Das Swiss Cancer Institute lanciert 2026 bereits zum elften Mal die Young Oncology Academy (YOA), ein Förderprogramm für den forschenden Nachwuchs. Es richtet sich an engagierte junge Ärzte aus den Bereichen Onkologie, Hämatologie, Radioonkologie, Urologie, Gynäkologie, Pathologie oder Dermatologie, die sich vertieft mit onkologischen und hämatologischen Fragestellungen auseinandersetzen möchten.

Das vielseitige einjährige Curriculum umfasst unter anderem Kongressbesuche im In- und Ausland (ESMO, EHA, ESTRO, ESP etc.), Präsentations- und Schreibtrainings, Networking, Grant-Submission-Workshops, Einblicke in Phase-I-Studien sowie in die klinische und translationale Forschung und Einführungen in statistische Grundlagen. Die Teilnehmer werden von erfahrenen onkologischen Fachpersonen als Mentoren begleitet und erhalten zudem die Möglichkeit, eigene Studienprojekte zu entwickeln und vorzustellen.

Zum Jahresende publizieren die YOA-Teilnehmer jeweils ein Paper zu ihren persönlichen Highlights eines internationalen Kongresses. Wir freuen uns, die Arbeiten aus dem Jahr 2025 in einer dreiteiligen Serie präsentieren zu dürfen. Nach den Beiträgen in den beiden vorangegangenen Ausgaben folgt in der vorliegenden Ausgabe der dritte und letzte Teil der Reihe mit weiteren Kongress-Highlights der Mentees.

Wir beide haben diese YOA besucht und können das Programm sehr empfehlen. Weitere Informationen finden sich auf der Website des Swiss Cancer Institute: www.swisscancerinstitute.ch/de/forschende/young-oncology-academy/

Dr. med. Tämer El Saadany                             Dr. med. Eveline Daetwyler

ESMO 2025: Advancing Precision in Adjuvant Treatment of ­Colorectal Cancer: Progress Made, but no Breakthrough yet

Review YOA 2025: Christina Bothou

Mentee: Dr. med. Christina Bothou, KSA/USZ | Mentor: Prof. Dr. med. Intidhar Labidi-Galy, HUG | Speciality: Lower GI

Although the ESMO Congress 2025 in Berlin did not present practice-changing studies in colorectal cancer (CRC), several findings offered valuable insights. Standard management of high-risk stage II (pT4) and stage III (pN+) colon cancer involves surgical resection followed by adjuvant chemotherapy, which typically consists of a fluoropyrimidine such as 5-fluorouracil or capecitabine, administered either alone or in combination with oxaliplatin for three to six months. However, nearly half of patients may be cured with surgery alone and could therefore avoid adjuvant chemotherapy, whereas a substantial proportion will relapse despite receiving chemotherapy. Recent efforts to improve risk stratification, including the DYNAMIC-III trial using circulating tumor DNA (ctDNA) and approaches integrating artificial intelligence with digital pathology, highlight ongoing strategies to individualize adjuvant therapy in CRC.

DYNAMIC-III Trial: ctDNA-Guided Adjuvant Therapy in Stage III CRC

ctDNA is a strong prognostic marker for relapse in colorectal cancer (1). The DYNAMIC trial, published in 2022 with recent updates, randomized stage II colon cancer patients to ctDNA-guided adjuvant chemotherapy or standard management. Only ctDNA-positive patients received chemotherapy, reducing treatment rates from 28 % to 15 % without compromising 2-year recurrence-free survival. At a median follow-up of 60 months, 5-year RFS was similar between groups (88 % vs 87 %, 95 % CI −5.8 % to 8.0 %). The trial met its primary endpoint, supporting ctDNA-guided therapy as a strategy to safely limit overtreatment in stage II CRC (2).

This year, from the same group, the ctDNA-negative arm of the DYNAMIC-III trial was presented at ESMO, and the ctDNA-­positive arm at ASCO (3). This multicenter, randomized, phase 2/3 study enrolled 968 patients with stage III colon cancer who underwent ctDNA testing 5–6 weeks post-surgery and were randomized to ctDNA-guided or standard management. A tumor-informed personalized approach for ctDNA analysis was used (SaferSeqS targeted CRC panel). In the ctDNA-guided arm, ctDNA-negative patients received deescalated therapy, whereas ctDNA-positive patients received intensified therapy. Primary endpoints were 3-year RFS for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients, with secondary endpoints including hospitalization and ctDNA clearance.

