ESMO 2026 Presidential Symposium II Showcases OS-Improving LBAs in Lung and GI Cancers

During Presidential Symposium II at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, experts presented 4 late-breaking abstracts featuring positive phase 3 results across KRAS G12C-mutated non–small cell lung cancer (NSCLC), EGFR-mutant NSCLC with MET alterations, gastroesophageal carcinoma, and biliary tract cancer. The session was chaired by Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology and the University of Milan in Italy, and Yelena Janjigian, MD, of Memorial Sloan Kettering Cancer Center in New York.

All 4 trials, Krascendo 1, SAFFRON, CLARITY-Gastric01, and HARMONi-GI1, showed significant overall survival (OS) benefits. Krascendo 1 and SAFFRON met their primary end points of progression-free survival (PFS), CLARITY-Gastric01 met its dual primary end point of OS but not PFS, and HARMONi-GI1 met its primary end point of OS. Together, the trials tested a next-generation KRAS G12C inhibitor, a combined EGFR and MET inhibitor regimen, an antibody-drug conjugate, and a bispecific antibody against active comparators.

LBA5: Divarasib Improves Survival vs Sotorasib or Adagrasib in Previously Treated KRAS G12C–Mutated NSCLC

Divarasib significantly improved PFS and OS vs sotorasib (Lumakras) or adagrasib (Krazati) in patients with previously treated KRAS G12C–mutated advanced or metastatic NSCLC, according to the primary analysis of the phase 3 Krascendo 1 trial (NCT06497556) presented by Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center.¹

The open-label trial randomized 338 patients 1:1 to divarasib (400 mg once daily; n = 167) or a control KRAS G12C inhibitor (n = 171), either sotorasib (960 mg once daily; n = 156) or adagrasib (600 mg twice daily; n = 15). Eligible patients were KRAS G12C inhibitor naive, had an ECOG performance status of 0 or 1, and had received 1 to 3 prior lines of therapy, including platinum-based chemotherapy and a PD-(L)1 inhibitor. Crossover was not permitted. The primary end point was PFS by blinded independent central review (BICR), followed hierarchically by OS, confirmed objective response rate (ORR) by BICR, and time to confirmed deterioration in selected patient-reported outcomes.

At a May 19, 2026, data cutoff and a median follow-up of 14.3 months, divarasib reduced the risk of progression or death by 42% (HR, 0.58; 95% CI, 0.44-0.76; P < .0001). Median PFS was 9.8 months (95% CI, 8.1-12.9) vs 5.7 months (95% CI, 4.2-6.8), and 12-month PFS rates were 43.9% vs 24.0%. At the first interim analysis, OS also improved (HR, 0.56; 95% CI, 0.41-0.78; P = .0005), with a median of 17.7 months (95% CI, 16.3-not estimable) vs 12.0 months (95% CI, 10.0-15.2) and 12-month rates of 67.1% vs 49.2%. Among 328 response-evaluable patients, confirmed ORR was 58% vs 32% (difference, 25.8 percentage points; 95% CI, 15.6-36.0), with a median duration of response of 11.9 vs 6.9 months.

Although median treatment duration was 11.3 months with divarasib vs 5.0 months with control, treatment-related grade 3 or 4 adverse events (AEs) occurred in 24.6% vs 34.5% of patients, treatment-related serious AEs in 7.8% vs 15.2%, and treatment-related AEs led to discontinuation in 4.8% vs 11.7%. There were no treatment-related deaths in either arm. Diarrhea (66% vs 38%), nausea (53% vs 20%), and vomiting (39% vs 8%) were more frequent with divarasib and were mainly grade 1, while increased alanine aminotransferase (15% vs 23%) and aspartate aminotransferase (14% vs 21%) were less frequent. No treatment-related QT prolongation or pneumonitis occurred with divarasib vs 2 and 3 patients, respectively, in the control arm.

“Divarasib represents a new standard of care for patients with previously treated KRAS G12C-mutated advanced or metastatic non–small cell lung cancer,” Skoulidis concluded.

LBA6: Osimertinib Plus Savolitinib Improves Survival in EGFR-Mutant, MET-Altered NSCLC After Osimertinib

Osimertinib (Tagrisso) plus savolitinib significantly improved PFS and OS vs platinum-pemetrexed in patients with EGFR-mutant advanced NSCLC with MET overexpression and/or amplification after progression on osimertinib, according to the primary analysis of the phase 3 SAFFRON trial presented by Shun Lu, MD, PhD, of Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, in China.²

The trial randomized 338 patients 1:1 to osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily; n = 171) or pemetrexed plus carboplatin or cisplatin for 4 cycles followed by pemetrexed maintenance (n = 167). Eligible patients had EGFR-mutant locally advanced or metastatic NSCLC that had progressed on first- or second-line osimertinib, with MET overexpression (immunohistochemistry 3+ in at least 90% of tumor cells) and/or amplification (at least 10 gene copies by fluorescence in situ hybridization) confirmed centrally on a postprogression biopsy. Of the 1746 patients screened, 35% of those evaluable for MET testing met these criteria. PFS by BICR was the primary end point, followed hierarchically by PFS in the MET-overexpressed analysis set and OS.

