LBA88 - PErioperative PEmbrolizumab (P) Plus Metastasis-Directed Therapy (MDT) Versus MDT Alone in Patients (Pts) with Oligometastatic Renal Cell Carcinoma (Omrcc): The Randomized Phase Aii PE-PE Trial

Presenter: Roberto Iacovelli

Background

For patients with oligometastatic renal cell carcinoma (omRCC) who are candidates for metastasis-directed therapy (MDT), the best management approach remains uncertain, even though anti-programmed cell death protein 1 (PD-1)-based combinations are an option. Adjuvant pembrolizumab is already the standard of care after nephrectomy for patients at intermediate-high/high risk of relapse, and for those who are metastatic with no evidence of disease (M1NED) within 1 year of prior nephrectomy.

Aim

To assess whether pembrolizumab given perioperatively with MDT delays tumour progression, compared with MDT alone, in patients with omRCC eligible for MDT.

Methods

• PE-PE (NCT05578664) is a randomised, open-label, multicentre phase II trial.
• Eligible patients had undergone prior nephrectomy and had ≤3 metastases within 5 years of nephrectomy or previous metastasectomy; MDT comprised surgery or stereotactic ablative radiotherapy (SABR) to all metastatic sites.
• Patients were randomised 2:1 to pembrolizumab 400 mg every 6 weeks for 9 cycles (1 year) plus MDT, or MDT alone; the first pembrolizumab dose was given before MDT.
• The primary endpoint was relapse-free survival (RFS); other endpoints included distant RFS, local relapse, overall survival (OS) and safety.

Results

• 85 patients randomised (March 2023–February 2026): pembrolizumab + MDT (n=56) vs MDT alone (n=29); baseline characteristics were well balanced.
• MDT modality (pembrolizumab + MDT vs MDT alone): SABR in 73% vs 72%; surgery in 23% vs 28%.
• Pembrolizumab exposure: median 6.6 cycles administered; most frequent reasons for discontinuation were disease progression (11 patients) and adverse events (AEs; 4 patients).
• Efficacy (median follow-up 17.5 months):
• RFS events: 35 in total (19 vs 16); 2 deaths (one in each arm)
• Median RFS: 25.4 vs 11.0 months; hazard ratio (HR) 0.47 (95% confidence interval [CI] 0.24–0.92; p=0.024)
• Safety (pembrolizumab + MDT vs MDT alone):
• ≥1 AE: 80% vs 21%
• Grade 3 AEs: 7% vs 3%
• Pembrolizumab-related AEs of any grade: 59%; most common were hypothyroidism (23%), fatigue (18%) and diarrhoea (16%)
• Grade 3 toxicity in 2 patients; no grade 4 or 5 events

Conclusion

In omRCC suitable for MDT, adding 1 year of perioperative pembrolizumab to MDT achieved a statistically significant and clinically meaningful improvement in RFS over MDT alone. Toxicity was manageable and consistent with the known profile, and the investigators regard these results as supporting this perioperative approach in patients eligible for MDT.

Reference

Iacovelli R. PErioperative PEmbrolizumab (P) plus metastasis-directed therapy (MDT) versus MDT alone in patients (pts) with oligometastatic renal cell carcinoma (omRCC): The randomized phase II PE-PE trial, LBA88. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA76 - A Global Phase 2, Open-Label Trial of Pumitamig (PD-L1 × VEGF-A bsab) + Docetaxel Post-Chemoimmunotherapy in mNSCLC: First Data from ROSETTA Lung-107

Presenter: Byoung Chul Cho

Background

Simultaneous blockade of programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor A (VEGF-A) within the tumour and tumour microenvironment (TME) is hypothesised to strengthen antitumour immunity and improve clinical outcomes. Pumitamig (BNT327/BMS986545) is an investigational bispecific antibody (bsAb) designed to achieve this dual blockade with a single molecule, and is being tested with docetaxel in metastatic non-small cell lung cancer (mNSCLC) after chemoimmunotherapy (CIT).

Aim

To report initial efficacy and safety of pumitamig plus docetaxel in patients with mNSCLC previously treated with CIT.

Methods

• ROSETTA Lung-107 (NCT06841055) is a global, open-label, single-arm phase 2 trial in patients with stage IV NSCLC who had received first-line (1L) CIT, with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1.
• Part 1 (safety run-in/dose escalation): pumitamig 1400 mg (n=3) or 2000 mg (n=3; data not shown) plus docetaxel every 3 weeks (Q3W).
• Part 2 (dose expansion): pumitamig 1400 mg plus docetaxel 75 mg/m² Q3W.
• Primary endpoints were dose-limiting toxicities (DLTs; Part 1 only), safety and objective response rate (ORR); secondary endpoints included disease control rate (DCR) and progression-free survival (PFS).
• Response-evaluable patients had ≥2 post-baseline tumour assessments, or 1 assessment followed by progressive disease (PD), death or study discontinuation.