Among 702 ctDNA-negative patients (72.5 %), deescalation reduced oxaliplatin use (34.8 % vs 88.6 %) and hospitalizations (8.5 % vs 13.2 %), with slightly lower 3-year RFS (85.3 % vs 88.1 % , 95 % CI of the difference −8 % to +2.5 %), though non-inferiority criteria were not met (non-inferiority was defined as the lower bound of the one-sided 97.5 % CI for the difference at 3 years not crossing −7.5 %). In ctDNA-positive patients, higher ctDNA levels were associated with increased recurrence risk (3-year RFS 77 % to 23 % ; P < 0.001). Escalated therapy did not improve outcomes (2-year RFS 51 % vs 61 %), and persistent ctDNA after treatment predicted markedly worse prognosis (3-year RFS 14 % vs 79 %).

Overall, these findings confirm ctDNA as a strong prognostic tool in colon cancer; however, the trial was formally negative for the primary endpoints. Considering that the non-inferiority design is the appropriate approach to assess these questions, and that the subgroup analysis did not substantially contribute to hypothesis generation, the study leaves open questions regarding clinician-driven ther-apy selection, the choice of deescalation strategies, and whether the SaferSeqS targeted CRC panel used was the most optimal and precise assay.

Abstract 726O: Prognostic value of the Combined Analysis of Pathologists and Artificial Intelligence (CAPAI) in high-risk stage II–III colon cancer treated without chemotherapy

In the Netherlands, the Combined Analysis of Pathologists and Artificial Intelligence (CAPAI) was developed to refine prognostic assessment and guide ACT in high-risk stage II and III colon cancer. CAPAI combines histopathologic features from H&E slides, analyzed using the DoMore-v1-CRC deep learning biomarker, with tumor stage (pT/pN) and lymph node count to classify patients into low-, intermediate-, or high-risk groups. DoMore-v1-CRC was previously optimized and validated in large European cohorts, demonstrating superior prognostic performance compared with traditional morphological and molecular markers, stratifying patients into good, uncertain, or poor prognosis categories with 3-year cancer-specific survival (CSS) up to 97 % in low-risk patients and hazard ratios exceeding 10 for high- versus low-risk groups (4). Leveraging the Netherlands’ restrictive ACT practices, a nationwide cohort of 453 patients under 70 years, with good performance status and R0 resection, who did not receive neoadjuvant or adjuvant therapy, was analyzed. CAPAI effectively stratified patients, identifying nearly half as low-risk (3-year CSS 93.7 %), 34 % as intermediate-risk (87.5 %), and 18 % as high-risk (60.4 %), with statistically significant differences (log-rank p<0.001). These findings suggest that integrating DoMore-v1-CRC with conventional staging enables precise identification of patients who may safely avoid ACT while highlighting those who might benefit from treatment intensification (5).

Outlook

Taken together, these findings underscore the need to reassess clinical trial designs and refine diagnostic and prognostic tools, with the ultimate goal of delivering adjuvant therapy only to patients most likely to benefit. The rapidly evolving landscape of emerging biomarkers presents an opportunity for coordinated evaluation. For ctDNA, the proliferation of assays in clinical investigation brings several key questions to the forefront, including whether systematic cross-assay comparisons are needed to establish analytical validity and clinical utility, and whether sequential measurements can provide additional insight into residual disease and relapse risk. Concurrently, advances in artificial intelligence applied to digital pathology suggest that AI-derived biomarkers may play an important role, particularly when integrated with established molecular and clinical markers. Incorporating these complementary, question-oriented approaches into future trials holds strong promise for improving patient stratification and advancing toward true precision in adjuvant colorectal cancer ther-apy.

