📬 GI Cancer Intelligence Digest — Week 2026-W28

ESMO GI 2026 dominated the week: KRAS G12D combinations (zoldonrasib) posted striking early PDAC activity while KRYSTAL-10 and GLEAM missed, EMERALD-1/-3 clarified the TACE-immunotherapy OS question, and PICC-2 pushed neoadjuvant dMMR CRC pCR to 89%.

⚡ TL;DR

📄 Publications

Perioperative systemic therapy versus surgery alone for resectable colorectal peritoneal-only metastases (CAIRO6): a randomised, open-label, phase 3 trial. — Median OS 44 months with perioperative systemic therapy vs 39 months with surgery alone, HR 0.85, p=0.28
[177Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial. — Median PFS 23.9 vs 14.1 months, HR 0.67, p=0.022
Neoadjuvant toripalimab plus celecoxib versus toripalimab monotherapy for mismatch repair-deficient or microsatellite instability-high, locally advanced colorectal cancer (PICC-2): an open-label, multicentre, randomised, phase 2 trial. — pCR 89% with toripalimab plus celecoxib vs 69% with monotherapy, p=0.014
Efficacy and Tolerability of Zenocutuzumab in Advanced NRG1 Fusion-Positive Cholangiocarcinoma: Results From the eNRGy Phase II Trial. — ORR 36.8% among 19 evaluable NRG1+ cholangiocarcinoma patients

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EMERALD-3: STRIDE plus lenvatinib and TACE improves PFS and ORR in embolization-eligible HCC — Adding STRIDE + TACE significantly improved PFS, ORR and DoR versus TACE alone
KRYSTAL-10: adagrasib plus cetuximab misses PFS and OS in 2L KRAS G12C mCRC despite higher response — mPFS 7.5 vs 8.1 months, HR 0.89, with ORR 47% vs 16%
ATOMIC exploratory analysis: does chemotherapy and atezolizumab duration matter in dMMR stage III colon cancer? — Patients receiving >6 cycles of FOLFOX derived greatest DFS benefit from atezolizumab (adjusted HR 0.45) vs HR 0.84 for ≤6 cycles
RMC-9805-001: dual KRAS G12D blockade with zoldonrasib plus daraxonrasib in pretreated PDAC — ORR 50% in 2L and 47% in ≥3L, DCR 97% and 90%, mPFS 9.6 months in 2L
Zoldonrasib plus chemotherapy posts striking first-line response rates in KRAS G12D PDAC — With mFOLFIRINOX ORR 82%, DCR 96%; with gemcitabine/nab-paclitaxel ORR 61%, DCR 90%

Full details below ↓

📄 What's Being Published

Manuscripts:

Perioperative systemic therapy versus surgery alone for resectable colorectal peritoneal-only metastases (CAIRO6): a randomised, open-label, phase 3 trial. — Rovers Koen P et al., Lancet Oncol

In this randomized phase 3 trial, median overall survival was 44 months (95% CI 30–54) in the perioperative systemic therapy group versus 39 months (95% CI 31–46) in the surgery alone group (HR 0.85, 95% CI 0.62–1.15; p=0.28). Major systemic therapy-related toxicity occurred in 92 (57%) of 161 patients who started perioperative systemic therapy, with no survival benefit to offset this burden.

Clinical bottom line: A powered negative trial: perioperative systemic therapy cannot be recommended for all patients with resectable colorectal peritoneal-only metastases.

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Neoadjuvant toripalimab plus celecoxib versus toripalimab monotherapy for mismatch repair-deficient or microsatellite instability-high, locally advanced colorectal cancer (PICC-2): an open-label, multicentre, randomised, phase 2 trial. — Hu Huabin et al., Lancet Oncol

Pathological complete response was observed in 49 of 55 patients (89% [95% CI 78–96]) in the toripalimab plus celecoxib group versus 38 of 55 (69% [55–81]) in the monotherapy group (between-group difference 19 percentage points [95% CI 4–34]; p=0.014). Grade 3 treatment-related adverse events occurred in three (5%) patients and four (7%) patients, respectively, indicating no meaningful added toxicity.

Clinical bottom line: Adding celecoxib to neoadjuvant toripalimab significantly raised pCR in dMMR/MSI-H locally advanced CRC with no added toxicity, meriting phase 3 testing.

