LBA69 - Savolitinib or Placebo Combined with Osimertinib in Treatment-Naïve Advanced NSCLC with EGFR Mutation and MET Overexpression: Results from The Phase 3 SANOVO Study

Presenter: Yi-Long Wu

Background

In advanced non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor mutation (EGFRm), de novo MET overexpression (MET-OE) has been linked to reduced efficacy of first-line (1L) EGFR tyrosine kinase inhibitor (TKI) monotherapy (Ma L, et al). Savolitinib is a potent, central nervous system (CNS)-penetrant MET inhibitor (METi), and the phase 3 SANOVO study in China compared savolitinib plus osimertinib with placebo plus osimertinib in this population.

Aim

To report the primary results of 1L savolitinib plus osimertinib versus placebo plus osimertinib in EGFRm, MET-OE advanced NSCLC.

Methods

• SANOVO (NCT05009836) is a phase 3, randomised, double-blind study conducted in China.
• Eligible patients had treatment-naïve, locally advanced/metastatic NSCLC with EGFRm (exon 19 deletion [del]/L858R) and MET-OE, defined as immunohistochemistry (IHC) 2+ (H-score ≥220, <90% of tumour cells with strong staining) or IHC 3+ (≥90% of tumour cells with strong staining).
• Patients were randomised 1:1 to savolitinib + osimertinib or placebo + osimertinib, stratified by EGFRm type (exon 19 del/L858R), brain metastases (yes/no) and MET-OE level (IHC 2+/3+).
• Savolitinib/placebo was given at 300 or 200 mg twice daily (BID; weight-based) and osimertinib at 80 mg once daily (QD) until disease progression, intolerable toxicity or death, whichever occurred first.
• The primary endpoint was investigator (INV)-assessed progression-free survival (PFS), tested hierarchically (MET IHC 3+ population first, then the intention-to-treat [ITT] population if positive). Data cutoff (DCO): 31 July 2026.

Results

• 326 patients randomised: savolitinib + osimertinib (n=162) vs placebo + osimertinib (n=164); 98 per group had MET IHC 3+ status; baseline characteristics were generally balanced.
• INV-assessed PFS (savolitinib + osimertinib vs placebo + osimertinib):
• MET IHC 3+ population (n=98 per group): median 24.8 vs 11.1 months; hazard ratio (HR) 0.45 (95% confidence interval [CI] 0.31–0.66); P<0.0001
• ITT population (n=162 vs n=164): median 24.9 vs 13.8 months; HR 0.56 (95% CI 0.43–0.74); P<0.0001
• Overall survival (OS), ITT population: median 44.5 vs 34.9 months; HR 0.48 (95% CI 0.33–0.68), at a median follow-up of 38.7 months.
• Treatment exposure and safety (savolitinib + osimertinib vs placebo + osimertinib):
• Median treatment exposure: 22.1 vs 12.9 months
• Adverse events (AEs) leading to discontinuation: 14.8% vs 4.3%
• Safety was consistent with the known profiles of this combination

Conclusion

In treatment-naïve EGFRm advanced NSCLC with MET-OE, adding savolitinib to osimertinib produced a statistically significant PFS improvement and a clinically meaningful OS benefit over osimertinib alone. Safety was manageable, with no new signals identified. The authors view this all-oral dual regimen as a potential new treatment option for this biomarker-defined population.

Reference

Wu YL. Savolitinib or placebo combined with osimertinib in treatment-naïve advanced NSCLC with EGFR mutation and MET overexpression: Results from the phase 3 SANOVO study, LBA69. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA71 - PANKU-Lung01: Randomized Phase III Study of Izalontamab Brengitecan (Iza-Bren) in EGFR-Mutant Non-Squamous Non-Small Cell Lung Cancer (NSCLC) After Progression on A Third-Generation EGFR TKI

Presenter: Li Zhang

Background

Once advanced/metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) progresses on an EGFR tyrosine kinase inhibitor (TKI), treatment options are limited. Izalontamab brengitecan (iza-bren) is a first-in-class bispecific antibody–drug conjugate (ADC) directed against EGFR and human epidermal growth factor receptor 3 (HER3), carrying a potent topoisomerase I inhibitor payload (Ed-04) attached through a cleavable tetrapeptide-based linker.

Aim

To compare iza-bren with platinum-based chemotherapy (PBC) in EGFR-mutant non-squamous NSCLC after progression on a third-generation EGFR TKI.

Methods

• PANKU-Lung01 (NCT06382116) is a randomised phase III study.
• Eligible patients had locally advanced or metastatic non-squamous NSCLC with an EGFR-sensitising mutation (exon 19 deletion or L858R) and progression on a prior third-generation EGFR TKI.
• Patients were randomised 1:1 to iza-bren 2.5 mg/kg intravenously (IV) on days 1 and 8 every 3 weeks (D1D8 Q3W) or PBC (pemetrexed + cisplatin/carboplatin, Q3W).
• The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR); secondary endpoints included overall survival (OS).
• A pre-planned interim analysis served as the final analysis for PFS and the interim analysis for OS.