Literatur
1. Nakamura Y, et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nat Med. 2024 Nov;30(11):3272-3283.
2. Tie J, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year out-comes of the randomized DYNAMIC trial. Nat Med. 2025 May;31(5):1509-1518.
3. Tie J, et al. Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the ran-domized phase 2/3 DYNAMIC-III trial. Nat Med. 2025 Oct 20.
4. Kleppe A, et al. A clinical decision support system optimising adjuvant chemotherapy for colorectal can-cers by integrating deep learning and pathological staging markers: a development and validation study. Lancet Oncol. 2022 Sep;23(9):1221-1232.
5. Bakker M-CE, et al. 726O Prognostic value of the combined analysis of pathologists and artificial intelligence (CAPAI) in high-risk stage II-III colon cancer treated without chemotherapy: Interim report from a nationwide validation. Ann Oncol. 2025;S0923‑7534(25)02221‑5.

The role of HER2-TKIs in HER2-mutant, advanced NSCLC: A Comparative Review of Beamion-LUNG 1 and SOHO-01

Review YOA 2025: Julia Jäger

Mentee: Dr. med. Julia Jäger | Mentor: Prof. Dr. med. et Dr. phil. nat. Sacha Rothschild | Speciality: Medical Oncology

HER2 belongs to the ERBB receptor family. HER2-mutated non-small cell lung cancer (NSCLC) accounts for approximately 2–4 % of all cases and represents a distinct molecular subgroup with an unfavorable prognosis. Most alterations are activating mutations, particularly exon 20 insertions fundamentally differing from HER2 overexpression or amplification in breast or gastric cancer (1–3). These biological differences explain the historically limited responses to conventional HER2-directed therapies and highlight the need for mutation-specific treatment approaches.

The current standard of care in the first line setting for advanced HER2-mutant NSCLC is pembrolizumab plus pemetrexed and platinum-based chemotherapy (KEYNOTE-189) (4). After disease progression, the HER2-directed antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) is available in Switzerland (5). Data from DESTINY-Lung01 and DESTINY-Lung02 demonstrated robust activity in pretreated HER2-mutant NSCLC, with objective response rates (ORR) around 55–57 %, a median progression-free survival (PFS) of roughly 8.2 months, and a median duration of response of approximately 9 months. Interstitial lung disease (ILD)/pneumonitis remains an important toxicity requiring close monitoring. Despite these challenges, T-DXd has become a key therapeutic option in the second-line setting.

Two next-generation, highly selective, covalent HER2 tyrosine kinase inhibitors (TKIs) – sevabertinib and zongertinib – are now being evaluated and may shift treatment pradigms in the future. BEAMI-ON-Lung1 and SOHO-01 are the respective trials that showed promising ORR. Both studies had multiple cohorts representing different treatment situations: untreated or pretreated, either with HER2-targeting ADC or with chemoimmunotherapy.

BEAMION-Lung 1 is a phase Ia/Ib study investigating the irreversible, selective HER2-TKI zongertinib. Primary endpoint was ORR. At the ESMO annual meeting the results of cohort 2 including treatment-naïve patients, were presented. ORR was 77 % with a rapid median time to response of 1.4 months (range, 1.1–6.9 months). Although PFS data remain immature yet, the 6-months PFS rate was 79 %. The 6 months DOR was 80 % with a median follow-up of 9.7 months. Responses were observed across different HER2 mutation types (6).
SOHO-01 is a phase I/II study of sevabertinib in advanced HER2-mutated NSCLC with ORR as a primary endpoint. Sevabertinib showed promising response rates in all cohorts, ranging from 38 % in the HER2-ADC pretreated patients to 71 % in untreated patients. In untreated patients PFS was not mature yet (with a median follow-up time of 9.9 months), the 12 months PFS was 55 %. The median D0R was 11 months. In the cohort with pretreated patients who were naïve to an HER2-ADC, an exploratory biomarker analysis was performed as it was the largest cohort with the longest follow-up. This analysis indicated that patients with HER2-TKD mutations, especially YVMA exon 20 insertions, had higher response rates (7).

Both TKIs were associated with manageable toxicities. Diarrhea and rash were common adverse events (AEs). In both studies patients needed to have dose reductions to complete treatment (15 % with zongertinib, 28 % with sevabertinib). Diarrhea grade ≥  2 occurred more frequently with sever-bertinib (34 % grade 2, 6.7 % grade 3), as well as paronychia. This is probably due to a greater inhibition of EGFR wildtype. With dose reductions and treatment interruptions, the toxicities were manageable with supportive care in both studies.
Both trials underline that HER2-TKIs have the potential to transform the management of HER2-mutant NSCLC. Ongoing phase III studies (BEAMION-LUNG 2, SOHO-02, DESTINY-Lung 04) are expected to clarify optimal sequencing strategies – such as whether TKI- or ADC-based therapy should be used first – and help to define which approach offers the greatest survival benefit.

