THE COMPLETE ESMO26 NEWSLETTER : Every key trial from Madrid, curated by oncologists

In the phase 3 APEX-Breast01 trial, 543 patients with chemotherapy-naïve HER2-low metastatic breast cancer (85% HR+, mostly CDK4/6i-pretreated) were randomized to the biparatopic HER2 ADC TQB2102 or physician’s choice chemotherapy. TQB2102 tripled median PFS (16.4 vs 5.5 mo; HR 0.29) in both HR+ and all HER2-low patients, with an early overall survival benefit trend. Safety was manageable: grade ≥3 neutropenia occurred in 30.1%, ILD in 2.2%, and discontinuation in only 1.5%.

FOURLIGHT-1 evaluated ATI (PF-07220060), a selective CDK4 inhibitor, plus fulvestrant versus investigator’s choice therapy in HR+/HER2− metastatic breast cancer progressing after prior CDK4/6 inhibition. Among 263 patients, ATI plus fulvestrant significantly improved progression-free survival, with consistent benefits across most subgroups. Overall survival remains immature. Neutropenia and leukopenia were the most common treatment-related adverse events, while only 4% discontinued ATI due to treatment-related toxicity, supporting a manageable safety profile.

The phase 2 BRIDGET trial added tucatinib to ongoing HP or T-DM1 after stereotactic radiosurgery in 47 evaluable patients with HER2+ metastatic breast cancer and isolated CNS progression (93.6% on HP). At 19.6 months’ median follow-up, median intracranial PFS was not reached versus a 5-month historical control (p<0.0001), with 12- and 18-month iPFS rates of 64% and 59%. Extracranial progression was rare (4.3%), and grade ≥3 toxicity occurred in 15%.

The phase 3 evERA trial randomized 373 patients with ER+/HER2− advanced breast cancer progressing after CDK4/6 inhibitor plus endocrine therapy to all-oral giredestrant plus everolimus or standard endocrine therapy plus everolimus. In ESR1-mutated tumors (n=207), median PFS nearly doubled (10.0 vs 5.5 months; HR 0.38), and benefit held in the overall population (8.8 vs 5.5 months; HR 0.56). Safety was similar, with stomatitis most common (47.3% vs 48.9%).

In this phase 3 trial conducted in China (n=885), patients with HER2-positive advanced breast cancer received, as first-line therapy, anbenitamab, a HER2-targeted bispecific antibody, plus albumin-bound docetaxel (HB1801), or standard docetaxel–trastuzumab–pertuzumab (THP). At interim analysis, 24-month progression-free survival was 58.5% vs 34.4% (HR 0.46), and objective response 87.6% vs 73.4%. Grade ≥3 adverse events occurred in 45.9% vs 34.4%, with neutropenia the most common (13.1% vs 8.4%).

HORIZON-Breast06 randomized 551 patients with HER2-low advanced breast cancer and ≤1 prior chemotherapy line to trastuzumab rezetecan, a HER2 ADC, or physician’s-choice chemotherapy. Rezetecan improved BICR-assessed PFS in chemo-naïve (16.6 vs 6.8 months; HR 0.25) and overall patients (16.4 vs 6.8; HR 0.27), consistently across HR-positive and HR-negative subgroups. ORR was 75.5% vs 41.2%. OS, though immature, trends favorably. Grade ≥3 TRAEs reached 84.1% vs 67.9%; ILD occurred in 2.5%.

In phase 3 KEYNOTE-B49 (n=342), patients with PD-L1–positive (CPS ≥1) HR+/HER2– advanced breast cancer progressing after endocrine therapy received pembrolizumab or placebo plus chemotherapy. Pembrolizumab significantly improved progression-free survival (median 6.7 vs 6.0 months; HR 0.74), with a numerically larger effect at CPS ≥10 (HR 0.59). Overall survival did not improve (21.0 vs 22.2 months; HR 1.04). Grade ≥3 treatment-related adverse events occurred in 38% vs 33%.

The 6-year NATALEE analysis showed that adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) improved overall survival (OS) compared with NSAI alone in patients with stage II/III HR+/HER2− early breast cancer. OS improved by 2.1%, while invasive disease-free survival improved by 5.3%, with consistent reductions in distant recurrence. Benefits persisted after treatment completion, and no new safety signals emerged, supporting ribociclib’s sustained efficacy and favorable safety profile.