Results

• 422 patients treated (data cutoff 15 July 2026): iza-bren (n=216) vs PBC (n=206); median follow-up for PFS 14.6 vs 15.2 months.
• Efficacy (iza-bren vs PBC):
• Median PFS (mPFS) by BICR: 11.14 (95% confidence interval [CI] 9.17–12.68) vs 5.65 (95% CI 5.45–5.95) months; hazard ratio (HR) 0.40 (95% CI 0.31–0.51); p<0.0001
• OS (immature): favourable trend towards improved median OS (mOS); HR 0.66 (95% CI 0.47–0.91)
• Confirmed objective response rate (cORR) by BICR: 60.2% vs 34.5%
• Median duration of response (mDOR): 10.45 vs 5.68 months
• Safety:
• Grade ≥3 treatment-related adverse events (TRAEs) were predominantly haematological; TRAEs were manageable with standard supportive care
• Discontinuation due to TRAEs in the iza-bren group: 1.9%
• Interstitial lung disease (ILD) was uncommon with iza-bren: adjudicated ILD in two patients (0.9%; one grade 3 and one grade 1)
• No new safety signals were observed

Conclusion

After progression on a third-generation EGFR TKI in EGFR-mutant non-squamous NSCLC, iza-bren met the primary endpoint, delivering a statistically significant and clinically meaningful PFS improvement over PBC, with a trend towards better OS. Its safety profile was manageable and consistent with earlier studies. The investigators consider these results supportive of iza-bren as a new standard of care for this population in China; a global study (NCT07100080) is ongoing.

Reference

Zhang L. PANKU-Lung01: Randomized phase III study of izalontamab brengitecan (iza-bren) in EGFR-mutant non-squamous non-small cell lung cancer (NSCLC) after progression on a third-generation EGFR TKI, LBA71. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA72 - Ruzaltatug Rezetecan, A HER3-Directed ADC, Vs Platinum-Based Chemotherapy (PBC) in EGFR-Mutated Advanced NSCLC Progressing after EGFR-TKI: Interim Analyses (IA) from The Phase 3 HERON-Lung01 Trial

Presenter: Chongrui Xu

Background

Ruzaltatug rezetecan (SHR-A2009) is a novel antibody–drug conjugate (ADC) built from a fully human anti-human epidermal growth factor receptor 3 (HER3) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), a cleavable peptide linker and a DNA topoisomerase I inhibitor payload. In an earlier phase 1 trial, it showed promising antitumour activity and manageable safety in pretreated epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), which supported pivotal investigation.

Aim

To compare SHR-A2009 with platinum-based chemotherapy (PBC) in EGFR-mutated advanced NSCLC progressing after an EGFR tyrosine kinase inhibitor (TKI), at the prespecified interim analysis (IA).

Methods

• HERON-Lung01 (NCT06671379) is a randomised phase 3 study in patients with EGFR-mutated (exon 19 deletion [Ex19del]/L858R) advanced non-squamous NSCLC progressing after EGFR-TKI.
• Patients were randomised 1:1 to SHR-A2009 8 mg/kg intravenously (IV) every 3 weeks (Q3W) or PBC (pemetrexed 500 mg/m² + carboplatin area under the curve [AUC] 5 or cisplatin 75 mg/m² Q3W for 4 cycles, followed by maintenance pemetrexed).
• Crossover from the PBC arm to SHR-A2009 was allowed after disease progression.
• The primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR).

Results

• 498 patients randomised: SHR-A2009 (n=250) vs PBC (n=248); at the prespecified PFS IA (data cutoff 15 April 2026), median follow-up was 7.7 months.
• Efficacy (SHR-A2009 vs PBC):
• BICR-assessed PFS: median 8.3 vs 5.4 months; hazard ratio (HR) 0.47 (95% confidence interval [CI] 0.36–0.60); 1-sided P<0.0001
• PFS benefit persisted across all prespecified subgroups, regardless of brain metastases or EGFR mutation type
• Overall survival (OS; immature): favoured SHR-A2009; HR 0.70 (95% CI 0.43–1.14), despite substantial post-progression crossover (19.4%) from the PBC arm
• Per BICR: objective response rate (ORR) 60.0% vs 34.3%; disease control rate (DCR) 92.8% vs 83.1%; median duration of response (DoR) 8.5 vs 4.4 months
• Safety (SHR-A2009 vs PBC):
• Grade ≥3 treatment-related adverse events (TRAEs): 40.7% vs 38.9%; most commonly decreased neutrophil count (25.8% vs 19.2%), decreased white blood cell (WBC) count (11.7% vs 12.1%) and anaemia (6.0% vs 10.9%)
• Interstitial lung disease (ILD) with SHR-A2009: 6 patients (2.4%; grade 1–2, n=5; grade 3, n=1)
• TRAEs leading to dose discontinuation: 1.2% vs 1.3%

Conclusion

In advanced EGFR-mutated NSCLC that has progressed after EGFR-TKI therapy, SHR-A2009 significantly extended PFS compared with PBC and had a manageable safety profile. On this basis, the authors position SHR-A2009 as a new standard-of-care option for this population.