Abbreviations
TKI = Tyrosine kinase inhibitor, NSCLC = non-small cell lung cancer,
ADC = antibody drug conjugate, ORR = overall response rate,
PFS = progression free survival, DOR = duration of response,
TKD = tyrosine kinase domaine

Literatur
1. Remon J, Hendriks LEL, Cardona AF, Besse B. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treat Rev. 2020;90:102105.
2. Riudavets M, Sullivan I, Abdayem P, Planchard D. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 al-terations. ESMO Open. 2021;6(5):100260.
3. Hong L, Patel S, Drusbosky LM, Xiong Y, Chen R, Geng R, et al. Molecular landscape of ERBB2 altera-tions in 3000 advanced NSCLC patients. NPJ Precis Oncol. 2024;8(1):217.
4. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-92.
5. Swissmedic. Summary Report on Authorisation – Enhertu 17 Jan 2025 [Available from: https://www.swissmedic.ch/swissmedic/en/home/about-us/publications/public-summary-swiss-par/public-summary-swiss-par-enhertu-03.html.
6. Popat S YN, Girard N, et al. Zongertinib as first-line treatment in advanced HER2-mutant NSCLC: BEAMION-LUNG 1. Presented at: ESMO 2025; Oct 17-21; Berlin Germany. Abstract LBA742025.
7. Le X, Kim TM, Loong HH, Prelaj A, Goh BC, Li L, et al. Sevabertinib in Advanced. N Engl J Med. 2025;393(18):1819-32.

ESMO 2025: Highlights in Genitourinary Oncology

Review YOA 2025: Dimitri Hasler

Mentee: Dr. med. Dimitri Hasler, USB | Mentor: Prof. Dr. med. Richard Cathomas, KSGR | Speciality: Urology

This year’s ESMO Congress featured numerous highlights in genitourinary malignancies. In the Presidential Symposium alone, four presentations focused on this field, underscoring the current dynamics in genitourinary oncology.

A particularly active area, as in the past few years, has been non-metastatic muscle-invasive urothelial carcinoma of the bladder (MIBC). The Keynote-905/EV-303 trial deserves particular attention: After the earlier EV-302 study had already redefined the new standard of care in advanced urothelial carcinoma with the combination of Enfortumab vedotin and pembrolizumab (EV-P), this trial now evaluates the EV-P regimen in the perioperative setting for cisplatin-ineligible patients (1, 2). According to current guidelines and due to insufficient data for neoadjuvant therapy, such patients usually undergo immediate cystectomy followed by adjuvant checkpoint inhibitor therapy in PD-L1 positive disease (3).
In Keynote-905, patients with MIBC (T2 – T4a and N0 or N1) who were cisplatin-ineligible were randomized. The observational arm underwent upfront cystectomy followed by observation (17 % received adjuvant nivolumab). The experimental arm received 3 cycles of neoadjuvant EV-P followed by cystectomy and postoperative enfortumab vedotin (6 cycles) and pembrolizumab (14 doses). The trial included an arm with pembrolizumab monotherapy but this was discontinued in 2022 and no results were currently reported.
The baseline characteristics reflect the generally elderly and frail nature of the cisplatin-ineligible population, with median age of 74 years and ECOG performance status 2 in up to 15 % of patients, respectively.

The primary endpoint event-free survival (EFS), was significantly improved by the addition of perioperative EV-P (HR 0.40, p < 0.0001) as was overall survival (OS) (HR 0.50, p = 0.0002). Furthermore, nearly 60 % of patients treated with EV-P achieved a pathological complete response. As expected, toxicity was higher in the EVP group (71 % vs. 46 % grade ≥ 3); however, this did not appear to lead to a clinically relevant compromise of surgical feasibility.

In summary, EV-P represents a safe and effective perioperative treatment option for cisplatin-ineligible patients and will likely become the new standard of care in this population. Some questions and limitations should be addressed: only 17 % of patients in the control arm received adjuvant nivolumab. Moreover, it would be interesting to know whether patients with a pathological complete response truly require adjuvant therapy.