PANKU-Breast01 randomized 383 patients with HR+/HER2− metastatic breast cancer, previously treated with CDK4/6 inhibitors, taxanes and 1–2 lines of chemotherapy, to iza-bren, an EGFR×HER3 bispecific ADC, or physician’s-choice chemotherapy. Iza-bren doubled median PFS by BICR (8.2 vs 4.0 months; HR 0.41; P<0.0001) and cORR (40.5% vs 20.2%). OS was immature with no detriment. Toxicity was mainly hematologic and manageable, with only 1.6% discontinuing for adverse events and 1.1% low-grade ILD.

In the final overall survival analysis of phase 3 postMONARCH (n=368), patients with HR+, HER2– advanced breast cancer progressing after a CDK4/6 inhibitor plus endocrine therapy received abemaciclib plus fulvestrant or placebo plus fulvestrant. Median OS was 32.1 vs 24.6 months (HR 0.80; P=0.11), not reaching statistical significance. Updated progression-free survival (HR 0.78), time to second progression, and chemotherapy-free survival favored abemaciclib, with no new safety signals.

The phase 2 SWITCH platform trial randomized 54 patients with HER2-negative metastatic breast cancer progressing on prior ADCs (94.4% TOP1i-exposed) to four novel TOP1i-payload ADCs targeting different antigens. Confirmed ORRs were minimal across cohorts (0–8.3%). The only responses occurred in patients switching from the microtubule-inhibitor ADC disitamab vedotin; switching antigens while keeping the same payload class produced none, implicating payload cross-resistance. Safety was manageable and consistent with each agent’s known profile.

The phase II TALENT study evaluated neoadjuvant trastuzumab deruxtecan (T-DXd), alone, with anastrozole, or sequentially with chemotherapy, in HR+/HER2-low early breast cancer. Among 132 patients, pathological complete or near-complete response rates were 16%, 17%, and 17%, respectively. Higher baseline and on-treatment HER2 levels were associated with complete response, while HER2 expression declined during treatment and TROP2 remained stable. Interstitial lung disease was rare.

The prospective, multicenter TOP-1 study enrolled 792 women aged ≥70 with low-risk ER+, HER2-negative early breast cancer treated with breast-conserving surgery alone—no radiotherapy and no endocrine therapy. At median 5.1-year follow-up, 5-year local recurrence was 14.8%, exceeding prior estimates and the 10% threshold. Most recurrences were salvageable surgically, usually with repeat BCS. Contralateral cancer occurred in 4.0%; only 2 of 81 deaths were breast cancer-related. Breast cancer-specific survival remained excellent.

This study evaluated darolutamide added to androgen deprivation therapy (ADT) and radiotherapy (RT) in 1,106 patients with very high-risk localized or biochemically persistent/recurrent prostate cancer. After a median follow-up of 3.8 years, darolutamide significantly improved metastasis-free survival, with 4-year rates of 95% versus 88% and a 58% relative reduction in the risk of metastasis or death. Grade ≥3 adverse events occurred in 43% versus 36% of patients.

The phase III ENERGIZE trial evaluated perioperative nivolumab plus gemcitabine-cisplatin (GC) in resectable muscle-invasive bladder cancer. After 54.5 months’ median follow-up, nivolumab did not significantly improve event-free survival (HR 0.94; P = 0.6697), despite a numerically higher pathological complete response rate (39.1% vs 29.6%). Overall survival was similar descriptively, and grade 3–4 treatment-related adverse events were comparable. Detectable baseline ctDNA and failure to clear ctDNA predicted poorer outcomes.

The final KEYNOTE-564 analysis confirmed sustained disease-free survival (DFS) and overall survival (OS) benefits with adjuvant pembrolizumab in patients with high-risk clear cell renal cell carcinoma (ccRCC) following surgery. At 85.9 months’ median follow-up, 7-year DFS was 57.2% versus 44.6%, and OS was 82.3% versus 76.6%, compared with placebo. No new serious treatment-related adverse events emerged, reinforcing pembrolizumab’s role as standard adjuvant treatment.