Reference

Xu C. Ruzaltatug rezetecan, a HER3-directed ADC, vs platinum-based chemotherapy (PBC) in EGFR-mutated advanced NSCLC progressing after EGFR-TKI: Interim analyses (IA) from the phase 3 HERON-Lung01 trial, LBA72. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA49 - A DESTINY-Breast09 (DB-)09 Analysis of Trastuzumab Deruxtecan (T-Dxd) + Pertuzumab (P) Vs Taxane + Trastuzumab + Pertuzumab (THP) for Patients (Pts) with HER2+ Advanced/Metastatic Breast Cancer (a/mBC) and Baseline (BL) Brain Metastases (Bms)

Presenter: Cristina Saura Manich

Background

Brain metastases (BMs) occur in 30–50% of patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC) and are associated with poor prognosis. Management relies on locoregional intervention, and systemic treatments with intracranial (IC) activity are still needed. Trastuzumab deruxtecan (T-DXd), recommended for HER2+ advanced/metastatic breast cancer (a/mBC) with BMs, showed substantial IC activity in previously treated patients in DESTINY-Breast12 (DB-12). First-line (1L) T-DXd plus pertuzumab is approved in the US and EU for HER2+ a/mBC, based on interim results from DESTINY-Breast09 (DB-09; NCT04784715), in which median progression-free survival (PFS) was 40.7 months with T-DXd + pertuzumab vs 26.9 months with taxane + trastuzumab + pertuzumab (THP) (hazard ratio [HR] 0.56).

Aim

To report an exploratory central nervous system (CNS) efficacy analysis of T-DXd + pertuzumab versus THP in DB-09 patients with baseline (BL) BMs.

Methods

• Patients had received no prior systemic therapy for a/mBC (1 line of endocrine therapy was allowed).
• Patients with clinically inactive, or treated and stable, BL BMs were permitted, provided ≥2 weeks had elapsed from the end of radiotherapy to randomisation.
• Magnetic resonance imaging (MRI)/computed tomography (CT) scans at BL and end of treatment were assessed by blinded independent central review (BICR) and/or the investigator (INV); patients with INV-assessed BL BMs had follow-up brain scans per protocol and Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.
• In patients with BL BMs by BICR and ≥1 post-BL brain scan, efficacy outcomes were PFS, CNS-PFS, CNS confirmed objective response rate (CNS-cORR; complete + partial response in brain) and CNS duration of response (CNS-DOR), all assessed by BICR per RECIST 1.1.
• Medians and confidence intervals (CIs) were calculated by the Kaplan–Meier method, HRs and CIs by an unstratified Cox proportional hazards model, and CNS-cORR CIs by the Clopper–Pearson method.

Results

• 61 patients with BL BMs by BICR and ≥1 post-BL brain scan: T-DXd + pertuzumab (n=31) vs THP (n=30); interim data cutoff 26 February 2025; median follow-up 23.6 months (range 2.8–41.4).
• Efficacy (T-DXd + pertuzumab vs THP):
• Median PFS: 36.5 vs 11.1 months
• CNS-PFS events: 9 (29.0%) vs 17 (56.7%)
• Median CNS-PFS: not estimable (NE; 95% CI 19.1–NE) vs 9.7 months (95% CI 4.2–19.2); HR 0.26 (95% CI 0.11–0.57)
• CNS-cORR: 51.6% (95% CI 33.1–69.8) vs 26.7% (95% CI 12.3–45.9)
• Median CNS-DOR: NE (95% CI 14.3–NE) vs 18.5 months (95% CI 8.3–NE)
• Best overall CNS response (T-DXd + pertuzumab vs THP):
• Complete response: 11 (35.5%) vs 7 (23.3%)
• Partial response: 5 (16.1%) vs 1 (3.3%)
• Stable disease: 12 (38.7%) vs 13 (43.3%)
• Progressive disease: 3 (9.7%) vs 6 (20.0%)
• Not evaluable: 0 vs 3 (10.0%)

Conclusion

In this exploratory DB-09 analysis of patients with BMs, 1L T-DXd plus pertuzumab produced robust CNS responses and prolonged CNS disease control, with a higher CNS-cORR and longer CNS-PFS than THP. These findings are consistent with the efficacy previously seen in the second-line setting in DB-12, and the authors regard them as supporting the use of T-DXd plus pertuzumab in 1L HER2+ mBC.