This leads directly to the next MIBC study presented at ESMO: the IMvigor011 trial, which evaluated ctDNA-guided adjuvant therapy with atezolizumab in patients with MIBC.
Following a posthoc analysis of its predecessor trial, the IMvigor010, which had suggested a possible benefit of adjuvant atezolizumab in ctDNA positive subgroups, IMvigor011 enrolled patients after cystectomy and without any evidence of distant metastase (4, 5). Patients were monitored for one year with serial tumour-informed ctDNA assessments. If ctDNA became detectable in the absence of radiologically evident metastases, patients were randomized to receive atezolizumab vs. placebo for one year. ctDNA-negative patients were observed without systemic therapy.

The results highlight the strong prognostic value of postoperative ctDNA detection. In ctDNA-positive patients, the primary endpoint, disease-free survival (DFS), favored the atezolizumab arm (HR 0.64, p = 0.005); however, the median DFS of 9.9 months (vs. 4.6 months with placebo) still indicates a high relapse rate despite adjuvant treatment. As expected, outcomes for patients who remained ctDNA-negative were excellent, with a 12-month DFS of 95 %.

The immediate impact of these findings on everyday clinical practice remains uncertain due to several limitations: Atezolizumab is not currently the standard of care for adjuvant treatment of MIBC, and the data cannot be directly extrapolated to the perioperative setting, which now defines the standard of care. Ongoing and future studies will further clarify how ctDNA can be integrated both for treatment escalation and deescalation, including assessments of cost-effectiveness.

Several important trials were presented in prostate cancer. The PSMAddition investigated the addition of radioligand therapy with Lu-PSMA-617 in patients with metastatic hormone-sensitive prostate cancer (mHSPC). After confirmation of PSMA-positive disease, patients were randomized receive current standard therapy with androgen deprivation therapy (ADT) and an androgen-receptor pathway inhibitor (ARPI), whereas the experimental arm received six cycles of Lu-PSMA-617 in addition to ADT + ARPI. The primary endpoint, radiographic progression-free survival (rPFS), was positive (HR 0.72, p = 0.002). However, at the current median follow-up of 23 months, there is no statistically significant difference in OS. Moerover,quality-of-life (QoL) analyses did not show a better outcome in the experimental arm. Toxicity was higher in the investigational arm, including a higher rate of secondary malignancies and renal adverse events even with short follow-up.

Thus, routine use of radioligand therapy already in the hormone-sensitive setting needs to be discussed critically, given the increased toxicity and lack of QoL benefit, and is probably not a «one size fits all» approach. It also remains unclear whether an OS benefit can ultimately be demonstrated, particularly in the context of the crossover design.

Another important study in the field of mHSPC is the CAPItello-281 trial: patients with phosphatase and tensin homolog (PTEN) deficiency were randomized to receive capivasertib or placebo in combination with ADT and an ARPI. Capivasertib is a protein kinase inhibitor targeting downstream effectors in the PTEN pathway and is therefore considered a promising targeted agent (6). In the trial, the primary endpoint of rPFS was significantly improved in the capivasertib arm (HR 0.81, p = 0.034), corresponding to a median rPFS extension of approximately 7.5 months (7). Mature OS data are not yet available. Patients on capivasertib experienced higher rates of severe toxicity especially diarrhea, hyperglycemia, rash and anemia. Whether this regimen will be adopted into routine practice in view of the modest magnitude of benefit and side effect profile remains unclear.

The list of impactful trials presented at this year’s ESMO Congress in the genitourinary field could easily be extended. Overall, the data presented reflect the remarkable dynamism of the field and the substantial progress being made for patients. We eagerly await future trials and datasets that will continue to reshape the therapeutic landscape of urogenital malignancies.

Literatur
1. Powles, T. et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N. Engl. J. Med. 390, 875–888 (2024).
2. Powles, T. et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann. Oncol. 35, 485–490 (2024).
3. Powles, T. et al. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33, 244–258 (2022).
4. Powles, T. et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 595, 432–437 (2021).
5. Bellmunt, J. et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 22, 525–537 (2021).
6. Eberlein, C. et al. Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer. Br. J. Cancer 130, 1377–1387 (2024).
7. Fizazi, K. et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann. Oncol. 0, (2025).