The phase III KEYNOTE-866 trial evaluated perioperative pembrolizumab plus cisplatin-based chemotherapy and cystectomy in muscle-invasive bladder cancer (MIBC). At 60.9 months’ median follow-up, pembrolizumab did not significantly improve event-free survival (HR 0.88; 95% CI 0.71–1.10). Pathological complete response was higher with pembrolizumab (44.4% vs 35.8%), while overall survival was similar (HR 1.00). Grade ≥3 adverse events were more frequent with pembrolizumab, although safety remained manageable.

LITESPARK-011, a phase 3 trial, compared belzutifan plus lenvatinib with cabozantinib in 747 patients with advanced clear-cell renal-cell carcinoma progressing after anti–PD-(L)1 therapy. At 38.8 months’ median follow-up, combination therapy improved progression-free survival (HR 0.74), response rate (53.1% vs 40.2%), and response duration (22.0 vs 11.9 months). Overall survival numerically favored combination therapy but was not statistically significant. Grade ≥3 adverse events occurred in 85.4% versus 83.0%.

LITESPARK-012, a phase 3 trial, evaluated adding belzutifan or quavonlimab to first-line pembrolizumab plus lenvatinib in 1,688 patients with advanced clear-cell renal-cell carcinoma. Neither combination improved progression-free or overall survival compared with standard therapy. Median PFS was 20.8 and 20.7 months in the investigational arms versus 23.7 months with control. Adverse-event-related drug discontinuation increased with both combinations (approximately 51% vs 36%).

TROPHY-U-01 Cohort 7 tested the triplet of sacituzumab govitecan, enfortumab vedotin and zimberelimab (with mandatory G-CSF) in 21 patients with treatment-naïve metastatic urothelial cancer. Among 18 evaluable patients, ORR was 83% (72% confirmed), including 3 complete responses. Grade ≥3 TEAEs occurred in 62% and 33% discontinued at least one drug, but only one DLT (febrile neutropenia) occurred and no additive toxicity was seen. SG 7.5 mg/kg was selected for expansion.

In the phase 3 VOLGA trial (n=695), patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin received perioperative durvalumab, with or without tremelimumab, plus three cycles of neoadjuvant enfortumab vedotin, or radical cystectomy alone. Durvalumab–enfortumab vedotin improved 24-month event-free survival (63.5% vs 45.1%; HR 0.51) and overall survival (78.4% vs 69.4%; HR 0.58). The triplet improved event-free survival (HR 0.61). Grade ≥3 adverse events were more common with the durvalumab-based regimens.

This phase 1 study evaluated XmAb819, an ENPP3×CD3 bispecific antibody, in heavily pretreated advanced clear-cell renal cell carcinoma (ccRCC). Among 60 patients treated at target doses with postbaseline imaging, objective response rate was 27% and disease control rate 68%, including patients previously receiving HIF2α inhibitors. Grade ≥3 treatment-related adverse events occurred in 61%, with 7% discontinuing treatment and no treatment-related grade 5 events reported.

The phase I/II ARROS-1 trial evaluated zidesamtinib 100 mg daily in TKI-naïve ROS1-positive advanced NSCLC. Among 94 evaluable patients, ORR was 94%, with 9- and 12-month DoR rates of 94% and 86%. In 10 patients with CNS metastases, intracranial ORR was 100% (70% complete responses). Across 532 treated patients, peripheral edema (34%) was the most common side effect, with dose reductions in 11% and discontinuation in only 1%.

In this phase 3 trial, 314 patients with EGFR-mutated, FISH-defined MET-amplified advanced NSCLC progressing on EGFR-TKIs were randomized to dalmelitinib plus aumolertinib or platinum-based chemotherapy. At 11.2 months' follow-up, median PFS was 6.2 vs 4.4 months (HR 0.60; P<0.001). ORR was 59.6% vs 38.6%, and median DoR 9.7 vs 4.4 months. OS was immature. Grade ≥3 TEAEs were similar (50.0% vs 51.0%), with more hepatic lab abnormalities on the combination.