Results

• 50 patients received pumitamig 1400 mg + docetaxel across Parts 1 and 2 (data cutoff 10 July 2026); 33 remained on treatment; median follow-up 12.2 weeks (0.1–41.3).
• Baseline: median age 67.0 years (34–83); 70.0% male; 26.0% squamous histology; 66.0% ECOG PS 1.
• Efficacy, response-evaluable patients (n=30), by PD-L1 tumour proportion score (TPS):
• Confirmed ORR: overall 11 (36.7%); TPS <1% (n=7) 3 (42.9%); TPS 1–49% (n=18) 6 (33.3%); TPS ≥50% (n=5) 2 (40.0%)
• Confirmed DCR: overall 27 (90.0%); TPS <1% 6 (85.7%); TPS 1–49% 17 (94.4%); TPS ≥50% 4 (80.0%)
• Unconfirmed ORR: overall 13 (43.3%); TPS <1% 3 (42.9%); TPS 1–49% 8 (44.4%); TPS ≥50% 2 (40.0%)
• Median time to response (TTR): 1.4 months (1.2–6.1)
• Median PFS: 6.9 months (4.2–not reached [NR])
• Safety (n=50):
• Pumitamig-related treatment-related adverse events (TRAEs): any grade 52.0%; grade ≥3 18.0%
• Pumitamig-related TRAEs leading to discontinuation: 8.0%
• Immune-mediated adverse events (AEs): 30.0% (grade ≥3 14.0%)
• VEGF-related events: 26.0% (grade ≥3 4.0%)
• Haemorrhage/bleeding: 16.0% (all grade 1/2)
• No DLTs reported

Conclusion

In mNSCLC progressing after CIT, pumitamig combined with docetaxel showed encouraging antitumour activity, with responses seen across PD-L1 expression levels, and a manageable safety profile. The investigators consider these early data supportive of further development of pumitamig in this setting and expect them to guide the design of a pivotal study.

Reference

Cho BC. A global phase 2, open-label trial of pumitamig (PD-L1 × VEGF-A bsAb) + docetaxel post-chemoimmunotherapy in mNSCLC: First data from ROSETTA Lung-107, LBA76. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA34 - First-In-Human Study of MRG007 (ARR-217), A CDH17-Directed Exatecan ADC, in Patients with Locally Advanced or Metastatic Solid Tumors

Presenter: Jian Li

Background

Once standard chemotherapy is exhausted, patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC) and other gastrointestinal (GI) malignancies have few remaining options. Cadherin-17 (CDH17) is frequently overexpressed in CRC and other GI tumours, making it an attractive antibody–drug conjugate (ADC) target. MRG007 (ARR-217) is a CDH17-targeting ADC with a hydrophilic, glycan-linked, site-specific exatecan design and a drug-to-antibody ratio of 4 (DAR4). Preclinically, it showed enhanced stability, rapid internalisation, potent cytotoxicity with bystander activity, and robust antitumour activity in CRC patient-derived xenograft (PDX) models, including those with low CDH17 expression.

Aim

To evaluate the safety, pharmacokinetics (PK) and preliminary antitumour activity of MRG007 in patients with advanced solid tumours, primarily CRC.

Methods

• MRG007-001/ARR-217-101 (NCT07066657) is a phase 1 study conducted in China and the US, comprising dose escalation/backfill followed by dose optimisation/expansion cohorts in CRC and other GI tumours.
• Eligible patients had advanced/metastatic solid tumours after standard therapies and received MRG007 intravenously every 3 weeks (Q3W).
• The primary objective of dose escalation was safety; the primary efficacy endpoint in expansion was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

Results

• 123 patients treated (data as of 5 August 2026), including 113 with CRC; median 2 prior lines for advanced disease (range 1–9).
• Dose escalation completed at 2, 4, 6 and 8 mg/kg; backfill is ongoing at 4–8 mg/kg, and randomised dose optimisation in CRC has started.
• Safety:
• Most common treatment-emergent adverse events (TEAEs) were cytopenias and GI toxicities, predominantly grade 1 or 2
• No interstitial lung disease (ILD) reported
• Discontinuation due to a TEAE: 1/123 patients (0.8%)
• PK: generally dose proportional; mean half-life (t1/2) ∼3.5 days for ADC/total antibody (TAb) and ∼5 days for payload; overlapping ADC and TAb profiles indicate enhanced conjugate stability.
• Efficacy, CRC at 6 mg/kg (preliminary recommended phase 2 dose [RP2D]), efficacy-evaluable patients:
• ORR: 44.8% (13/29; 95% confidence interval [CI] 26.4%–64.3%), including 7 confirmed partial responses (PRs) and 4 PRs pending confirmation
• Disease control rate (DCR): 93.1% (27/29)
• RAS wild-type CRC: ORR 50.0% (4/8); RAS-mutant CRC: ORR 42.1% (8/19)
• Efficacy, CRC at doses ≥4 mg/kg, efficacy-evaluable patients: ORR 34.2% (25/73; 95% CI 23.5%–46.3%).