Perioperative vs Adjuvant Immunotherapy in locally advanced Head and Neck Cancer: Lessons from KEYNOTE-689 and ADRISK Trial

Review YOA 2025: Philipp Reinhardt

Mentee: Dr. med. Philipp Reinhardt, PSI | Mentor: Dr. med. Francesca Caparrotti, Genève | Speciality: Radiation Oncology

Head and neck cancers are a heterogeneous group of tumors arising from the nasopharynx to the larynx. The majority are histologically classified as head and neck squamous cell carcinoma (HNSCC). Approximately 50–60 % of patients present with locally advanced HNSCC (LA-HNSCC) at diagnosis (1, 2). For decades, the stand-ard of care (SOC) was surgery followed by adjuvant radiotherapy (RT), with the addition of concurrent chemo-therapy based on pathological risk factors (3). The combined analysis of RTOG 9501 and EORTC 22931, recently updated by Zumsteg et al., confirmed that adding cisplatin to postoperative RT significantly improves overall sur-vival (OS) in patients with high-risk features such as positive margins and/or extracapsular extension (ECE) of positive lymph nodes (4). Despite multimodal therapy, 5-year OS remains below 50 %, highlighting the need for treatment intensification. Immunotherapy, particularly PD-1 inhibition (e.g. pembrolizumab), has demonstrated efficacy in recurrent and metastatic HNSCC. Based on promising phase II and III data (5), there has been growing interest in integrating pembrolizumab into the primary management of resectable LA-HNSCC.

The phase III KEYNOTE-689 trial evaluated perioperative pembrolizumab in resectable LA-HNSCC (oral cavity, larynx, hypopharynx, or oropharynx; stages III–IVA, AJCC 8th edition) (6). Patients (n=714) were randomized 1:1 to either perioperative pembrolizumab or SOC. In the experimental arm, patients received two cycles of neoadjuvant pembrolizumab prior to surgery, followed by adjuvant pembrolizumab administered concurrently with RT (with or without cisplatin) for three cycles, and subsequently up to twelve cycles of maintenance therapy. In the control arm (SOC), patients underwent surgery followed by postoperative RT with or without concomitant cisplatin, according to high-risk features. Patients with high-risk disease, defined as positive margins and ECE-positive lymph nodes, received RT (33 x 2 Gy) with concomitant cisplatin. Patients with low-risk disease were treated with RT alone (30 x 2 Gy). Most patients in the study had oral cavity carcinoma (60.3 % in the pembrolizumab arm versus 60.7 % in the control arm) and were HPV-negative (> 95 %). At the time of the first interim analysis, with a median follow-up of 38.3 months, the 36-month event-free survival (EFS) rate was 59.8 % in the pembrolizumab arm versus 45.9 % in the control arm among patients with a CPS ≥ 10 (HR 0.66; 95 % CI, 0.49–0.88; p = 0.004). In the CPS ≥ 1 population, the corresponding EFS rates were 58.2 % and 44.9 % (HR 0.70; 95 % CI, 0.55–0.89; p=0.003). In the overall study population, EFS at 36 months was 57.6 % with pembrolizumab compared with 46.4 % in the control group (HR 0.73; 95 % CI, 0.58–0.92; p=0.008). Major pathological response occurred in 9.4 % of patients, including 3 % with complete pathological response. The incidence of grade ≥ 3 treatment-related adverse events was similar between arms, though immune-mediated toxicities were higher with pembrolizumab (43.2 % vs. 10.2 %).

Compared to the Keynote-689, the ADRISK phase IIb trial examined pembrolizumab exclusively in the adjuvant setting (7). Patients with intermediate and high-risk LA-HNSCC were randomized after surgery if they had a close resection margin (R0 <5mm), a microscopic residual tumor (R1) or ECE-positive lymph nodes. All patients received adjuvant cisplatin-based chemoradiotherapy (CRT), with or without concomitant and maintenance pembrolizumab. Approximately two-thirds of the patients were diagnosed with an HPV-positive oropharyngeal carcinoma. After a median follow-up of 30 months, pembrolizumab addition did not significantly improve EFS (HR 0.812; 95 % CI, 0.487 – 1.353; p=0.423) or OS (HR 0.85; 95 % CI 0.46; 1.57; p=0.591). Subgroup analyses showed that p16-positive oropharyngeal carcinoma had the most favorable 2-year EFS with 89.9 %, whereas oral cavity cancers had the poorest 2-year EFS with 41.3 %.