In the phase 3 DeLLphi-304 trial, tarlatamab versus chemotherapy in relapsed SCLC after platinum maintained its benefit at ~23 months' follow-up. Median OS was 13.6 vs 8.4 months; 24-month OS 30.3% vs 14.9%. Median PFS was 4.2 vs 3.2 months. ORR was 35.4% vs 20.4%, with 31.1% vs 3.8% of responses ongoing. TRAE-related discontinuation was 3.2% vs 6.6%; CRS/ICANS were early, mostly low-grade, with no serious TRAEs starting beyond 12 months.

In this phase 3 trial (n=563), patients with extensive-stage small-cell lung cancer without progression after first-line chemoimmunotherapy received maintenance tarlatamab, a DLL3×CD3 bispecific T-cell engager, plus durvalumab, or durvalumab alone. Tarlatamab–durvalumab extended median overall survival (21.1 vs 12.7 months; HR 0.42) and progression-free survival (7.4 vs 1.9 months; HR 0.34). Grade ≥3 adverse events occurred in 46.8% vs 40.6%. Cytokine release syndrome, mostly grade 1–2, affected nearly half of tarlatamab-treated patients.

Patient-reported outcomes from the phase 3 DESTINY-Lung04 trial (n=454) compared first-line T-DXd with pembrolizumab plus chemotherapy in HER2-mutant NSCLC. T-DXd delayed deterioration in cough (26.2 vs 11.0 months; HR 0.66), with favorable trends for dyspnea and chest pain. Physical function was maintained more often with T-DXd from week 20 and at end of treatment (66.7% vs 57.7%), while side-effect bother was comparable despite longer T-DXd exposure (high bother 13.4% each).

This AACR Project GENIE real-world analysis described 164 patients with HER2-mutant NSCLC from five institutions (2019–23); 68% were female, 50% never smokers and 82% had adenocarcinoma. YVMA duplication was the most common ERBB2 variant (52%), and 82% had co-alterations, mainly TP53 (43%). In 64 advanced-disease patients, first-line therapy was mostly immunotherapy (41%) or platinum chemotherapy (30%), while HER2-directed therapy (53%), chiefly T-DXd (44%), was largely deferred to later lines.

In this phase 3, open-label trial, 338 patients with previously treated KRAS G12C-mutated advanced NSCLC received divarasib or sotorasib/adagrasib. Divarasib significantly improved median progression-free survival (9.8 vs 5.7 months; HR 0.58) and overall survival (17.7 vs 12.0 months; HR 0.56). Response rates were higher (58.4% vs 32.3%), with longer response duration (11.9 vs 6.9 months). Grade 3–4 treatment-related adverse events were less frequent with divarasib (24.6% vs 34.5%).

The phase 2 MDT-BRIDGE study tested MDT-guided neoadjuvant durvalumab plus chemotherapy in 142 patients with resectable (64.8%) or borderline resectable (35.2%) NSCLC, followed by surgery or, if unresectable, CRT. The overall resection rate was 74.6%, with R0 resection in 96.2% of those operated. 92.3% received curative-intent surgery or CRT, and 82.4% went on to adjuvant or consolidation durvalumab. Grade 3/4 AEs during durvalumab occurred in 7.4% (resected) and 17.4% (CRT).

NeoCOAST-2, a randomized phase 2 trial in resectable stage IIA–IIIB NSCLC, evaluated perioperative durvalumab and chemotherapy combined with oleclumab, monalizumab, or datopotamab deruxtecan (Dato-DXd). Pathological complete response rates were 20.3%, 25.7%, and 35.2%, respectively, with 24-month event-free survival of 70.5%, 75.7%, and 77.9%. Circulating tumor DNA clearance was highest with Dato-DXd and strongly associated with improved event-free survival.

In this phase 3 trial, 455 patients with previously untreated, PD-L1–negative advanced nonsquamous NSCLC without targetable alterations received sacituzumab tirumotecan plus pembrolizumab or chemotherapy plus pembrolizumab. Combination therapy significantly improved median progression-free survival (15.0 vs 5.7 months; HR 0.49). Response rates were similar (50.2% vs 47.3%), but response duration was longer (13.6 vs 6.8 months). Overall survival favored combination therapy, although data were immature. Grade ≥3 adverse events were lower (47.6% vs 60.6%).