Conclusion

In this first-in-human study, MRG007 showed dose-proportional PK and enhanced conjugate stability, together with promising preliminary activity in CRC, with responses in both RAS wild-type and RAS-mutant disease, and a manageable safety profile. These findings support continued development of MRG007, with phase 1b dose optimisation ongoing.

Reference

Li J. First-in-human study of MRG007 (ARR-217), a CDH17-directed exatecan ADC, in patients with locally advanced or metastatic solid tumors, LBA34. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA42 - HexAgon-HN: A Phase 2/3 Study of The Hexavalent OX40 Agonist ordastobart (INBRX-106) in Combination with Pembrolizumab As First-Line Treatment (1L tx) of PD-L1–High Recurrent/Metastatic Head And Neck Squamous Cell Carcinoma (R/M HNSCC) - Phase 2 Primary Analysis

Presenter: Jong Chul Park

Background

Pembrolizumab is a standard first-line (1L) treatment option for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), but response rates with it remain low. Ordastobart (INBRX-106) is a hexavalent agonist engineered to promote higher-order OX40 clustering; adding it to pembrolizumab may amplify and prolong the antitumour immune response.

Aim

To compare ordastobart plus pembrolizumab with pembrolizumab alone as 1L treatment for R/M HNSCC with high programmed death-ligand 1 (PD-L1) expression.

Methods

• In the randomised phase 2 part of the phase 2/3 HexAgon-HN study (NCT06295731), patients with 1L R/M HNSCC and a PD-L1 combined positive score (CPS) ≥20 were randomised 1:1 to open-label ordastobart + pembrolizumab or pembrolizumab alone.
• The primary endpoint was confirmed objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1; success was defined as an observed ORR difference (ΔORR) of ≥8 percentage points favouring the combination.
• Key secondary endpoints included progression-free survival (PFS) and safety.

Results

• 68 patients randomised (data cutoff 19 August 2026; median follow-up 7.0 months); median age 64.5 years; 85.3% male; 57.4% distant disease; 27.9% human papillomavirus-positive (HPV+) disease.
• ORR, response-evaluable patients (n=63):
• Ordastobart + pembrolizumab (n=29): 48.3% (95% confidence interval [CI] 29.4–67.5)
• Pembrolizumab (n=34): 26.5% (95% CI 12.9–44.4)
• Absolute ΔORR: 21.8%
• ORR, HPV+ subgroup (prespecified):
• Ordastobart + pembrolizumab (n=10): 80.0% (3 complete responses [CR] + 5 partial responses [PR])
• Pembrolizumab (n=9): 33.3% (3 PR)
• ΔORR: 46.7%
• PFS: preliminary analyses suggest a substantial improvement with ordastobart + pembrolizumab; updated analyses are to be presented.
• Safety (safety population, n=65; ordastobart + pembrolizumab vs pembrolizumab):
• Treatment-emergent adverse events (AEs): 100% vs 85.3%
• Grade ≥3 AEs: 58.1% vs 47.1%
• Serious AEs: 38.7% vs 35.3%
• Most frequent treatment-related AEs with the combination (any grade/grade ≥3): rash (32.3%/3.2%), maculo-papular rash (32.3%/9.7%), diarrhoea (29.0%/9.7%) and fatigue (29.0%/3.2%)
• Infusion-related reactions: 22.6%/3.2%; manageable and mainly at first dose

Conclusion

In PD-L1 CPS ≥20 R/M HNSCC, adding ordastobart to 1L pembrolizumab increased ORR and showed a preliminary PFS benefit without new safety signals. The effect was more pronounced in the prespecified HPV+ subgroup, which the authors consider worth further investigation. According to the investigators, these positive randomised phase 2 data provide clinical proof of concept for OX40 agonism in cancer immunotherapy.

Reference

Park JC. HexAgon-HN: A phase 2/3 study of the hexavalent OX40 agonist ordastobart (INBRX-106) in combination with pembrolizumab as first-line treatment (1L tx) of PD-L1–high recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) - Phase 2 primary analysis, LBA42. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA44 - TPF Versus A Novel Regimen of Paclitaxel, Carboplatin, and Oral Metronomic Chemotherapy As Neoadjuvant Treatment for Technically Unresectable Oral Cancers: Multicentric Phase III Randomized Non-Inferiority Study

Presenter: Vanita Noronha

Background

In technically unresectable or borderline resectable oral cancers, neoadjuvant chemotherapy (NACT) can improve outcomes, but the commonly used docetaxel–platinum–5-fluorouracil (TPF) regimen is toxic and logistically demanding. Weekly paclitaxel–carboplatin combined with triple oral metronomic chemotherapy (PCm) is a novel regimen that has shown promise as an alternative.