At a July 6, 2026, data cutoff, the combination reduced the risk of progression or death by 45% (HR, 0.55; 95% CI, 0.42-0.72; P < .001), with a median PFS of 7.6 months (95% CI, 5.6-9.7) vs 5.4 months (95% CI, 4.2-5.8) and 12-month rates of 36% vs 10%. Results were consistent in the MET-overexpressed set (8.5 vs 5.6 months; HR, 0.51; 95% CI, 0.37-0.71; P < .001) and in the MET-amplified set, which was not formally tested (7.6 vs 4.2 months; HR, 0.48; 95% CI, 0.35-0.66).

OS also improved at 53% maturity (HR, 0.68; 95% CI, 0.50-0.91; P = .010), with a median of 17.8 months (95% CI, 15.6-23.7) vs 12.9 months (95% CI, 10.6-16.8) and 12-month rates of 70% vs 53%. Confirmed ORR was 51% vs 27% (odds ratio, 2.90; 95% CI, 1.85-4.61), and median duration of response was 9.7 vs 5.7 months.

Median exposure was 8.5 months with the combination vs 3.5 months with chemotherapy. Grade 3 or higher AEs occurred in 64% vs 63% of patients, and treatment-related grade 3 or higher AEs in 40% vs 52%. AEs led to discontinuation of any treatment in 14% vs 8%. Fatal AEs occurred in 12 patients (7%) receiving the combination vs none with chemotherapy; 1 was treatment related, and 9 of the 12 patients had documented disease progression. The most common AEs with the combination were peripheral edema (49% vs 8%), anemia (26% vs 54%), and diarrhea (26% vs 8%).

“Osimertinib plus savolitinib establishes a new global standard of care for patients with EGFR-mutant, MET-overexpressed and/or MET-amplified advanced NSCLC after progression on osimertinib,” said Lu.

LBA7: Sonesitatug Vedotin Improves Survival in Previously Treated CLDN18.2-Positive Gastroesophageal Carcinoma

Sonesitatug vedotin, a claudin 18.2 (CLDN18.2)-targeted antibody-drug conjugate, significantly improved OS vs investigator’s choice of therapy in patients with previously treated advanced or metastatic CLDN18.2-positive gastroesophageal carcinoma, according to the phase 3 CLARITY-Gastric01 trial (NCT06346392) presented by Rui-Hua Xu, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China.³

The open-label, sponsor-blinded trial enrolled patients whose tumors showed CLDN18.2 membranous staining in at least 25% of tumor cells and who had received at least 1 prior line of therapy. Patients were initially randomized 1:1:1 to sonesitatug vedotin at 2.2 mg/kg or 1.8 mg/kg every 3 weeks or investigator’s choice. After the 2.2-mg/kg dose was selected, the 1.8-mg/kg arm (n = 62) closed and randomization continued 1:1. In total, 594 patients were randomized, including 267 to sonesitatug vedotin 2.2 mg/kg and 265 to investigator’s choice of ramucirumab plus paclitaxel, paclitaxel, or docetaxel in the second line or irinotecan, trifluridine/tipiracil, or apatinib in the third line or later. Dual primary end points were OS in the third-line or later population and PFS by BICR in the intention-to-treat (ITT) population. Two-thirds of patients were receiving third-line or later therapy, and 61.0% vs 55.8% had peritoneal metastases.

In the third-line or later population, median OS doubled to 10.0 months (95% CI, 7.2-11.4) from 5.0 months (95% CI, 4.2-6.4) (HR, 0.47; 95% CI, 0.36-0.62; P < .000001), with 12-month rates of 38.1% vs 18.1%. In the ITT population, median OS was 10.6 vs 6.4 months (HR, 0.58; 95% CI, 0.47-0.73; P = .000004), with 12-month rates of 42.6% vs 27.8%. The OS benefit held for patients with CLDN18.2 expression of at least 75% (HR, 0.59; 95% CI, 0.45-0.78) and of 25% to less than 75% (HR, 0.63; 95% CI, 0.42-0.94).