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[177Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial. — Walter Thomas et al., Lancet

Median progression-free survival was significantly longer with [177Lu]Lu-edotreotide versus everolimus (23.9 months [95% CI 18.7–30.0] vs 14.1 months [9.2–20.9]; stratified HR 0.67 [95% CI 0.48–0.95]; p=0.022). Grade 3–4 treatment-related adverse events were reported in 18% of patients in the [177Lu]Lu-edotreotide group compared with 40% in the everolimus group.

Clinical bottom line: [177Lu]Lu-edotreotide significantly prolongs PFS over everolimus and supports its use in early lines for advanced progressive GEP NETs.

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A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without cobimetinib in previously-treated unresectable biliary tract cancer. — Heumann Thatcher Ross et al., Clin Cancer Res

Median PFS was 2.40 months in the cobimetinib plus atezolizumab plus varlilumab (CAV) arm and 1.84 months in the atezolizumab plus varlilumab (AV) arm (HR 0.67, 95% CI [0.38, 1.18]). Objective responses were rare at 0% in the CAV arm and 3.8% in the AV arm.

Clinical bottom line: Atezolizumab and varlilumab with or without cobimetinib were safe but did not meaningfully improve outcomes in later-line biliary tract cancer.

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High-Sensitivity ctDNA Analysis Uncovers Relevant Signals Missed by NGS in Pancreatic Cancer. — Sridalla Krishay et al., Clin Cancer Res

At diagnosis, KRAS ctDNA was detected in 17.2% (17/99) of patients by NGS and 64.9% (63/97) by ddPCR. Median OS was shortest in patients with ctDNA detected by both NGS and ddPCR (10.9 months), longest in those not detected by either platform (40.7 months), and intermediate in patients detected only by ddPCR (26.9 months; p<0.001).

Clinical bottom line: In localized PDAC, high-sensitivity ddPCR ctDNA detects prognostically relevant disease missed by NGS, potentially sharpening perioperative risk stratification.

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Efficacy and Tolerability of Zenocutuzumab in Advanced NRG1 Fusion-Positive Cholangiocarcinoma: Results From the eNRGy Phase II Trial. — Cleary James M et al., J Clin Oncol

Seven of 19 evaluable patients achieved a response, resulting in an ORR of 36.8% (95% CI, 16.3 to 61.6) in NRG1 fusion-positive cholangiocarcinoma. Median PFS was 9.2 months (95% CI, 3.9 to 11.1).

Clinical bottom line: Zenocutuzumab shows clinically meaningful, durable activity in NRG1+ cholangiocarcinoma, supporting its FDA approval and dual RNA/DNA NGS testing for these fusions.

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Circulating Methylated SEPT9 for Detection of Hepatocellular Carcinoma in Cirrhosis. — Oussalah Abderrahim et al., JAMA Oncol

Methylated SEPT9 outperformed AFP (AUROC: 0.79 [95% CI, 0.74–0.84] vs 0.71 [95% CI, 0.66–0.76]; P=.002; posterior probability of superiority >99.8%). For BCLC 0–A disease, tier 1a sensitivity was 74.5% (95% CI, 62.2–86.5) versus 23.5% (95% CI, 12.5–35.8) for AFP, a 3.2-fold increase.

Clinical bottom line: Combining methylated SEPT9 with AFP substantially improves HCC detection in cirrhosis, especially for early-stage disease amenable to cure.

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Camrelizumab, apatinib and radiotherapy in locally advanced, unresectable hepatocellular carcinoma: a phase 2 study. — Wang Hongzhi et al., Clin Cancer Res

The objective response rate was 84.1%, with a median PFS of 13.8 months and median OS not reached. The 24-month PFS rate was 38.1% and the 24-month OS rate was 70.2%.

Clinical bottom line: Camrelizumab plus apatinib with IMRT produced high response rates with manageable toxicity in locally advanced unresectable HCC, meriting randomized validation.

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🗣️ What People Were Discussing This Week

How these are chosen: filtered for clinical relevance, grouped by the new development discussed, then ordered by engagement (bookmarks and reposts).

EMERALD-3: STRIDE plus lenvatinib and TACE improves PFS and ORR in embolization-eligible HCC

Adding STRIDE plus TACE significantly improved PFS, ORR, and duration of response versus TACE alone, with a manageable safety profile, and an early OS trend was noted pending longer follow-up. The primary endpoint was met, with both ORR and PFS improved and an OS benefit observed for STRIDE. The central debate is whether the PFS benefit from adding systemic therapy reflects a true gain or compensation for TACE's poor local control.