Reference

Saura Manich C. A DESTINY-Breast09 (DB-)09 analysis of trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for patients (pts) with HER2+ advanced/metastatic breast cancer (a/mBC) and baseline (BL) brain metastases (BMs), LBA49. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

2519O - Association of Biomarkers with Efficacy in the Phase 3 KEYNOTE-671 Study of Perioperative Pembrolizumab (Pembro) Plus Neoadjuvant Chemotherapy (Chemo) in Early-Stage Non–Small-Cell Lung Cancer (NSCLC)

Presenter: Marina C. Garassino

Background

In resectable stage II–IIIB (N2) non-small cell lung cancer (NSCLC), KEYNOTE-671 showed that perioperative pembrolizumab plus neoadjuvant chemotherapy improved event-free survival (EFS), overall survival (OS), major pathological response (MPR) and pathological complete response (pCR) compared with neoadjuvant chemotherapy and surgery. How tumour biomarkers relate to these outcomes has now been examined.

Aim

To assess the associations of the 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) and tumour mutational burden (TMB) with efficacy in KEYNOTE-671, and to describe EFS and OS by TcellinfGEP, TMB and KRAS mutation status.

Methods

• Post hoc analysis of KEYNOTE-671 (NCT03425643) participants with an evaluable baseline tumour sample; results are reported for the pembrolizumab and placebo arms.
• RNA sequencing (RNAseq) was used to assess TcellinfGEP, and whole exome sequencing (WES; also with a matched-normal sample) to assess TMB and KRAS mutation status.
• Associations of TcellinfGEP and TMB with EFS and OS were analysed using an adjusted Cox proportional hazards model, and with MPR and pCR using a logistic regression model; 1-sided (pembrolizumab) and 2-sided (placebo) P values were calculated (prespecified α=0.05).
• EFS and OS were also analysed in biomarker-based subgroups; EFS was assessed per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 by investigator.

Results

• Biomarker-evaluable patients (of 797):
• RNAseq data: 387 (pembrolizumab, n=198; placebo, n=189)
• WES data: 459 (pembrolizumab, n=230; placebo, n=229)
• TcellinfGEP: positively associated with EFS (P=0.021) and MPR (P=0.019) in the pembrolizumab arm, and with OS (P=0.002) in the placebo arm.
• TMB: positively associated with EFS (P=0.000164) and OS (P=0.005) in the pembrolizumab arm, and in both arms with MPR (pembrolizumab, P=0.001; placebo, P=0.014) and pCR (pembrolizumab, P=0.000695; placebo, P=0.044).
• EFS and OS hazard ratios (HRs), pembrolizumab vs placebo, by subgroup (generally comparable across subgroups):
• TcellinfGEP low (<1st tertile; N=129): EFS HR 0.71 (95% confidence interval [CI] 0.46–1.11); OS HR 0.59 (95% CI 0.36–0.97)
• TcellinfGEP high (≥1st tertile; N=258): EFS HR 0.53 (95% CI 0.38–0.75); OS HR 0.82 (95% CI 0.55–1.22)
• TMB low (<175 mutation/exome; N=266): EFS HR 0.63 (95% CI 0.47–0.86); OS HR 0.70 (95% CI 0.49–1.01)
• TMB high (≥175 mutation/exome; N=193): EFS HR 0.49 (95% CI 0.32–0.73); OS HR 0.67 (95% CI 0.40–1.12)
• KRAS mutation (N=86): EFS HR 0.73 (95% CI 0.42–1.28); OS HR 0.88 (95% CI 0.45–1.75)
• KRAS wild-type (N=169): EFS HR 0.75 (95% CI 0.50–1.12); OS HR 0.85 (95% CI 0.49–1.47)
• KRAS subgroups were limited to matched-normal, non-squamous samples

Conclusion

Baseline TcellinfGEP and TMB showed positive associations with efficacy in both treatment arms. Perioperative pembrolizumab retained its benefit over neoadjuvant chemotherapy irrespective of TcellinfGEP, TMB or KRAS mutation status, which the authors consider supportive of its use in early-stage NSCLC.

Reference

Garassino MC. Association of biomarkers with efficacy in the phase 3 KEYNOTE-671 study of perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) in early-stage non–small-cell lung cancer (NSCLC), 2519O. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

2511O - Final Analysis of Adjuvant Pembrolizumab (Pembro) in Resected Early-Stage Non–Small-Cell Lung Cancer (NSCLC): Phase 3 PEARLS/KEYNOTE-091 Study

Presenter: Mary E. O'Brien

Background

In completely resected stage IB–IIIA non-small cell lung cancer (NSCLC), the second interim analysis (IA2) of PEARLS/KEYNOTE-091 showed that adjuvant pembrolizumab improved disease-free survival (DFS) over placebo in the intention-to-treat (ITT) population (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.63–0.91; P=0.0014) and in the subgroup that had received chemotherapy (HR 0.73; 95% CI 0.60–0.89).

