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However, these positive results must be viewed against the backdrop of the negative CALLA trial, which evaluated durvalumab in a similar setting and a similar patient cohort and failed to meet its primary endpoints (7). Combination of CRT and PD-1 blockade has also failed in other tumors, like KEYNOTE-412, which tested pembrolizumab with definitive CRT in head and neck cancer (8). This raises important questions about why KEYNOTE-A18 succeeded where similar trials failed. For cervical cancer pembrolizumab plus CRT represents the new standard of care, as does induction chemotherapy prior to CRT. The INTERLACE trial showed that induction chemotherapy prior to CRT also improves overall survival in locally advanced cervical cancer (9). This creates both opportunities and challenges: while both approaches show an overall survival benefit, it is unclear whether combination will have a synergistic effect. A major challenge in the INTERLACE protocol is the high hematologic toxicity associated with induction chemotherapy. In the induction chemotherapy group 33% of the patients did not complete all 5 cycles of cisplatin during CRT. Therefore, important questions remain about the optimal integration of various treatment modalities and the duration of immunotherapy, currently set at two years based on KEYNOTE-A18. Combining anti-PD-1 blockade with induction chemotherapy needs careful study, particularly regarding the management of cumulative toxicities.
Author: Anton Oseledchyk, Universitätsspital Basel Mentor: Prof. Dr. med. Intidhar Labidi-Galy, Hôpitaux Universitaires Genève HUG
AI Assistance Statement: The initial draft of this manuscript was generated using Claude AI (Anthropic, version 3.5 Sonnet, accessed May 2024), an artificial intelligence large language model. The content was then critically reviewed, edited, and refined by the author to ensure accuracy, appropriate academic standards, and original analysis. All statements, analyses, and conclusions were verified against primary sources and reflect the authors' interpretations of the data.
References: 1. Van Gorp T et al.: LBA28 ENGOT-en11/GOG-3053/KEYNOTE-B21: A phase III
study of pembrolizumab or placebo in combination with adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. Ann Oncol. 2024;35:S1221. 2. Eskander RN et al.: Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023. 3. Mirza MR et al.: Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023. 4. Colombo N et al.: Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2024;25(9):1135-46. 5. Westin SN et al.: Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: The Phase III DUO-E trial. J Clin Oncol. 2024;42(3):283-99. 6. Patel SP et al.: Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med. 2023;388(9):813-23. 7. Lorusso D et al.: 709O Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: Overall survival results from the randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Ann Oncol. 2024;35. 8. Machiels J-P et al.: Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): A randomised, double-blind, phase 3 trial. Lancet Oncol. 2024;25(5):572-87. 9. McCormack M et al.: Induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced cervical cancer (GCIG INTERLACE): An international, multicentre, randomised phase 3 trial. Lancet. 2024;404(10462):1525-35.

Advances in Breast Cancer Treatment – three major trials
Recent advances in breast cancer research have shown practice changing findings. This review article wants to highlight key insights from three major breast cancer trials presented at the last 2024 ESMO congress: the HypoG-01 trial, which evaluated hypofractionated radiotherapy in localized breast cancer requiring nodal irradiation, the KEYNOTE-522 trial, which investigated the addition of pembrolizumab to chemotherapy in localized node positive triple-negative breast cancer (TNBC), and the NATALEE trial, which assessed adjuvant ribociclib in hormone receptor-positive high risk early breast cancer. These studies contribute to ongoing developments in personalized treatment strategies across various breast cancer subtypes.
HypoG-01 Study The HypoG-01 trial evaluated the non-inferiority of hypofractionated radiotherapy compared to normofractionated radiotherapy in patients with localized breast cancer requiring nodal irradiation (1). While previous studies support the use of lower doses for breast-only irradiation, evidence in the context of nodal irradiation was lacking before this trial. Up to now patients needing nodal irradiation underwent treatment with a standard dose of 50 Gy over 25 fractions over five weeks, which involves larger irradiation volumes. HypoG-01 is a multicenter, open-label, randomized phase 3 trial including participants with stage T1-3, N0-3 breast cancer requiring regional nodal radiotherapy. Patients were randomized to receive either hypofractionated radiotherapy (40 Gy in 15 fractions over three weeks) or normofractionated radiotherapy (50 Gy in 25 fractions over five weeks). The primary endpoint was the 3-year cumulative incidence of arm lymphoedema, defined by a ≥10% increase in arm circumference at specific distances from the olecranon. The study met its primary endpoint, establishing that hypofractionated radiotherapy is non-inferior to normofractionated radiotherapy for patients requiring nodal irradiation. The 5-year cumulative incidence of lymphoedema was 33.3% in the hypofractionated group versus 32.8% in the normofractionated group. Secondary endpoints, including overall survival (OS), locoregional-free survival (LRFS), distant disease-free survival (DDFS), and breast cancer-specific survival (BCSS), also resulted to be noninferior, further confirming the efficacy and non-inferirority of hypofractionated therapy in this patient population. The safety profile was consistent across treatment groups, with only minor differences in radiation skin injuries, which were clinically insignificant. Hypofractionated radiotherapy is now positioned as the new standard of care for patients with localized breast cancer requiring nodal irradiation, providing an effective, less burdensome treatment option.

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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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