Aim

To determine whether neoadjuvant PCm is non-inferior to TPF for overall survival (OS) in technically unresectable oral cancers.

Methods

• Multicentric, open-label, randomised phase III study (CTRI/2023/08/056693) in patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 and technically unresectable oral cancer (soft-tissue oedema up to the zygoma/hyoid/infratemporal fossa/oropharynx, extensive skin involvement, or bulky lymph nodes).
• Patients were randomised 1:1 to:
• TPF every 3 weeks for 2–4 cycles, or
• PCm: weekly paclitaxel 80 mg/m² and carboplatin area under the curve (AUC) 1.5, with methotrexate 9 mg/m² once weekly, celecoxib 200 mg twice daily and erlotinib 150 mg once daily, for 6–9 cycles
• After NACT, patients whose tumours became resectable underwent surgery, followed by adjuvant chemoradiation if indicated.
• The primary endpoint was OS; the non-inferiority hazard ratio (HR) margin was 1.3.

Results

• 475 patients enrolled (September 2023–April 2026): TPF (n=236; reported as DCF in the results) vs PCm (n=239).
• Baseline: median age 45 years (interquartile range [IQR] 39–53); primary site buccal mucosa in 341 (71.8%) and tongue in 134 (28.2%); stage IVA in 114 (24%) and IVB in 361 (76%).
• Treatment delivery (TPF vs PCm): median cycles 2 (IQR 2–3) vs 7 (IQR 6–9); growth factor use 100% vs 20.5%.
• Toxicity: grade >3 toxicities 86.4% vs 43.2%; P<0.001.
• Response and resectability (TPF vs PCm):
• Objective response rate (ORR): 23.4% vs 45.6%; P<0.001
• Deemed resectable after NACT: 80 (33.9%) vs 137 (57.3%)
• Surgery performed: 61 (26%) vs 109 (45.6%); P<0.001
• Pathological complete response (CR): 4 (6.6%) vs 6 (5.5%)
• Adjuvant radiation ± chemotherapy: 58 (95.1%) vs 97 (89%)
• OS (TPF vs PCm): median 13.99 vs 13.31 months; HR 0.826 (one-sided 95% confidence interval [CI] 0.668–1.021); non-inferiority P=0.0002.

Conclusion

For technically unresectable oral cancers, neoadjuvant weekly paclitaxel and carboplatin combined with oral metronomic chemotherapy met the non-inferiority criterion for OS against TPF, while causing less toxicity and requiring fewer resources.

Reference

Noronha V. TPF versus a novel regimen of paclitaxel, carboplatin, and oral metronomic chemotherapy as neoadjuvant treatment for technically unresectable oral cancers: Multicentric phase III randomized non-inferiority study, LBA44. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA66 - Sacituzumab tirumotecan (Sac-TMT) Plus pembrolizumab (P) Versus Chemotherapy (Chemo) Plus pembrolizumab (P) As First-Line (1L) Treatment for PD-L1-Negative Advanced Non-Squamous (nsq) NSCLC: Randomized Phase 3 OptiTROP-Lung06 Study

Presenter: Caicun Zhou

Background

For advanced non-squamous non-small cell lung cancer (nsq-NSCLC) that is negative for programmed death-ligand 1 (PD-L1) and lacks actionable genomic alterations, pembrolizumab plus chemotherapy is the standard first-line (1L) treatment, yet outcomes remain suboptimal. Sacituzumab tirumotecan (sac-TMT), a trophoblast cell-surface antigen 2 (TROP2)-directed antibody–drug conjugate (ADC), previously showed encouraging activity with programmed cell death protein 1 (PD-1) blockade in 1L PD-L1-positive NSCLC (Xiong et al., Lancet, 2026).

Aim

To report the preplanned interim progression-free survival (PFS) analysis of sac-TMT plus pembrolizumab versus chemotherapy plus pembrolizumab in 1L PD-L1-negative nsq-NSCLC.

Methods

• OptiTROP-Lung06 (NCT06711900) is a randomised phase 3 study.
• Eligible patients had treatment-naïve, locally advanced or metastatic nsq-NSCLC without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) alterations and a PD-L1 tumour proportion score (TPS) <1% (22C3 assay).
• Patients were randomised 1:1 to sac-TMT 4 mg/kg every 2 weeks (Q2W) plus pembrolizumab 400 mg every 6 weeks (Q6W), or chemotherapy plus pembrolizumab.
• The primary endpoint was PFS per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 by blinded independent central review (BICR); overall survival (OS) was a secondary endpoint.