Aim

To report results, including overall survival (OS), from the final analysis (FA) of PEARLS/KEYNOTE-091.

Methods

• PEARLS/KEYNOTE-091 (NCT02504372) is a phase 3 study.
• Eligible patients were aged ≥18 years with completely resected, pathologically confirmed stage IB (T ≥4 cm), II or IIIA NSCLC per American Joint Committee on Cancer (AJCC) v7, and had received ≤4 cycles of adjuvant chemotherapy per local guidelines.
• Patients were randomised 1:1 to adjuvant pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for 18 cycles (~1 year).
• Primary endpoints were DFS per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 by investigator assessment in the ITT and programmed death-ligand 1 (PD-L1) tumour proportion score (TPS) ≥50% populations; secondary endpoints included OS, lung cancer–specific survival (LCSS) and safety.

Results

• 1177 patients in the ITT population: pembrolizumab (n=590) vs placebo (n=587); median follow-up from randomisation to data cutoff (21 January 2026) was 87.7 months (range 68.6–120.1).
• OS (pembrolizumab vs placebo):
• ITT population: 6-year OS 68.5% (95% CI 64.5%–72.1%) vs 66.4% (95% CI 62.4%–70.1%); HR 0.98 (95% CI 0.81–1.18); P=0.41826
• Patients who received chemotherapy: 6-year OS 68.9% (95% CI 64.6%–72.8%) vs 65.4% (95% CI 61.0%–69.4%); HR 0.91 (95% CI 0.74–1.12)
• DFS (pembrolizumab vs placebo):
• ITT population (n=590 vs n=587): median 58.7 (95% CI 47.0–70.4) vs 43.3 (95% CI 35.0–55.6) months; 6-year DFS 44.0% (95% CI 39.7–48.2) vs 39.2% (95% CI 35.0–43.2); HR 0.85 (95% CI 0.73–0.98)
• Patients who received chemotherapy (n=506 vs n=504): median 58.7 (95% CI 47.0–70.5) vs 39.1 (95% CI 31.3–51.7) months; 6-year DFS 43.6% (95% CI 38.9–48.1) vs 38.1% (95% CI 33.7–42.5); HR 0.80 (95% CI 0.68–0.94)
• LCSS (pembrolizumab vs placebo; median not reached [NR] in all groups):
• ITT population: 6-year LCSS 81.3% (95% CI 77.7–84.4) vs 76.9% (95% CI 73.1–80.2); HR 0.81 (95% CI 0.63–1.03)
• Patients who received chemotherapy: 6-year LCSS 81.6% (95% CI 77.7–84.9) vs 75.0% (95% CI 70.8–78.7); HR 0.69 (95% CI 0.53–0.91)
• Safety:
• Grade ≥3 adverse events (AEs): 197/580 (34.0%) with pembrolizumab vs 149/581 (25.6%) with placebo
• Grade ≥3 immune-mediated AEs and infusion reactions: 46 (7.9%) and 11 (1.9%) patients, respectively

Conclusion

At the final analysis, adjuvant pembrolizumab maintained a consistent DFS advantage over placebo in resected early-stage NSCLC, with a favourable trend in LCSS and manageable safety. OS was not significantly improved; the authors note that OS was a secondary endpoint and that the study was not powered to detect an OS benefit.

Reference

O'Brien ME. Final analysis of adjuvant pembrolizumab (pembro) in resected early-stage non–small-cell lung cancer (NSCLC): Phase 3 PEARLS/KEYNOTE-091 study, 2511O. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

1678RO - Phase 3 LEAP-012 Study of Lenvatinib + Pembrolizumab Vs Dual Placebo with Transarterial Chemoembolization (TACE) for Unresectable Non-Metastatic Hepatocellular Carcinoma: Long-Term OS Results

Presenter: Josep M. Llovet

Background

In unresectable, non-metastatic hepatocellular carcinoma (HCC), the global phase 3 LEAP-012 study showed at its first interim analysis (IA1; the prespecified final analysis of progression-free survival [PFS]; data cutoff 30 January 2024) that adding lenvatinib plus pembrolizumab to transarterial chemoembolisation (TACE) significantly improved PFS per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 by blinded independent central review (BICR) compared with dual placebo plus TACE (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.51–0.84; one-sided P=0.0002).

Aim

To report overall survival (OS) results from the third interim analysis (IA3) of LEAP-012 (data cutoff 19 August 2025).