PERSEE randomized 321 patients with untreated advanced NSCLC and PD-L1 expression ≥50% to pembrolizumab alone or pembrolizumab plus platinum-based chemotherapy. Combination therapy significantly improved median progression-free survival (16.1 vs 6.9 months; HR 0.56). Overall survival numerically favored combination therapy (50.2 vs 29.9 months), although not statistically significant. Grade ≥3 treatment-related adverse events increased (54% vs 19%), while severe immune-related events were similar (13% each).

In this phase 3, open-label trial, 338 patients with EGFR-mutated advanced NSCLC and MET overexpression/amplification progressing on osimertinib were randomized to osimertinib–savolitinib or platinum–pemetrexed. Combination therapy significantly improved progression-free survival (HR 0.55) and overall survival (HR 0.68). At 12 months, PFS was 36% versus 10%, and OS 70% versus 53%. Grade ≥3 adverse events were similar (64% vs 63%); edema, anemia, and diarrhea were common, with comparable overall severe toxicity.

This SOHO-01 update evaluated sevabertinib 20 mg BID in HER2 TKD-mutant non-squamous NSCLC: treatment-naïve (Cohort F, n=73), pretreated (Cohort D, n=81) and active brain metastases (Cohort G, n=31). Median DoR was longer first-line (15.1 vs 9.5 months), with YVMA ORRs of 75–78%. In heavily pretreated Cohort G (45% ≥3 lines; 26% prior T-DXd), intracranial response was 25% (19% CR), disease control 61% and median intracranial DoR 6.9 months. Safety was consistent.

In phase 3 ACTICCA-1 (n=591; median follow-up 4.8 years), patients with resected biliary tract cancer received adjuvant cisplatin–gemcitabine or capecitabine for 24 weeks. Median disease-free survival was 25.7 vs 17.9 months (log-rank P=0.097, not significant). Restricted mean survival analysis showed 2.6 additional DFS months with cisplatin–gemcitabine over three years, but overall survival did not differ significantly (median 58.1 vs 48.2 months). Cisplatin–gemcitabine caused more serious adverse events (130 vs 113).

AMPLIFY-7P randomized 144 patients with resected KRAS-mutated PDAC (stages I–III) 2:1 to camupepimut (ELI-002 7P), an mKRAS-targeted vaccine, or observation. The primary DFS endpoint was not met (HR 0.85; p=0.539), though 6-month DFS favored vaccination (75.7% vs 61.7%; HR 0.55). Patients mounting mKRAS-specific T-cell responses had markedly better DFS (HR 0.22). An imbalance in baseline ctDNA positivity (20.8% vs 12.5%) may have confounded results. A phase 3 trial is planned.

AZUR-1 evaluated neoadjuvant dostarlimab monotherapy in 154 patients with previously untreated stage II/III dMMR/MSI-H locally advanced rectal cancer. At 26.3 months’ median follow-up, 68% achieved a sustained clinical complete response at 12 months, while 76% achieved clinical or pathological complete response. Among patients achieving complete response, 98% maintained it for at least 12 months. Grade ≥3 immune-mediated adverse events occurred in 3%, supporting potential organ preservation.

This phase 1 trial tested BGB-B2033, a first-in-class GPC-3 × 4-1BB bispecific antibody, in 110 patients with heavily pretreated HCC (72% ≥2 prior lines; 66% prior anti-PD-(L)1 and TKI) across dose-escalation and dose-optimization cohorts. Treatment-related AEs occurred in 52%, with only 5% grade 3 and no grade 4/5 events. Encouraging responses were seen across doses, with a 6-month DoR of 72.7% in escalation. The recommended phase 2 dose is 450 mg.

In the final overall survival analysis of phase 3 CheckMate 8HW (n=839; median follow-up 68.0 months), nivolumab plus ipilimumab significantly improved overall survival versus nivolumab across all lines (HR 0.61) and versus chemotherapy in first line (HR 0.37) in MSI-H/dMMR metastatic colorectal cancer. First-line OS also favored the combination over nivolumab (HR 0.66), though not statistically significant. Grade 3/4 treatment-related adverse events occurred in 22% vs 14%, without new safety signals.

