Abstracts' contents for non-LBA and non-Presidential abstracts are not available...
1328MO - Hypofractionated radiotherapy of single tumor lesion increases systemic response rate to pembrolizumab in recurrent or metastatic head-and-neck cancer (R/M-HNSCC): Primary endpoint of the randomized Keynote-717 trial
Background
Pembrolizumab (P) improves survival in R/M-HNSCC, whereas the response rate is low. Pre-clinical and early clinical studies suggested that radiotherapy (RT) can function as an in-situ vaccine, broadening tumor-specific T-cell repertoires and inducing systemic (abscopal) immune-mediated tumor regression when combined with immune-checkpoint inhibitors.
Methods
Keynote-717 is an investigator-initiated prospective, open-label, randomized phase II trial in adults with R/M- HNSCC. Study inclusion required a PD-L1 CPS ≥ 1 for first line therapy; no PD-L1 threshold for second line therapy. In addition, a tumor lesion (≥ 2ml) amenable to RT plus ≥ 1 additional measurable lesion according to iRECIST criteria was required. Patients were randomized 1:1 to pembrolizumab 200mg q3w (P) or P plus hypofractionated RT (36 Gy in 12 fractions) to a tumor lesion (RT+P). Primary endpoint was overall response rate (ORR) of unirradiated lesions according to iRECIST. Hypothesis was an increase of the ORR from 18 to 36 %, which resulted in a total of 130 patients to be randomized (one-sided p=0.10 and power 80%; intention to treat; ITT). Patients with at least 2 cycles of P were defined as per protocol (PP). Secondary endpoints included duration of response (DOR) and overall survival (OS).
Results
Between 2018 and 2024 a total of 115 patients were randomized in 8 German sites (n=57 RT+P vs. n=58 P). Median follow-up time was 9.3 months. ORR according to iRECIST was 35 % in the RT+P arm versus 22 % in the P arm (OR = 1.87; one-sided p = 0.097, meeting the prespecified phase-II success criterion). In the PP analysis (n=46 RT+P vs. n=54 P) the ORR was 43% for RT+P and 24% for P (OR=2.43; p=0.033). Median DOR was 10.4 months for RT+P vs. 8.3 months for P (log-rank p=0.59). Median OS was 11.4 months and 11.3 months, respectively (HR 1.04, 95 % CI 0.67–1.63). The number of patients with any treatment-related adverse event (trAE) grade 3-4 was 11% for RT+P and 5% for P (no grade 5 trAE).
Conclusions
The trial met the prespecified phase-II efficacy endpoint. Local RT increased the systemic response rate to P. Exploratory analyses revealed no significant effect on OS.
1317O - Results from CompARE phase III RCT: neoadjuvant durvalumab plus chemoradiotherapy (CRT) followed by adjuvant durvalumab immunotherapy (IO) vs CRT alone in intermediate and high-risk oropharyngeal cancer (OPC)
Background
Trials of IO in the radical CRT setting for locally advanced head neck cancer have been negative to date, postulated to be due to concomitant delivery of IO with CRT (Javelin-100, KeyNote412) or starting adjuvant IO late (ImVOKE-10). CompARE is a phase III RCT [ISRCTN41478539] using an adaptive, multi-arm multi-stage design that evaluates neoadjuvant and adjuvant IO immediately after end of CRT.
Methods
Patients with intermediate risk OPC (HPV-positive TNM7 N2b+ and >10 pack year history of smoking, N3 or T4), or high-risk OPC (HPV-negative), aged 18-70 years with ECOG PS 0-1 were randomised to standard therapy (70Gy in 35 fractions with concurrent cisplatin, Arm1) or neoadjuvant 1500mg durvalumab, followed by standard therapy, then within 2-6 weeks, durvalumab 1500mg, repeated every 4 weeks for 6 months (Arm5). Primary outcome was overall survival (OS) with interim outcome of event-free survival (EFS). Secondary outcomes included toxicity, QoL, swallowing and gastrostomy dependence.