Methods

• LEAP-012 (NCT04246177) enrolled patients with non-metastatic HCC not amenable to curative treatment, liver-only disease with no portal vein invasion, Child-Pugh class A and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
• Patients were randomised 1:1 to TACE + pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) + lenvatinib 12 mg (body weight [BW] ≥60 kg) or 8 mg (BW <60 kg) orally (PO) once daily (QD), or TACE + dual placebo (PO + IV), for ≤2 years.
• Primary endpoints were PFS per RECIST v1.1 by BICR and OS; secondary endpoints included objective response rate (ORR), duration of response (DOR) and time to progression (TTP) per RECIST v1.1 by BICR, and safety.

Results

• 480 patients: lenvatinib + pembrolizumab + TACE (n=237) vs placebo + TACE (n=243); median follow-up 44.2 months (range 31.3–62.1).
• OS (lenvatinib + pembrolizumab vs placebo; 253 OS events):
• Median OS: 40.4 (95% CI 34.4–47.0) vs 40.8 (95% CI 35.2–45.8) months; HR 0.98 (95% CI 0.76–1.26)
• 24/36-month OS rates: 74.4%/55.3% vs 67.5%/55.4%
• PFS (data cutoff 30 January 2024):
• Median PFS: 14.6 (95% CI 12.6–16.7) vs 10.2 (95% CI 8.1–12.3) months; HR 0.70 (95% CI 0.56–0.89)
• 24/36-month PFS rates: 23.9%/19.1% vs 18.9%/12.4%
• Descriptive analysis of PFS per RECIST v1.1 by BICR at IA3 remained consistent with IA1 results
• Other efficacy endpoints (lenvatinib + pembrolizumab vs placebo):
• ORR per RECIST v1.1: 48.1% (95% CI 41.6–54.7) vs 33.7% (95% CI 27.8–40.1)
• ORR per modified RECIST (mRECIST): 71.3% (95% CI 65.1–77.0) vs 49.4% (95% CI 42.9–55.8)
• Median DOR: 14.3 (range 1.3+ to 58.0+) vs 12.6 (range 2.0+ to 51.8+) months
• Median TTP: 16.6 (95% CI 14.6–18.5) vs 10.4 (95% CI 8.2–12.5) months
• Safety (lenvatinib + pembrolizumab vs placebo):
• Grade ≥3 treatment-related adverse events (TRAEs): 72.2% vs 32.0%
• Discontinuation due to TRAEs: 21 (8.9%) vs 4 (1.7%) patients
• TRAE-related deaths: 4 (1.7%) vs 2 (0.8%) patients

Conclusion

LEAP-012 met its primary endpoint for PFS, but adding lenvatinib plus pembrolizumab to TACE did not improve OS. According to the authors, the median OS of approximately 40 months sets a new benchmark for trial design in unresectable, non-metastatic HCC. The safety profile of lenvatinib plus pembrolizumab was consistent with previous reports and with earlier LEAP-012 analyses.

Reference

Llovet JM. Phase 3 LEAP-012 study of lenvatinib + pembrolizumab vs dual placebo with transarterial chemoembolization (TACE) for unresectable non-metastatic hepatocellular carcinoma: Long-term OS results, 1678RO. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA22 - OPTIMUM: A Randomized Phase 2 Study of Maintenance Olaparib (Ola) with or without Durvalumab (Durva) in DDR Gene-Mutated Advanced Biliary Tract Cancer (aBTC)

Presenter: Changhoon Yoo

Background

Platinum-containing therapy is the standard of care for advanced biliary tract cancer (aBTC), yet no maintenance strategy has been validated once disease control is achieved. DNA damage repair (DDR) gene mutations are identified in patients with aBTC, and in this population poly(ADP-ribose) polymerase (PARP) inhibitor maintenance may improve survival.

Aim

To evaluate maintenance olaparib with or without durvalumab in DDR gene-mutated aBTC without progression after first-line (1L) platinum-based therapy.

Methods

• OPTIMUM (NCT05222971) is a randomised, open-label, non-comparative phase 2 trial.
• Eligible patients had aBTC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, at least one predefined somatic or germline DDR gene mutation, and no disease progression after ≥16 weeks of 1L platinum-based therapy.
• Patients were randomised 1:1 to Arm A (olaparib 300 mg twice daily [BID] + durvalumab 1,500 mg intravenously [IV] every 4 weeks [Q4W]) or Arm B (olaparib 300 mg BID).
• The primary endpoint was the 6-month progression-free survival (PFS) rate in the full analysis set (FAS); 62 patients were required to detect an improvement from a historical 48.0% to 69.3% (hazard ratio [HR] 0.5; one-sided α=0.05; power 80%).