Both trials explored pembrolizumab integration into multimodal therapy for resectable LA-HNSCC but differed substantially in design and patient populations. KEYNOTE-689 assessed pembrolizumab in the perioperative setting, incorporating neoadjuvant and adjuvant treatment, whereas the ADRISK trial assessed pembrolizumab exclusively in the adjuvant setting. ADRISK enrolled patients with more advanced pathological features [close surgical margins (R0 < 5 mm), microscopic residual disease (R1), and/or ECE-positive lymph nodes] with all participants receiving adjuvant cisplatin-based CRT. Despite these high-risk criteria, approximately two-thirds of patients had HPV-positive oropharyngeal carcinoma, a subgroup generally associated with favorable outcomes. In contrast, KEYNOTE-689 included mainly HPV-negative tumors (> 95 %), with only a small proportion of oropharyngeal cancers. This trial also enrolled some lower-risk patients treated with postoperative RT alone, while high-risk patients received concurrent cisplatin. Notably, only 38.9 % of patients in the pembrolizumab arm and 50.5 % in the control arm received concurrent CRT. Taken together ADRISK focused on intermediate- and high-risk patients uniformly treated with adjuvant CRT ± pembrolizumab, and its population predominantly comprised tumors with favorable HPV-associated biology. Conversely, KEYNOTE-689 addressed a broader and biologically more ag-gressive cohort, largely HPV-negative, which may explain the differing clinical outcomes observed between the two trials.

Overall, the available data suggest that the therapeutic benefit of pembrolizumab in LA-HNSCC may be confined to specific subgroups (particularly patients with HPV-negative tumors and higher PD-L1 scores). In contrast, those with HPV-positive oropharyngeal carcinoma generally exhibit a favorable prognosis and are unlikely to benefit from additional treatment intensification. Furthermore, the timing of immunotherapy appears to play a critical role, with perioperative administration demonstrating greater potential to improve outcomes compared to adjuvant-only use. Nevertheless, treatment escalation involving immunotherapy must be carefully balanced against the increased risk of immune-related adverse events.

Literatur
1. Barsouk A, Aluru JS, Rawla P, Saginala K, Barsouk A. Epidemiology, Risk Factors, and Prevention of Head and Neck Squamous Cell Carcinoma. Medical Sciences. 2023;11:42. https://doi.org/10.3390/MEDSCI11020042.
2. Braakhuis BJM, Brakenhoff RH, René leemans C. Treatment choice for locally advanced head and neck can-cers on the basis of risk factors: Biological risk factors. Annals of Oncology. 2012;23 SUPPL. 10. https://doi.org/10.1093/annonc/mds299.
3. Machiels JP, René Leemans C, Golusinski W, Grau C, Licitra L, Gregoire V. Reprint of «Squamous cell carcino-ma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up.» Oral Oncol. 2021;113:1462–75. https://doi.org/10.1016/j.oraloncology.2020.105042.
4. Zumsteg ZS, Luu M, Fortpied C, Jang JK, Chen MM, Mallen-St. Clair J, et al. Re-examining post-operative chemoradiotherapy in head and neck cancer: an updated long-term combined analysis of RTOG 9501/EORTC 22931. Annals of Oncology. 2025. https://doi.org/10.1016/j.annonc.2025.07.004.
5. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. The Lancet. 2019;394:1915–28. https://doi.org/10.1016/S0140-6736(19)32591-7.
6. Uppaluri R, Haddad RI, Tao Y, Le Tourneau C, Lee NY, Westra W, et al. Neoadjuvant and Adjuvant Pembroli-zumab in Locally Advanced Head and Neck Cancer. New England Journal of Medicine. 2025;393:37–50. https://doi.org/10.1056/NEJMOA2415434;PAGE:STRING:GATEWAY;SUBPAGE:STRING:METEREDCONTENT.
7. Dietz A et al. Postoperative adjuvant radiochemotherapy with cisplatin (aRCH) vs. aRCH plus pembrolizumab in locally advanced head and neck squamous cell carcinoma (HNSCC): First data of the ADRISK trial. ESMO 2025 FPN: 1320O; 2025.