Results
594 patients (306 Arm1; 288 Arm5) were recruited in 34 centres. 85% patients had intermediate risk OPC; 15% high risk. In Arm5, 98% received induction durvalumab; 81% received adjuvant durvalumab. Overall median follow up was 37 months (95% CI. 28, 37). 3y-OS was 84% (95%CI 79, 88%) and 82% (95%CI 76, 86%) in Arm1 and Arm5 respectively (stratified logrank p=0.99); Cox regression Hazard Ratio (HR) Arm5:Arm1 =0.97 (95% CI 0.65, 1.46). 3y-OS rates for the intermediate group, Arm1, were 90% (95%CI 84, 93) and Arm5 84% (95%CI 78, 89), HR=1.24 (95%CI 0.75, 2.03, p=0.40). For the high-risk group, 3y-OS rates for Arm1 were 52% (95%CI 35, 67) and Arm5, 65% (95%CI 45, 80); HR= 0.60 (95%CI 0.30, 1.24, p=0.17). PD-L1 sample analysis is underway and will be presented as well as secondary outcomes and updated follow up data.
Conclusions
Addition of neoadjuvant and adjuvant durvalumab to standard of care did not demonstrate benefit in OPC patients, but high-risk patients may potentially derive some benefit, warranting further exploration of PD-1/PD-L1 inhibition in HPV-negative disease. This work was supported by Cancer Research UK [C19677/A17226] and AstraZeneca.
1320O - 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
Background
Primary curative resection of locally advanced HNSCC often reveals pathologically intermediate or high risk features for relapse requiring adjuvant cisplatin-based radiochemotherapy (aRCH). Adding pembrolizumab (aPD-1) to aRCH may improve event-free survival (EFS).
Methods
The 1:1 randomized phase IIB trial ADRISK (NCT03480672) aimed to improve EFS (primary endpoint) by adding pembrolizumab to standard aRCH (stratified for p16+ oropharynx and localizations, q1w/q3w cisplatin regimen). 240 patients with 100 events were expected to show significantly improved EFS with 80% power in a Cox regression model. Patients and treatment: From 2018 until 2023, 211 patients with resected stage III or IV HNSCC of oral cavity, oropharynx, hypopharynx or larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0 < 5 mm; pN ≥ 2) needing aRCH were randomized, of which 204 were treated. Patients received standard aRCH (64 Gy with 202 mg/m2 cisplatin [total dose, median]; n = 102, arm A) or aRCH + pembrolizumab (64 Gy, 202 mg/m2 + 2600 mg; 200 mg iv q3w, max. 12 months; n = 102; arm B). To avoid transition to CTIS, enrollment did not reach the planned case number.
Results
We present results after 30 months median follow up. Pembrolizumab improved EFS numerically (28/34 events in B/A). Due to fewer events than expected, neither EFS (HR 0.81 [95% confidence interval 0.52; 1.46]; p = .423) nor OS (HR 0.85 [0.46; 1.57]; p = .591) were significantly different. Only 11 EFS events (5/6 in B/A, HR 0.91 [0.28; 2.98]) were observed in p16+ oropharynx patients (44%). All other patients (56%) had similar benefit (HR 0.89 [0.51; 1.54]) favoring arm B (51 events, 23/28 in B/A). The highest difference in EFS events (18/23 in B/A) was among the 80 HPV-unrelated cases with CPS ≥ 10 (38/42 in B/A; HR 0.80 [0.43; 1.48]; p = .470). No new safety signals were detected.
Conclusions
Due to 44% p16+ cases with fewer events ADRISK could not demonstrate significantly improved EFS through added pembrolizumab. Especially patients with HPV-unrelated, CPS ≥ 10 HNSCC (39%) could benefit from added pembrolizumab.
1818MO - Surgery versus radiotherapy after induction therapy with serplulimab combined with chemotherapy for unresectable stage IIIB-IIIC non-small cell lung cancer: a randomized controlled, open-label, phase 2 trial
Background
Chemoradiation followed by durvalumab is recommended for unresectable stage III non-small cell lung cancer (NSCLC) based on the PACIFIC trial. While the role of surgery remains controversial in this population.