Results

• 63 patients enrolled (April 2022–February 2026); 61 in the FAS: Arm A (n=32) vs Arm B (n=29); baseline characteristics were well balanced.
• Most frequent DDR alterations: ATM (34%), BRCA2 (25%) and BAP1 (25%).
• Primary endpoint, 6-month PFS rate: Arm A 62.5% (95% confidence interval [CI] 46.8–74.7); Arm B 62.1% (95% CI 45.5–74.9); overall FAS 62.3% (51.2–71.5).
• Other efficacy outcomes (overall FAS, n=61 / Arm A, n=32 / Arm B, n=29):
• Median PFS (90% CI): 8.2 (6.8–11.1) / 7.7 (5.5–11.8) / 8.2 (4.9–14.0) months
• 1-year PFS rate: 37.2% (26.7–47.7) / 31.7% (17.4–47.0) / 41.1% (26.1–55.5)
• Median overall survival (OS): 18.9 (15.7–27.2) / 16.5 (11.8–19.9) / 29.6 (15.7–not estimable [NE]) months
• 1-year OS rate: 70.5% (58.4–79.7) / 64.3% (45.9–77.8) / 75.9% (58.1–86.9)
• 2-year OS rate: 40.1% (28.0–51.9) / 25.0% (11.4–41.4) / 53.6% (35.3–68.8)
• Objective response rate (ORR): 27.5 (16.3–41.4) / 30.0 (14.0–50.8) / 25.0 (10.4–45.6)
• Core homologous recombination deficiency (cHRD) group (n=18, 30%) vs others:
• Median PFS: 20.5 vs 7.4 months; P=0.008
• Median OS: not reached vs 16.5 months; P=0.007
• Circulating tumour DNA (ctDNA): higher variant allele frequency (VAF) at the time of study treatment correlated negatively with PFS and OS.
• Safety: no new safety profile was observed with olaparib ± durvalumab.

Conclusion

In this non-comparative study, 6-month PFS rates with olaparib alone and with olaparib plus durvalumab were closely matched, and the cHRD group was significantly associated with longer PFS and OS than other patients. The authors suggest that cHRD-defined, DDR-mutated aBTC derives durable benefit from PARP inhibitor maintenance, supporting further development of homologous recombination deficiency (HRD)-targeted therapy in aBTC.

Reference

Yoo C. OPTIMUM: A randomized phase 2 study of maintenance olaparib (Ola) with or without durvalumab (Durva) in DDR gene-mutated advanced biliary tract cancer (aBTC), LBA22. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA9 - Risvutatug Rezetecan (Ris-Rez) Versus Gemcitabine and Docetaxel (GD) in Heavily Pretreated Patients (Pts) with Relapsed or Refractory (R/R) Osteosarcoma: Primary Results from the Phase 3 ARTEMIS-011 Study

Presenter: Lu Xie

Background

Risvutatug rezetecan (Ris-Rez; HS-20093/GSK5764227), a B7-H3-directed antibody–drug conjugate (ADC), previously showed promising antitumour activity with manageable toxicity in heavily pretreated patients with relapsed or refractory (R/R) sarcomas. ARTEMIS-011 compared it with gemcitabine and docetaxel (GD) in Chinese patients with R/R osteosarcoma.

Aim

To report the primary results of Ris-Rez versus GD in heavily pretreated R/R osteosarcoma.

Methods

• ARTEMIS-011 (NCT06935409) was a multicentre, open-label, randomised phase 3 trial.
• Eligible patients (≥12 years) had progressed or relapsed after ≥2 prior lines of systemic therapy.
• Patients were randomised 2:1 to Ris-Rez 12.0 mg/kg every 3 weeks (Q3W) or GD Q3W.
• The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR).

Results

• 122 patients randomised (data cutoff 17 June 2026): Ris-Rez (n=80) vs GD (n=42); median follow-up 7.1 months.
• Baseline: median age 21.0 years; 31 patients (25.4%) were adolescents (12–18 years).
• Efficacy (Ris-Rez vs GD):
• BICR-assessed median PFS (mPFS): 5.5 vs 1.4 months; hazard ratio (HR) 0.33; p<0.0001
• Investigator-assessed mPFS: 5.6 vs 1.0 months
• Overall survival (OS; immature): favourable trend toward Ris-Rez; HR 0.51
• Safety (Ris-Rez vs GD):
• Grade ≥3 treatment-emergent adverse events (TEAEs): 92.5% vs 83.3%
• Treatment-related serious adverse events (SAEs): 63.8% vs 28.6%; numerically higher with Ris-Rez, mainly driven by haematological toxicities
• Discontinuation due to treatment-related adverse events (TRAEs): 3.8% vs 2.4%
• One treatment-related interstitial lung disease in the Ris-Rez group (Common Terminology Criteria for Adverse Events [CTCAE] grade 2, resolved)
• No treatment-related deaths or new safety signals

Conclusion

In heavily pretreated R/R osteosarcoma, Ris-Rez achieved a statistically significant and clinically meaningful improvement in BICR-assessed PFS over GD, together with a favourable OS trend and a manageable safety profile. The authors see these results as pointing to its potential as a new treatment standard for patients with R/R osteosarcoma.