Results

• 455 patients randomised: sac-TMT + pembrolizumab (n=229) vs chemotherapy + pembrolizumab (n=226); median age 63 years; 72.1% male; 82.4% Eastern Cooperative Oncology Group (ECOG) 1; 91.6% stage IV.
• Median follow-up: 9.7 months (data cutoff 9 June 2026).
• Efficacy (sac-TMT + pembrolizumab vs chemotherapy + pembrolizumab):
• Median PFS by BICR: 15.0 vs 5.7 months; hazard ratio (HR) 0.49 (95% confidence interval [CI] 0.36–0.65); p<0.0001
• OS (immature): favourable trend; HR 0.58 (95% CI 0.38–0.88)
• Objective response rate (ORR) by BICR: 50.2% vs 47.3%
• Median duration of response (DoR): 13.6 vs 6.8 months; HR 0.47 (95% CI 0.29–0.77)
• Safety (sac-TMT + pembrolizumab vs chemotherapy + pembrolizumab):
• Grade ≥3 treatment-emergent adverse events (TEAEs): 47.6% vs 60.6%
• Neutrophil count decreased: 19.7% vs 28.8%
• White blood cell count decreased: 9.6% vs 16.4%
• Anaemia: 6.1% vs 20.4%
• Platelet count decreased: 3.9% vs 14.6%
• Sac-TMT-associated adverse events of special interest (AESIs) were manageable; grade ≥3 stomatitis occurred in 2.2%

Conclusion

In PD-L1-negative advanced nsq-NSCLC, sac-TMT plus pembrolizumab significantly extended PFS and produced more durable responses than chemotherapy plus pembrolizumab, with a manageable safety profile. The authors report this as, to their knowledge, the first randomised phase 3 trial in NSCLC in which a TROP2-directed ADC plus PD-1 blockade achieved superior PFS over standard immunotherapy plus chemotherapy, supporting sac-TMT plus pembrolizumab as a potential 1L option for this population.

Reference

Zhou C. Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (P) versus chemotherapy (chemo) plus pembrolizumab (P) as first-line (1L) treatment for PD-L1-negative advanced non-squamous (nsq) NSCLC: Randomized phase 3 OptiTROP-Lung06 study, LBA66. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA46 - Niraparib and Dostarlimab Plus Radiotherapy (RT) in Locally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC) Patients (TTCC-2022-01 RADIAN)

Presenter: Marc Oliva

Background

Patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) receive definitive cisplatin plus radiotherapy (CRT), or radiotherapy (RT) alone when unfit for cisplatin. The RADIAN trial added niraparib and dostarlimab to each of these backbones; after preliminary results were reported for the CRT cohort, final analyses at study completion are now presented.

Aim

To report final efficacy and safety of niraparib plus dostarlimab combined with CRT (cohort A) or RT alone (cohort B) in LA-HNSCC.

Methods

• RADIAN (NCT05784012; EU-CT 2024-516779-33-00) enrolled patients with programmed death-ligand 1 (PD-L1) combined positive score (CPS) >1, stage III–IVB HNSCC and Eastern Cooperative Oncology Group (ECOG) performance status 0–1, who were candidates for standard CRT (cohort A) or RT alone if unfit for cisplatin (cohort B).
• All patients received one dose of dostarlimab 500 mg intravenously at week −3 before RT, and niraparib 200–300 mg/day from week −2 until the start of CRT (cohort A) or continuously until the end of RT (cohort B).
• Maintenance dostarlimab (500 mg every 3 weeks) plus niraparib began 4 weeks after RT, for up to 14 cycles.
• The primary endpoint was 1-year disease-free survival (1yDFS), with an expected hazard ratio (HR) <0.64 versus historical controls (one-sided α <0.10); secondary objectives included safety and other efficacy measures, with overall response rate (ORR) after RT assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.
• Planned sample size N=34; data cutoff 01/09/26.