PFS by BICR in the ITT population did not reach statistical significance (4.2 vs 3.8 months; HR, 0.77; 95% CI, 0.62-0.96; P = .053), although PFS improved in the third-line or later population (HR, 0.56; 95% CI, 0.43-0.74) and by investigator assessment in the ITT population (4.4 vs 3.0 months; HR, 0.59; 95% CI, 0.48-0.73). Confirmed ORR was 23.3% vs 13.8%, and median duration of response was 8.5 vs 6.8 months.

Grade 3 or higher AEs occurred in 52.9% of patients receiving sonesitatug vedotin vs 61.1% with investigator’s choice, and AEs led to discontinuation in 5.0% vs 4.4%. Gastrointestinal AEs were more common with sonesitatug vedotin, including nausea (54.4% vs 26.6%), decreased appetite (43.3% vs 24.2%), and vomiting (41.0% vs 24.6%), while hematologic toxicity was lower, including grade 3 or higher neutropenia (10.3% vs 25.4%). AEs led to death in 11 patients (4.2%) vs 6 (2.4%), of which 3 (1.1%) vs 2 (0.8%) were considered possibly treatment related.

“Sonesitatug vedotin is a potential new standard of care in the second- or later-line setting for patients with advanced or metastatic CLDN18.2-positive gastroesophageal carcinoma,” Xu said in his closing remarks.

LBA8: Ivonescimab Plus Chemotherapy Improves Survival vs Durvalumab Plus Chemotherapy in Advanced Biliary Tract Cancer

Ivonescimab plus chemotherapy significantly improved OS vs durvalumab (Imfinzi) plus chemotherapy as first-line treatment for advanced biliary tract cancer (BTC), according to an interim analysis of the phase 3 HARMONi-GI1 trial presented by Jian Zhou, MD, PhD, of Zhongshan Hospital in Shanghai, China.⁴

The double-blind trial randomized 682 patients in China 1:1 to ivonescimab (20 mg/kg every 3 weeks; n = 340) or durvalumab (1500 mg every 3 weeks; n = 342), each with gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) on days 1 and 8 for up to 8 cycles, followed by maintenance ivonescimab or durvalumab. Eligible patients had locally advanced or metastatic BTC that was initially unresectable or recurrent after curative surgery, no prior systemic therapy, and an ECOG performance status of 0 or 1. OS was the primary end point, with investigator-assessed PFS and ORR as key secondary end points. Most patients (90.6%) had metastatic disease, and intrahepatic cholangiocarcinoma was the most common primary site (58.2% vs 57.3%).

At a June 30, 2026, data cutoff and a median follow-up of 14.3 months, median OS was 14.9 months (95% CI, 12.9-not estimable) with ivonescimab vs 12.1 months (95% CI, 11.0-13.4) with durvalumab (HR, 0.75; 95% CI, 0.61-0.92; 1-sided P = .0031). The 12-month OS rates were 59.7% vs 50.7%, and 18-month rates were 44.0% vs 32.5%.

Median PFS was 8.4 vs 5.8 months (HR, 0.61; 95% CI, 0.51-0.72; 1-sided P < .0001), and ORR was 53.8% vs 32.5% (P < .0001), with higher response rates across intrahepatic, extrahepatic, and gallbladder primaries. Fewer patients in the ivonescimab arm received subsequent anticancer therapy (31.8% vs 45.9%).

Median exposure was 7.8 months to ivonescimab vs 5.7 months to durvalumab. Grade 3 or 4 treatment-emergent AEs occurred in 82.0% vs 72.3% of patients, and serious AEs in 43.4% vs 43.7%. AEs led to discontinuation of ivonescimab or durvalumab in 3.5% vs 5.6% and to death in 3.2% vs 3.8%, with 0.9% vs 1.8% of deaths attributed to the study antibody. Immune-related AEs occurred in 26.3% vs 22.1% of patients, with grade 3 or higher events in 4.1% of each arm and no immune-related deaths.

“HARMONi-GI1 supports ivonescimab plus chemotherapy as a new standard of care for first-line biliary tract cancer,” Zhou concluded.

Additional Insight: John Bridgewater, BA, MBBS, MRCP, PHD, discusses the potential impact of the phase 3 HARMONi-GI1 trial on treating advanced biliary tract cancer.

REFERENCES

1. Skoulidis F et al. 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. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA5.

2. Lu S et al. 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. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA6.

3. Xu RH et al. 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). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA7.

4. Zhou J et al. Ivonescimab plus chemotherapy versus durvalumab plus chemotherapy as first-line treatment for advanced biliary tract cancer: a randomized, controlled, double-blinded, phase 3 trial (HARMONi-GI1). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA8.