Reference

Xie L. Risvutatug rezetecan (Ris-Rez) versus gemcitabine and docetaxel (GD) in heavily pretreated patients (pts) with relapsed or refractory (R/R) osteosarcoma: Primary results from the phase 3 ARTEMIS-011 study, LBA9. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

LBA12 - KEYNOTE-C93/GOG-3064/ENGOT-en15: Phase 3, Randomized, Open-Label Study of First-Line (1L) Pembrolizumab (Pembro) Vs Carboplatin (C) + Paclitaxel (P) in Mismatch Repair-Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (a/rEC)

Presenter: Brian M. Slomovitz

Background

For mismatch repair-deficient (dMMR) advanced or recurrent endometrial carcinoma (a/rEC), the preferred first-line (1L) therapy is carboplatin + paclitaxel (CP) with an immune checkpoint inhibitor (ICI), followed by ICI maintenance. A chemotherapy (CTx)-free option for this setting remains an unmet need.

Aim

To compare 1L pembrolizumab monotherapy with CP in dMMR a/rEC.

Methods

• KEYNOTE-C93/GOG-3064/ENGOT-en15 (NCT05173987) is a phase 3, randomised, open-label study.
• Participants had inoperable, stage III/IV a/rEC that was radiologically evaluable (measurable or non-measurable by investigator; for stage IVB, no evidence of disease following surgical resection was allowed) and centrally confirmed dMMR.
• Prior systemic therapy was not allowed, except (neo)adjuvant therapy if recurrence occurred ≥6 months after the last dose.
• Patients were randomised 1:1 to pembrolizumab every 6 weeks (Q6W) for 18 cycles or CP every 3 weeks (Q3W) for 6 cycles.
• Primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS); quality of life (QoL) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL scale.

Results

• 299 patients randomised: pembrolizumab (n=149) vs CP (n=150); median follow-up 36.5 months; prespecified interim analysis (data cutoff 24 April 2026).
• PFS (pembrolizumab vs CP):
• Median 38.2 (95% confidence interval [CI] 17.9–not reached [NR]) vs 8.4 (95% CI 6.8–10.4) months; hazard ratio (HR) 0.57 (95% CI 0.42–0.79); P=0.0002 (prespecified 1-sided p-value boundary of 0.025 met)
• 36-month PFS rate: 52.8% (95% CI 44.2–60.7) vs 30.0% (95% CI 22.4–37.9)
• OS (pembrolizumab vs CP):
• Median NR (95% CI NR–NR) vs NR (95% CI 38.9–NR); HR 0.77 (95% CI 0.52–1.15)
• 36-month OS rate: 70.7% (95% CI 62.4–77.5) vs 62.0% (95% CI 53.1–69.8)
• Response, patients with measurable disease per BICR at baseline (n=145 per arm):
• Objective response rate (ORR): 64.1% (95% CI 55.8–71.9) vs 62.1% (95% CI 53.6–70.0)
• Complete response (CR): 33.8% vs 26.2%; partial response (PR): 30.3% vs 35.9%
• Duration of response (DOR), responders with measurable disease at baseline (pembrolizumab, n=93; CP, n=90):
• Median: NR vs 10.2 months
• DOR ≥24 months: 77.0% vs 41.3%; ≥36 months: 70.7% vs 40.0%
• Subsequent therapy after BICR-assessed progressive disease (PD): in the CP arm, 85.2% received crossover pembrolizumab or subsequent programmed cell death protein 1/ligand 1 (PD-[L]1) inhibitors off study; in the pembrolizumab arm, 47.6% received subsequent platinum CTx off study.
• QoL: clinically meaningful improvement in GHS/QoL scores from baseline to week 12 (primary time point) with pembrolizumab vs CP; between-group difference 7.02 (95% CI 2.54–11.50).
• Safety (pembrolizumab vs CP):
• Grade ≥3 treatment-related adverse events (AEs): 18.1% vs 50.7%; most common was anaemia (2.0% vs 18.1%)
• Grade ≥3 immune-mediated AEs and infusion reactions: 7.4% and 3.5%, respectively

Conclusion

In dMMR a/rEC, 1L pembrolizumab alone produced a statistically significant, clinically meaningful and durable PFS improvement, along with a favourable OS trend, compared with conventional CP chemotherapy, and no new safety signals emerged in either arm. The authors conclude that single-agent pembrolizumab can be an option for this patient population.

Reference

Slomovitz BM. KEYNOTE-C93/GOG-3064/ENGOT-en15: Phase 3, randomized, open-label study of first-line (1L) pembrolizumab (pembro) vs carboplatin (C) + paclitaxel (P) in mismatch repair-deficient (dMMR) advanced or recurrent endometrial carcinoma (a/rEC), LBA12. Paper presented at: ESMO Congress 2026; October 23–27, 2026; Madrid, Spain

ESMO Congress 2026, 23 - 27 October 2026, Madrid