Results

• Baseline (cohort A, n=17 vs cohort B, n=17): median age 65 (41–68) vs 73 (68–75) years; male 12 (71%) vs 16 (94%); ECOG 0 in 6 (35%) in each cohort; larynx primary 9 (53%) vs 8 (47%).
• Treatment compliance (cohort A vs cohort B):
• Completed RT (70 Gy): 15 (88%) vs 17 (100%)
• Maintenance started: 14 (82%) vs 13 (76%)
• Discontinued dostarlimab and/or niraparib due to treatment-related adverse events (TRAEs): 7 (41%) vs 10 (59%)
• Niraparib dose reductions/interruptions: 11 (65%)/12 (71%) vs 10 (67%)/15 (88%)
• Cohort A (CRT):
• ORR (evaluable in 15/17): 93% (13 complete responses [CR], 1 partial response [PR])
• 2 patients died during CRT due to adverse events (AEs), 1 related to niraparib
• 1yDFS: 88.2% (95% confidence interval [CI] 74.2–100) vs 65% historical; HR 0.19, p=0.01
• At a median follow-up (mFU) of 17 months (95% CI 16–25), all 15 patients were alive without recurrence
• Cohort B (RT alone):
• Grade >3 TRAEs in all patients; niraparib TRAEs in 76% and dostarlimab TRAEs in 29%
• Most common TRAEs leading to niraparib and/or dostarlimab interruption/discontinuation: mucositis and odynodysphagia
• 5 deaths: 2 related to niraparib–RT, 1 due to an unrelated AE, 2 due to progression
• ORR (evaluable in 15/17): 100% (11 CR, 4 PR); 4 patients recurred
• 1yDFS: 61% (95% CI 40–91) vs 55% historical; HR 0.72, p=0.19
• At an mFU of 13.6 months (95% CI 7.8–16.4), 10/12 patients were alive with no recurrence

Conclusion

The two cohorts diverged. With CRT (cohort A), adding niraparib and dostarlimab met the primary endpoint, improving 1yDFS over historical controls. With RT alone in cisplatin-unfit patients (cohort B), niraparib intensified and prolonged RT-related toxicity, including 2 toxic deaths, and provided no DFS benefit.

Reference

Oliva M. Niraparib and dostarlimab plus radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients (TTCC-2022-01 RADIAN), LBA46. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA5 - Krascendo 1: Efficacy and Safety of Divarasib (Diva) Vs Sotorasib (Soto) or Adagrasib (Ada) in Previously Treated Locally Advanced or Metastatic KRAS G12C-Mutated NSCLC

Presenter: Ferdinandos Skoulidis

Background

Divarasib is an oral, next-generation KRAS G12C inhibitor that, in vitro, is more potent and more selective for KRAS G12C than the existing inhibitors sotorasib and adagrasib. Krascendo 1 compared divarasib head-to-head with these agents in advanced/metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC).

Aim

To report the primary analysis of efficacy and safety of divarasib versus sotorasib or adagrasib in previously treated advanced/metastatic KRAS G12C-mutated NSCLC.

Methods

• Krascendo 1 (NCT06497556) is a global, randomised, open-label phase 3 trial.
• Eligible patients were aged ≥18 years, had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, and had received ≥1 prior systemic treatment (including anti-PD-1/PD-L1 [programmed cell death protein 1/programmed death-ligand 1] therapy and platinum-based chemotherapy) for advanced/metastatic KRAS G12C-mutated NSCLC.
• Patients were randomised 1:1 to divarasib 400 mg orally once daily (QD) or investigator's choice of sotorasib 960 mg orally QD or adagrasib 600 mg orally twice daily (BID).
• Stratification factors were KEAP1 status, history of central nervous system (CNS) metastases and intended KRAS G12C inhibitor (sotorasib/adagrasib); treatment continued until unacceptable toxicity, loss of clinical benefit, consent withdrawal or death.
• The primary endpoint was progression-free survival (PFS) per blinded independent committee review (BICR); secondary endpoints included overall survival (OS), confirmed objective response rate (ORR) per BICR (Response Evaluation Criteria in Solid Tumours [RECIST] 1.1), patient-reported outcomes, duration of response (DoR) and safety.

Results

• 338 patients randomised: divarasib (n=167) vs control (n=171; sotorasib n=156, adagrasib n=15); baseline characteristics were generally balanced.
• Median follow-up: 14.3 months (data cutoff 19 May 2026).
• Efficacy (divarasib vs control):
• Median PFS per BICR: 9.8 (95% confidence interval [CI] 8.1–12.9) vs 5.7 (95% CI 4.2–6.8) months; stratified hazard ratio (HR) 0.58 (95% CI 0.44–0.76); p<0.0001
• Median OS: 17.7 (95% CI 16.3–not estimable [NE]) vs 12.0 (95% CI 10.0–15.2) months; stratified HR 0.56 (95% CI 0.41–0.78); p=0.0005
• Confirmed ORR per BICR (response-evaluable set): 58.4% (94/161; 95% CI 50.4–66.1) vs 32.3% (54/167; 95% CI 25.3–40.0); statistically significant improvement
• Safety (divarasib vs control):
• Median treatment duration: 11.3 (range 0–19.8) vs 5.0 (range 0–19.8) months
• All-grade adverse events (AEs)/treatment-related AEs (TRAEs): 166 (99.4%)/155 (92.8%) vs 167 (97.7%)/137 (80.1%)
• Grade 3–4 AEs/TRAEs: 72 (43.1%)/41 (24.6%) vs 88 (51.5%)/59 (34.5%); no grade 5 TRAEs
• Serious AEs/TRAEs: 51 (30.5%)/13 (7.8%) vs 70 (40.9%)/26 (15.2%)
• AEs/TRAEs leading to discontinuation: 12 (7.2%)/8 (4.8%) vs 25 (14.6%)/20 (11.7%)
• Safety profile manageable and consistent with previous reports for divarasib and other KRAS G12C inhibitors