Methods
Patients with unresectable stage IIIB-IIIC NSCLC were enrolled to receive 4 cycles (q21d) of serplulimab and platinum-based doublet chemotherapy. After the induction therapy, those with resectable disease were randomized to receive surgery or radiotherapy in a ratio of 1:1, and those with unresectable disease after induction therapy were then treated by oncologists. Primary endpoint was event-free survival (EFS). Secondary endpoints included objective response rate (ORR), major pathologic response (MPR), overall survival (OS), R0 rate of resection, and severe adverse event (SAE) rate.
Results
One hundred patients were enrolled, and the median follow-up time was 20.3 months by the data cutoff date (April 28, 2025). Sixty-six and 34 patients were diagnosed with stage IIIB and IIIC disease, respectively. Fifty patients were randomly assigned to either the surgery group (n = 23) or the radiotherapy group (n = 27). The percentage of squamous carcinomas, adenocarcinomas, and NSCLC not otherwise specified were 70.0%, 16.0%, and 14.0%, respectively. In the entire enrolled patients, ORR was 75.0%. In total, 33 patients received surgery (all achieving R0 resection) after 1-4 cycles of induction chemoimmunotherapy, and the MPR rate was 66.7% (22/33). The median EFS and OS for the entire study cohort were 17.7 months and not reached, respectively. Among randomized patients, the hazard ratio for surgery versus radiotherapy in EFS in the intention-to-treat and per-protocol populations were 0.38 (95% CI: 0.14-1.01) and 0.21 (95% CI: 0.06-0.66), respectively. While, no significant difference in OS was observed. SAE and grade 3-5 treatment-related adverse event rates in induction therapy phase were 12.0% and 58.0%, respectively.
Conclusions
Induction chemoimmunotherapy showed good efficacy and safety in unresectable stage IIIB-IIIC NSCLC, and surgery brought longer EFS than radiotherapy.
656O - Proton versus Carbon Ion Radiotherapy in Skull Base Chordoma and Chondrosarcoma: Initial Clinical Outcomes from a Phase II Randomized Trial
Background
Chordoma and chondrosarcoma are rare mesenchymal malignancies posing unique therapeutic challenges due to their anatomical complexity and radioresistant biology. This study aimed to evaluate and compare the clinical outcomes of intensity-modulated proton therapy (IMPT) and intensity-modulated carbon ion therapy (IMCT) in patients with skull base chordoma or chondrosarcoma treated with curative intent.
Methods
This phase II randomized trial was conducted at the Shanghai Proton and Heavy Ion Center. Eligible patients aged 18–70 years with histopathologically confirmed classic skull base chordoma or chondrosarcoma were randomized (1:1) to receive either IMPT (64–70 GyRBE) or IMCT (63–70 GyRBE). The primary endpoint was 5-year local progression-free survival (LPFS). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and the incidence of adverse events as well as quality of life.
Results
Between August 2018 and December 2020, 103 patients were screened, and 52 were enrolled and randomized (26 in each group). The median follow-up was 58 months (range: 7–73 months), with 60 months (range: 36–73 months) for the IMPT group and 56 months (range: 7–71 months) for the IMCT group. Five patients died during the study: four due to tumor progression (two in each group) and one due to brain hemorrhage (IMPT group). Local recurrence occurred in 11 patients (four in the IMPT group and seven in the IMCT group). The 5-year LPFS, OS, and PFS rates for the entire cohort were 78.7%, 89.2%, and 74.7%, respectively. Specifically, the IMPT group achieved 5-year LPFS, OS, and PFS rates of 82.4%, 88.0%, and 75.3%, while the IMCT group achieved 75.7%, 91.3%, and 75.7%. No statistically significant differences were observed between the two groups in LPFS (p=0.179), OS (p=0.805), or PFS (p=0.437). Toxicities were tolerable and comparable between the two groups, with no significant differences.