CG-01, a randomized phase 3 trial, evaluated the CLDN18.2-targeting antibody–drug conjugate sonesitatug vedotin (Sone-Ve) versus investigator’s choice in previously treated advanced gastroesophageal cancer (GEC). Among 532 patients, Sone-Ve significantly improved overall survival in third-line or later treatment (10.0 vs 5.0 months; HR 0.47) and the overall population (10.6 vs 6.4 months; HR 0.58). Progression-free survival did not meet statistical significance.

In the randomized phase 2/3 COMPANION-002 trial (n=168), patients with advanced biliary tract cancer after one prior therapy received tovecimig, a DLL4×VEGF-A bispecific antibody, plus paclitaxel, or paclitaxel alone. The combination improved response rate (18.0% vs 5.3%) and median PFS (4.7 vs 2.6 months; HR 0.44). Overall survival did not differ (HR 1.05), in the setting of 54% crossover. Grade ≥3 adverse events occurred in 93.5% vs 64.2%.

This post-hoc EMERALD-3 analysis assessed tremelimumab plus durvalumab (STRIDE) ± lenvatinib with TACE versus TACE alone in embolization-eligible HCC by baseline ALBI grade. Liver function (ALBI, Child-Pugh) remained stable during treatment. OS trends favored STRIDE-based arms across grades, most clearly for STRIDE + TACE in ALBI grade 1 (HR 0.57). PFS2 and time to next treatment improved numerically, subsequent therapy was used less often (43–53% vs 68–72%), and grade 3/4 toxicity was similar.

G-HOPE-001 randomized 408 patients from China and Japan with CLDN18.2-high (≥75% IHC 2+) gastric/GEJ adenocarcinoma after 2–4 prior regimens to arcotatug tavatecan, an Fc-silenced CLDN18.2 ADC, or physician’s-choice chemotherapy. IRRC-assessed median PFS improved (5.5 vs 2.9 months; HR 0.47; P<0.0001), with early OS favoring the ADC (9.9 vs 7.4 months; HR 0.63). ORR was 23.6% vs 5.3%. Grade ≥3 TEAEs were lower (45.8% vs 57.9%), and no ILD was observed.

In this phase 3 Chinese trial, 682 patients with advanced biliary tract cancer received first-line ivonescimab or durvalumab, each combined with gemcitabine and cisplatin. At 14.3 months’ median follow-up, ivonescimab significantly improved overall survival (14.9 vs. 12.1 months; HR 0.75), progression-free survival (8.4 vs. 5.8 months; HR 0.61), and response rate (53.8% vs. 32.5%). Safety was manageable, with predominantly hematological toxicities.

This randomized phase 3 trial compared adjuvant mFOLFIRINOX with mFOLFOX6 in 795 patients with resected high-risk stage III colon cancer (T4 and/or N2). At 55 months’ median follow-up, 3-year disease-free survival was similar (65.6% vs 66.3%; HR 1.07; P=0.61), with no significant overall survival difference. Grade ≥3 diarrhea and fatigue were more frequent with mFOLFIRINOX, while severe neutropenia was more common with mFOLFOX6.

KEYNOTE-975 randomized 703 patients with untreated, locally advanced unresectable esophageal or GEJ cancer to pembrolizumab or placebo plus definitive chemoradiotherapy. At the second interim analysis (median follow-up 47.1 months), EFS was not improved in PD-L1 CPS ≥10 patients (15.2 vs 14.7 months; HR 0.97), nor was OS (32.2 vs 35.0 months; HR 1.00). Hierarchical testing stopped and the study ended. Grade 5 AEs occurred in 13% vs 10% of patients.

MASTERPLAN, a randomized phase 2 trial, evaluated adding stereotactic body radiotherapy (SBRT) to chemotherapy in 74 patients with high-risk localized pancreatic ductal adenocarcinoma. SBRT reduced 12-month locoregional recurrence from 52.0% to 20.2% (subdistribution HR 0.44; P=0.022). Grade ≥3 adverse events were similar between groups (70% vs 64%), although two serious events were attributed to SBRT. The small sample size warrants confirmation in larger trials.