Conclusion

In previously treated advanced/metastatic KRAS G12C-mutated NSCLC, divarasib outperformed sotorasib or adagrasib, with statistically significant gains in both PFS and OS, a higher response rate and a manageable safety profile. On the basis of these results, the investigators position divarasib as a new standard of care for this population.

Reference

Skoulidis F. Krascendo 1: Efficacy and safety of divarasib (diva) vs sotorasib (soto) or adagrasib (ada) in previously treated locally advanced or metastatic KRAS G12C-mutated NSCLC, LBA5. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA6 - Osimertinib (Osi) + savolitinib (Savo) Vs platinum–pemetrexed (plat–pem) in EGFRm MET-Overexpressed (OE) and/or -Amplified (AMP) Advanced NSCLC post-osi: SAFFRON Phase (Ph) 3 Primary Results

Presenter: Shun Lu

Background

For advanced non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor mutation (EGFRm) and MET overexpression (OE) and/or amplification (AMP) that has progressed on osimertinib, targeted treatment options are limited. In the phase 2 SAVANNAH study (NCT03778229), osimertinib, a third-generation, irreversible, central nervous system (CNS)-active EGFR tyrosine kinase inhibitor (TKI), combined with savolitinib, an oral, potent, highly selective, CNS-penetrant MET-TKI, produced high and clinically meaningful response rates in this setting.

Aim

To assess the efficacy and safety of osimertinib plus savolitinib versus platinum–pemetrexed in EGFRm MET-OE and/or -AMP advanced NSCLC after osimertinib.

Methods

• SAFFRON (NCT05261399) is a global, randomised phase 3 study.
• Eligible patients were aged ≥18 years with EGFRm (Ex19del/L858R and/or T790M), MET-OE and/or -AMP advanced NSCLC (MET immunohistochemistry [IHC] 3+ intensity in ≥90% of tumour cells and/or ≥10 MET gene copies by fluorescence in situ hybridisation [FISH]) after first- or second-line osimertinib.
• Patients were randomised 1:1 to osimertinib 80 mg once daily (QD) plus savolitinib 300 mg twice daily (BID), or platinum–pemetrexed (pemetrexed + carboplatin/cisplatin every 3 weeks [Q3W] for 4 cycles, then maintenance pemetrexed Q3W), until progression per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 or discontinuation.
• The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR; RECIST 1.1); secondary/exploratory endpoints included overall survival (OS), investigator-assessed PFS and safety. Data cutoff: 6 July 2026.

Results

• 338 patients randomised: osimertinib + savolitinib (n=171) vs platinum–pemetrexed (n=167).
• Efficacy (osimertinib + savolitinib vs platinum–pemetrexed):
• Median PFS by BICR: 7.6 (95% confidence interval [CI] 5.6–9.7) vs 5.4 (95% CI 4.2–5.8) months; hazard ratio (HR) 0.55 (95% CI 0.42–0.72); p<0.001
• Median investigator-assessed PFS: 7.4 (95% CI 5.6–9.7) vs 4.2 (95% CI 3.4–4.5) months; HR 0.47 (95% CI 0.36–0.61)
• Median OS: 17.8 (95% CI 15.6–23.7) vs 12.9 (95% CI 10.6–16.8) months; HR 0.68 (95% CI 0.50–0.91); p=0.010
• Median duration of response (DoR) by BICR: 9.7 (95% CI 7.6–12.5) vs 5.7 (95% CI 4.4–8.1) months
• PFS benefit was consistent across the MET-OE and MET-AMP subgroups
• Safety (osimertinib + savolitinib vs platinum–pemetrexed):
• All-causality treatment-emergent adverse events (TEAEs): 99% (grade ≥3 64%) vs 97% (grade ≥3 63%)
• TEAEs leading to treatment discontinuation: 14% vs 8%
• Serious TEAEs: 41% vs 28%
• Treatment-related adverse events: 93% (grade ≥3 40%) vs 92% (grade ≥3 52%)

Conclusion

After progression on osimertinib, adding savolitinib to osimertinib gave statistically significant and clinically meaningful gains in both PFS and OS over platinum–pemetrexed in EGFRm NSCLC with MET-OE and/or -AMP, and its safety profile was manageable. The authors conclude that this all-oral targeted combination is an effective treatment for these patients and establishes a new global standard of care.

