KONGRESSBERICHT

Young Oncology Academy
Was junge Onkologen von ESMO, EHA, ESTRO und ESP berichten
Die Young Oncology Academy (YOA) der SAKK bietet ein intensives Mentorenprogramm für junge Onkologinnen und Onkologen. Ein Jahr lang werden die Teilnehmer von renommierten Fakultätsmitgliedern betreut und erhalten einen Einblick in die Planung, Leitung und Durchführung sowie die Publikation von klinischen Studien. Zudem erhalten sie die Möglichkeit, internationale Jahreskongresse der jeweiligen Fachgesellschaften zu besuchen. Lesen Sie, was die jungen Kollegen als berichtenswert erachteten.

ESMO 2024
PD-1 Blockade in early Endometrial and Cervical Cancers
At this year’s ESMO 2024 annual meeting, two pivotal phase 3 trials investigating pembrolizumab in advanced non-metastatic gynecologic cancers were presented, potentially changing the treatment landscape in both cervical and endometrial cancer.
KEYNOTE-B21 Study KEYNOTE-B21 investigated pembrolizumab plus chemotherapy with/without radiotherapy in high-risk endometrial cancer (EC) after curative surgery (1). This phase 3 trial enrolled 1095 patients with stage I/II non-endometrioid or p53-abnormal tumors, or stage III/IVA of any histology. At median follow-up of 23.7 months, the trial showed no improvement in disease-free survival (DFS) in the overall population (HR 1.02, 95% CI 0.79-1.32). However, subgroup analysis revealed a significant benefit in dMMR patients (HR 0.31, 95% CI 0.14-0.69) but no benefit in pMMR patients (HR 1.20, 95% CI 0.91-1.57). Grade 3 adverse events occurred in 71% of pembrolizumab patients versus 63% in the placebo group. Results for the dMMR subgroup align with all four randomized 1st line trials of Atezolozumab (AtTEND), Durvalumab (DUO-E), Dostarlimab (RUBY) and Pembrolizumab (NRGGY018) with hazard ratios ranging from 0.28 to 0.42 (2–5). In regard to pMMR EC, efficacy of PD-(L)1 blockade in 1st line treatment is less clear. Only in NRG-GY018 there was a statistically significant improvement of DFS, in RUBY the was a numerical difference and in AtTEND and DUO-E trials DFS improvement was minimal and not clinically meaningful.

This subtle effect in metastatic EC did not translate into adjuvant treatment. One possible explanation is that patients with pMMR EC may require chemotherapy induced immunogenic cell death to develop a sustained anti-tumor immune response. The neoadjuvant approach is standard in the majority if tumor types. In malignant melanoma a direct comparison of neoadjuvant versus adjuvant treatment showed longer event-free-survival in the neoadjuvant therapy group (6). Also, limited efficacy in non-metastatic EC may not be unexpected, as in subgroup analyses of RUBY and AtTEND trial patients with stage II disease or patients with no disease at baseline did not derive benefit from the addition of PD-(L)1 blockade. It is conceivable that a neoadjuvant treatment approach would have yielded a different result and a trial investigating this approach is warranted. As for the current standard, PD-1 blockade in EC should be only used in patients with measurable tumor or high risk dMMR disease. The role of other molecular markers, particularly p53 status, requires further investigation to optimize patient selection.
KEYNOTE-A18 Study KEYNOTE-A18, on the other hand, represents a clear success in locally advanced cervical cancer (7). KEYNOTE-A18 evaluated pembrolizumab plus concurrent chemoradiotherapy (CRT) in high-risk locally advanced cervical cancer. This phase 3 trial randomized 1060 patients to receive either pembrolizumab or placebo with standard CRT. At median follow-up of 29.9 months, the trial demonstrated significant improvement in overall survival in the pembrolizumab group (HR 0.67, 95% CI 0.50-0.90; P=0.0040), with 36-month OS rates of 82.6% versus 74.8%. The benefit was consistent across subgroups but particularly pronounced in FIGO stage III-IVA disease (HR 0.57). Grade 3 treatment-related adverse events were slightly higher in the pembrolizumab arm (69.1% vs 61.3%).

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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.
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