Conclusions
This phase II trial demonstrates no significant differences in LPFS, OS, PFS, or toxicity between IMPT and IMCT for skull base chordoma or chondrosarcoma. Both modalities exhibit promising long-term outcomes and represent viable treatment options for this patient population.
1038MO - Single-dose carboplatin and involved-node radiotherapy for seminoma stage IIA/B: long-term follow-up from the international multicenter phase II trial SAKK 01/10
Background
The SAKK 01/10 trial (NCT01593241) tested de-escalated treatment with single-dose carboplatin followed by involve-node radiotherapy (RT) for seminoma stage IIA or IIB. The primary analysis of the trial in 2021 showed favorable progression-free survival (PFS) and minimal toxicity (Lancet Oncol. 2022;23:1441-1450). The current National Cancer Center Network (NCCN) guidelines endorse this regimen as a treatment alternative to standard of care. We report extended follow-up, addressing efficacy and safety.
Methods
SAKK 01/10 is a multicenter, single arm, phase II trial of the Swiss Group for Clinical Cancer Research (SAKK) and the German Testicular Cancer Study Group (GTCSG) in patients with seminoma stage IIA/B (de novo or relapse on active surveillance). Treatment consisted of one cycle carboplatin AUC7 followed by involved-node RT (IIA: 30 Gy; IIB: 36 Gy). The primary endpoint was 3-year progression-free survival (PFS). Key secondary endpoints included late renal, thromboembolic and gastrointestinal events as well as secondary malignancies (SM) at least possibly related to treatment.
Results
A total of 120 pts were included and 116 pts were eligible. 46 pts had stage IIA and 70 pts IIB seminoma. Current median follow-up is 8 years (minimal 5.9, maximal 12) for 85 patients still on follow-up. PFS at 10 years is 92.8% (IIA: 95.2%; IIB: 91.3%) and no further events have been recorded since the primary analysis in 2021. OS at 10 years is 99.1% (1 death due to SM). One late thromboembolic event was reported, possibly related to treatment. A total of 9 cases of SM, including 4 contralateral germ cell tumors, were recorded, none of which were deemed related to treatment.
Conclusions
Extended follow-up of SAKK 01/10 confirms the favorable efficacy with no further events in the past 5 years and a 10-year PFS of 92.8%. Furthermore, this novel treatment causes minimal toxicity also in the long-term. Our findings oppose concerns about higher incidence of SM or late toxicities due to the combined treatment. Single-dose carboplatin and involved-node radiotherapy for seminoma stage IIA/B should be considered as a new standard of care given its efficacy, minimal acute toxicity, and long-term safety.
660MO - A phase I, first-in-human study of regorafenib plus temozolomide with or without radiotherapy in patients with newly diagnosed MGMT methylated, IDH wildtype glioblastoma: The REGOMA-2 trial
Background
Regorafenib (REG) is an oral multikinase inhibitor. In vivo studies demonstrated a synergistic antitumor effect when combined with radiotherapy (RT) and temozolomide (TMZ) against glioblastoma (GBM). We conducted a phase 1 study to evaluate the safety, dose limiting toxicity (DLT), maximum tolerated dose (MTD) of REG, pharmacokinetics (PK), and preliminary activity of this combination.
Methods
This phase 1 multicenter academic study used a 3+3 design to evaluate REG 80 mg (Level 1), 120 mg (Level 2), and 160 mg (Level 3) in 2 cohorts of pts with MGMT-methylated, IDH wt GBM (WHO 2021) and ECOG PS 0-1. Cohort A received REG with maintenance TMZ after completing standard chemoradiotherapy (CT-RT); cohort B received REG concurrently with CT-RT and continued with TMZ. REG was given 3 weeks on/1 week off. DLT was evaluated during the first 2 maintenance cycles (cohort A) or during CT-RT (cohort B), with weekly clinical and lab assessments. Toxicity was graded per CTCAE v5.0, neuroradiologic response by RANO, and PK was also evaluated.