Reference

Lu S. Osimertinib (osi) + savolitinib (savo) vs platinum–pemetrexed (plat–pem) in EGFRm MET-overexpressed (OE) and/or -amplified (AMP) advanced NSCLC post-osi: SAFFRON phase (Ph) 3 primary results, LBA6. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA7 - CLARITY-Gastric 01 (CG-01): A Phase 3 Study of Sonesitatug Vedotin (Sone-Ve) in Second or Later-Line (2L+) Advanced or Metastatic Claudin 18.2 (CLDN18.2)-Positive Gastroesophageal Carcinoma (GEC)

Presenter: Rui-Hua Xu

Background

Claudin 18.2 (CLDN18.2) is a validated therapeutic target in advanced gastroesophageal carcinoma (GEC). Sonesitatug vedotin (Sone-Ve), a CLDN18.2-targeting antibody–drug conjugate carrying a monomethyl auristatin E payload, showed clinical activity in phase 1/2 studies of advanced GEC.

Aim

To compare Sone-Ve with investigator's choice of therapy (INV) in second-line or later (2L+) advanced or metastatic CLDN18.2-positive GEC.

Methods

• CLARITY-Gastric 01 (CG-01; NCT06346392) is a randomised, open-label, global phase 3 study in patients with unresectable, locally advanced/metastatic GEC after ≥1 prior therapy, with CLDN18.2 expression in ≥25% of tumour cells (membranous staining at any intensity); this 2L+ population formed the intention-to-treat (ITT) population.
• Patients were initially randomised 1:1:1 to Sone-Ve 1.8 mg/kg, Sone-Ve 2.2 mg/kg or INV; after dose selection, randomisation was 1:1 to Sone-Ve 2.2 mg/kg or INV.
• INV options: in second line (2L), ramucirumab + paclitaxel, paclitaxel or docetaxel; in third line or later (3L+), irinotecan, trifluridine/tipiracil or apatinib (China only).
• Randomisation was stratified by region, prior gastrectomy and line of therapy.
• Dual primary endpoints were overall survival (OS) in 3L+ and progression-free survival (PFS) by blinded independent central review (BICR) in the ITT population; OS in ITT was the key secondary endpoint.

Results

• 532 of 594 total patients randomised to Sone-Ve 2.2 mg/kg (n=267) or INV (n=265); data cutoff 31 May 2026; median follow-up 8.6 months.
• OS, 3L+ (Sone-Ve n=178 vs INV n=177): median 10.0 (95% confidence interval [CI] 7.2–11.4) vs 5.0 (95% CI 4.2–6.4) months; hazard ratio (HR) 0.47 (95% CI 0.36–0.62); p<0.001
• OS, ITT/2L+ (n=267 vs n=265): median 10.6 (95% CI 9.1–12.0) vs 6.4 (95% CI 5.8–7.6) months; HR 0.58 (95% CI 0.47–0.73); p<0.001
• Consistent benefit across CLDN18.2 expression subgroups: ≥75%, HR 0.59 (95% CI 0.45–0.78); ≥25–<75%, HR 0.63 (95% CI 0.42–0.94)
• PFS by BICR, ITT: median 4.2 (95% CI 3.5–5.3) vs 3.8 (95% CI 3.0–4.2) months; HR 0.77 (95% CI 0.62–0.96); p=0.05; did not meet the threshold for statistical significance.
• Safety (safety analysis set [SAS]: all patients who received ≥1 dose; Sone-Ve n=261 vs INV n=252):
• Any treatment-related adverse events (TRAEs): 224 (85.8%) vs 205 (81.3%)
• Grade ≥3 TRAEs: 95 (36.4%) vs 113 (44.8%)
• Gastrointestinal toxicity: 29 (11.1%) vs 16 (6.3%)
• Haematological toxicity: 20 (7.7%) vs 40 (15.9%)
• TRAEs leading to death: 3 (1.1%) vs 2 (0.8%)
• TRAEs leading to discontinuation: 8 (3.1%) vs 11 (4.4%)

Conclusion

In previously treated CLDN18.2-positive advanced GEC, Sone-Ve 2.2 mg/kg significantly prolonged OS versus INV both in 3L+ and in the overall ITT population, with a manageable safety profile, although the PFS endpoint did not reach statistical significance. The authors view these results as supporting Sone-Ve as a potential 2L+ treatment for a broad population of patients with advanced CLDN18.2-positive GEC.

Reference

Xu RH. CLARITY-Gastric 01 (CG-01): A phase 3 study of sonesitatug vedotin (Sone-Ve) in second or later-line (2L+) advanced or metastatic Claudin 18.2 (CLDN18.2)-positive gastroesophageal carcinoma (GEC), LBA7. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

ESMO Congress 2026, 23 - 27 October 2026, Madrid