of chemotherapy use. Participants received seven intramuscular doses over 10 weeks, with optional maintenance vaccinations. IFN-γ ELISpot analysis indicated that 77% of patients exhibited antigen-specific T cell responses, with 84% showing de novo immune activation. Among evaluable patients, 69% demonstrated CD8+ T cell responses, 31% had CD4+ responses, and only 23% displayed both. After a median follow-up of 7.2 months, only 2 patients in the highest dosage group remained on treatment without progression. The vaccine was well-tolerated, with primarily mild-to-moderate adverse events such as headache, fever, and chills. Based on these findings, the study selected 100 µg as the recommended dose for further clinical trials. The available evidence supports the use of this therapy in a Phase 2

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study, though a groundbreaking new drug remains elusive. CVGBM represents the first of its kind and could pave the way for treatments utilizing comparable therapeutic strategies, either as standalone interventions or in combination of regimens.
Efficacy and safety of ponsegromab in patients with cancer cachexia Ponsegromab, a monoclonal antibody, inhibits growth differentiation factor 15, a driving factor for cancer cachexia. A phase 2 randomized, placebo-controlled trial evaluated Ponsegromab's efficacy and safety in 187 patients with cachexia, elevated GDF-15 levels (>1500 pg/ml) and various cancers (NSCLC, Pancreatic cancer, Colorectal Cancer), regardless of tumor stage (2). Patients were randomly assigned to receive Ponsegromab (100 mg, 200 mg, or 400 mg) or placebo, administered subcutaneously every four weeks for 12 weeks. The primary endpoint was change in body weight, while notable secondary endpoints included improvement in cachexia symptoms, physical activity, and increase in lumbar skeletal muscle index. After 12 weeks, patients receiving 400 mg Ponsegromab experienced a significant, placebo-adjusted median weight increase of 3.00 kg. This weight response was observed across all subgroups. Similarly, the 200 mg and 100 mg cohorts saw weight gains of 2.08 kg and 1.33 kg, respectively. Furthermore, the 400 mg group demonstrated a significant 4.11 point improvement in the FAACT-Anorexia Cachexia Subscale score, indicating enhanced appetite, and a significant increase in physical activity of 50 minutes of non-sedentary time per day. The side-effect profile was similar to placebo For me, Ponsegromab represents a very hopeful new class of drugs for an important unmet need of our patients. It has the potential to substantially improve the quality of life of patients in a difficult period of the cancer journey. I hope further studies will confirm these promising early results.
Author: Dr. med. Dennis Hoch, Inselspital Bern Mentor: Prof. Dr. med. Miklos Pless, Kantonsspital Winterthur
References: 1. Annals of Oncology (2024) 35 (suppl_2): S406-S427. 10.1016/annonc/
annonc1587 2. Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623
Prostate cancer
Many interesting studies in the field of prostate cancer (PC) were presented at ESMO 2024. In my opinion three studies deserve to be highlighted: one in the localized setting, one in the metastatic hormone-sensitive setting (mHSPC) and one in the metastatic castration resistant setting (mCRPC).
A large randomized study in patients with localized PC planned to undergo androgen deprivation therapy (ADT)

evaluated the use of transdermal oestradiol (te2) compared with LHRH analogue (LHRHa) (1). It is known that LHRHa cause hot flushes which negatively affect patients’ quality of life (2). LHRHa also cause long-term side effects such osteoporosis, metabolic syndrome and cardiovascular events (3). The rationale of using te2 to achieve castration is to reduce these side effects compared to LHRHa. This phase 3 non-inferiority study showed that te2 is noninferior to LHRHa regarding metastasis free survival (MFS) and overall survival (OS) and it achieved a similar castration rate. In terms of side effects, a reduction in hot flushes (44% vs 89%) was seen on te2, but it had a greater risk of developing gynecomastia (85% vs 42%). No data on cardiovascular events, bone health or metabolic syndrome were presented. Transdermal estrogen appears to be an interesting option but many questions remain especially regarding prophylaxis of gynecomastia and patient compliance (need to change 4 patches twice per week). Finally, only data from non-metastatic patients were presented so we do not know the effect of this therapy in patients with metstatic disease who should receive an ARPI.
ARANOTE study The ARANOTE study was done in the mHSPC setting. This is a phase 3 study evaluating the benefit of the addition of darolutamide to ADT (4). It demonstrated a statistically significant reduction (-46%) in the risk of radiographic progression (rPFS) compared to ADT alone (primary endpoint). Although the overall survival (OS) is still immature, I think that darolutamide could become a new therapeutic option in addition to ADT in patients with mHSPC. It is important to emphasize the very favorable toxicity profile of darolutamide, almost similar to placebo. The only side effect that seems to increase with darolutamide is bone fractures highlighting the importance to evaluate bone health in all patients with mHSPC. Overall this is a potentially practicechanging study altough we have to wait final OS data.
PEACE-3 study Finally, in the mCRPC setting, the PEACE-3 study was presented by Prof. Silke Gillessen at the plenary session (5). This study demonstrated that the combination of enzalutamide + radium-223 improved radiographic progression-free survival (rPFS) compared to enzalutamide monotherapy in patients with mCRPC and bone metastases. A combination therapy between radium-223 and an androgen receptor pathway inhibitor (ARPI) had already been evaluated in the ERA-223 study (abiraterone + radium-223) (6). However, this trial was unblinded early after more fractures and deaths were observed in the experimental arm. Analyzing the fractures, it was found that in the majority of cases they were osteoporotic and non-pathological. Following the release of the ERA-223 data, the PEACE-3 study was amended with an urgent safety letter to investigators: bone protecting therapy with either zoledronic acid or denosumab became mandatory at the monthly dose. The introduction

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