Results
In cohort A, none of the 9 pts (median age 52) had DLT. One pt at Level 2 had REG delayed and TMZ reduced due to G (grade) 2 thrombocytopenia; one G3 haematologic AE at Level 1 and 2 each; at Level 3, one pt had G3 GI toxicity. In cohort B (12 pts, median age 53), at Level 3, 2/6 pts had DLT [G3 hypertransaminasemia with REG (51%) and TMZ (50%) reductions; G4 thrombocytopenia on last RT day]. Also reported: G3 hypertension, G3 hypertransaminasemia, and REG reduced in one pt for G2 pain (non-DLT); at Level 2, one G3 hyperbilirubinemia. No G3–4 AEs at Level 1. PK analysis of REG showed a significant reduction (p=0.038) in the AUC, with a geometric mean ratio (GMR) of 80% (CI90 64–98%) when given together with TMZ. PK analysis of TMZ showed a slight but significant reduction in the Cmax and AUC (p=0.003 and 0.015, respectively) when given with REG. This suggest a weak PK interaction.
Conclusions
The MTD of REG for cohort A was 160 mg, for cohort B 120 mg with a weak PK interaction between the two drugs. The MTD of 120 mg can be considered the recommended dose of REG in combination with standard Stupp therapy for the phase 2 study. Preliminary activity analyses are ongoing.
662MO - Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide (TMZ) in unresectable high-grade gliomas patients (pts): Results from the phase IIa (OLA-TMZ-RTE-01)
Background
The Stupp protocol (Intensity modulated radiotherapy (IMRT) + TMZ) remains the mainstay first-line treatment of glioblastoma (GBM) after extended surgery. PARPi may enhance its efficacy. We conducted a phase 1/2a trial to assess safety and efficacy of olaparib in concomitant with the Stupp protocol as a first-line treatment in unresectable GBM pts: the phase 1 (30 pts) concluded the recommended phase II dose (RP2D) of olaparib was 100 mg Q12H Day (D) 1-3. We report results of the phase 2a.
Methods
Two treatment periods were considered. The radiotherapy period (RT) occurs after surgery: pts received IMRT (60 Gy/30 fr/6 wks), oral TMZ (75 mg/m2) during IMRT, and oral olaparib (RP2D) until 4 wks after IMRT end. For the maintenance period (MT) from 4 wks after IMRT, pts received TMZ (150 mg/m2, D 1-5 every 28 days, 6 cycles) plus olaparib (RP2D) up to disease progression or unacceptable toxicity. Using a two-step Case and Morgan design, 55 assessable pts (37 in interim analysis) were required to assess the 12-month (mo) overall survival (OS) rate expected to be higher than 57%.
Results
From 2020 to 2024, 68 pts were enrolled and treated in the phase 2a: 41 (60%) men, median age 59 yrs [range 20-70], 66 pts (97%) had GBM and 2 (3%) anaplastic astrocytoma. Biopsy-only was performed for 27 pts (40%). ECOG PS 0 for 34 pts (51%), 1 for 28 pts (42%) and 2 for 5 (7%). 12 pts (18%) stopped the study before MT, including 3 for toxicity. Among the 56 pts who began the MT, 9 stopped the treatment for toxicity. 16 pts remain on treatment. Interim analysis conducted in 41 pts, with 7.6 mo median follow-up, led to pursue the study: 12-mo OS rate of 72.9% [95%CI: 56.7-93.9]. To date (9.5 mo median follow-up), 30 deaths (43%) occurred. Median OS was 17.2 mo and 12-mo OS rate of 67.3% [95%CI: 35.7-66.5]. Required assessable pts for final analysis is expected to July 2025. Grade ≥ 3 hematological toxicities of interest were observed for 15 pts. One toxic death was noted (febrile aplasia).
Conclusions
Intermittent olaparib combined with the Stupp protocol is promising to improve survival of poor prognosis unresectable GBM pts, with a safety profile quite similar to that of the standard radiochemotherapy.