In the pragmatic phase 3 PRABITAS trial (n=970) in Japan, patients with refractory metastatic colorectal cancer received trifluridine–tipiracil plus bevacizumab on a conventional 28-day or simplified 14-day schedule. The 14-day schedule was non-inferior for overall survival (median 11.3 vs 10.3 months; HR 0.93) and reduced grade ≥3 neutropenia (13% vs 39%) and grade ≥2 anorexia (15% vs 26%). Two treatment-related deaths occurred with the 14-day schedule, versus none.

Daraxonrasib, an oral RAS(ON) multi-selective inhibitor, was evaluated against standard chemotherapy in previously treated metastatic pancreatic ductal adenocarcinoma. In RASolute 302, daraxonrasib demonstrated overall survival benefit across clinically relevant RAS mutation subgroups, including patients without identified RAS mutations. Survival benefits were consistent across chemotherapy regimens, with hazard ratios ranging from 0.32 to 0.46. These findings reinforce daraxonrasib's potential as a new treatment standard, although additional follow-up remains necessary.

SANO enrolled 309 patients with locally advanced esophageal cancer achieving clinical complete response after neoadjuvant chemoradiotherapy, assigning 198 to active surveillance and 111 to standard surgery in a stepped-wedge cluster-randomized design. At five years, overall survival was similar (50% vs 54%; HR 1.17), as was disease-free survival (HR 1.39). However, distant metastases were more frequent with surveillance (46% vs 29%; P<.01). Overall, at least 43% of surveillance patients avoided esophagectomy.

In this phase 1 study (NCT05029882), 83 patients with heavily pretreated advanced colorectal cancer, unselected for c-Met expression, received the c-Met–directed antibody-drug conjugate telisotuzumab adizutecan (Temab-A) plus bevacizumab or trifluridine-tipiracil plus bevacizumab. At 2.4 mg/kg, Temab-A achieved a 30% response rate (vs 0%), median progression-free survival of 6.8 vs 4.2 months, and median overall survival of 14.7 vs 10.2 months (HR 0.62), with manageable gastrointestinal and hematologic toxicity.

The phase 3 KEYNOTE-C93 trial randomized 299 patients with first-line dMMR advanced/recurrent endometrial cancer to pembrolizumab monotherapy or carboplatin-paclitaxel. At 36.5 months' median follow-up, pembrolizumab significantly and durably improved PFS, with a favorable OS trend despite 85.2% of progressing chemotherapy patients crossing to PD-(L)1 inhibitors. QoL improved meaningfully at week 12 (difference 7.02). Grade ≥3 TRAEs occurred in 18.1% vs 50.7%, with grade ≥3 immune-mediated AEs in 7.4% on pembrolizumab.

The phase 3 TroFuse-005 trial randomized 776 patients with advanced or recurrent endometrial cancer, previously treated with platinum and anti-PD-(L)1, to the TROP2-directed ADC sacituzumab tirumotecan or physician's-choice doxorubicin/paclitaxel. At 14.0 months' follow-up, sac-TMT significantly improved PFS (HR 0.59) and OS (HR 0.68), both P≤0.0001, with ORR also significantly improved. Grade ≥3 TRAEs occurred in 54.4% vs 41.4%, anemia most common (20.8% vs 13.4%). QoL was maintained in both arms.

The French phase 3 MOIO trial randomized 340 patients with advanced solid tumors responding after 6 months of standard-dose immunotherapy to standard dosing or reduced intensity (every 3 months). At 18.6 months' follow-up, median PFS was 25 vs 21.9 months (HR 1.35), failing non-inferiority and crossing futility boundary. Reduced dosing doubled the risk of death (HR 2.0; p=0.014), with harm greatest in urothelial cancer (PFS HR 2.9). Toxicity was similar.

In the phase 3 ARTEMIS-011 trial, 122 Chinese patients with R/R osteosarcoma after ≥2 prior lines were randomized 2:1 to the B7-H3 ADC risvutatug rezetecan or gemcitabine-docetaxel. BICR-assessed median PFS was 5.5 vs 1.4 months (HR 0.33; P<0.0001). OS was immature (HR 0.51). Grade ≥3 TRAEs occurred in 93% vs 83%, mainly hematologic, with dose reductions in 71% vs 26%. Discontinuations were rare (3.8% vs 2.4%), and no treatment-related deaths occurred.