Discussed by: @ArndtVogel, @NiuSanford, @jryckman3

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KRYSTAL-10: adagrasib plus cetuximab misses PFS and OS in 2L KRAS G12C mCRC despite higher response

Adagrasib plus cetuximab did not meet its dual primary endpoints of PFS and OS versus chemotherapy ± anti-VEGF/R, with mPFS of 7.5 versus 8.1 months and HR 0.89 (95% CI 0.71–1.13), despite ORR being numerically higher at 47% versus 16%. The disconnect between a dramatically improved response rate and the absence of PFS or OS benefit in second line has led oncologists to ask whether KRAS G12C targeting in CRC should instead move upfront in combination with chemotherapy.

Discussed by: @GIMedOnc, @CathyEngMD, @ArndtVogel, @GillSharlene

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ATOMIC exploratory analysis: does chemotherapy and atezolizumab duration matter in dMMR stage III colon cancer?

An exploratory analysis of ATOMIC found that patients receiving more than 6 cycles of FOLFOX appeared to derive the greatest DFS benefit from the addition of atezolizumab (adjusted HR 0.45), whereas that benefit was not apparent among patients receiving 6 or fewer cycles (HR 0.84), though this subgroup was relatively small. No DFS benefit from adding atezolizumab was observed with fewer than 6 cycles of mFOLFOX6, DFS benefit increased with the number of chemotherapy cycles, and no additional DFS benefit was seen with atezolizumab beyond 12 cycles — raising the question of whether chemotherapy intensity matters more with the less-active atezolizumab, and whether 3 months of CAPOX can suffice in dMMR disease.

Discussed by: @GIMedOnc, @GillSharlene, @ArndtVogel, @CathyEngMD

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RMC-9805-001: dual KRAS G12D blockade with zoldonrasib plus daraxonrasib in pretreated PDAC

In pretreated KRAS G12D PDAC, zoldonrasib plus daraxonrasib produced an ORR of 50% in second line and 47% in third line or beyond, with disease control rates of 97% and 90% respectively, and mPFS of 9.6 months in second line versus 7.6 months in third line or later, alongside a manageable safety profile and no unexpected toxicities. The phase 3 RASolute 309 trial is planned as the next step, leaving open the question of whether a chemo-free dual RAS-inhibitor regimen could become a real second-line option ahead of that readout.

Discussed by: @MarioBalsaMD, @Aiims1742, @ArndtVogel, @MallaMidhun

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Zoldonrasib plus chemotherapy posts striking first-line response rates in KRAS G12D PDAC

In first-line KRAS G12D PDAC, zoldonrasib combined with mFOLFIRINOX achieved an ORR of 82% and DCR of 96%, while the gemcitabine/nab-paclitaxel combination produced an ORR of 61% and DCR of 90%. Notably, 100% of evaluable patients achieved greater than 50% ctDNA reduction, intensifying debate about what the optimal first-line combination and sequencing of zoldonrasib should be, and whether chemotherapy will remain necessary.

Discussed by: @graokane, @ArndtVogel, @DraMartinezLago, @UOzkerim

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GALAXY liver-metastasis analysis: ctDNA guides adjuvant chemotherapy after CRLM resection

In the GALAXY liver-metastasis analysis, ctDNA-positive patients in the upfront surgery cohort derived an OS benefit from adjuvant chemotherapy, while ctDNA-negative patients showed favorable OS without a clear benefit from adjuvant treatment; in the neoadjuvant cohort, ctDNA positivity remained prognostic. OS was higher for adjuvant chemotherapy in MRD-positive patients after liver resection, focusing debate on whether postoperative ctDNA status should routinely direct adjuvant chemotherapy decisions after colorectal liver metastasis resection.

Discussed by: @CathyEngMD, @DaisukeKotani, @p_ciracimd

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GLEAM: zolbetuximab plus gemcitabine/nab-paclitaxel misses OS in CLDN18.2+ PDAC

GLEAM was a negative study: mOS was 13.7 versus 13.6 months with HR 0.99 (P=0.50), and the primary endpoint was not met with no OS or PFS benefit observed. Toxicity was manageable, and while zolbetuximab failed, oncologists noted that CLDN18.2 may still represent a viable target for next-generation ADCs and bispecifics rather than this agent.

Discussed by: @ArndtVogel, @DrAngelaLamarca, @graokane, @CentralParkWMD

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EMERALD-1: durvalumab ± bevacizumab plus TACE improves PFS but not OS in unresectable HCC

Adding durvalumab plus bevacizumab to TACE significantly improved PFS (HR 0.77), but this benefit did not translate into an overall survival advantage (OS HR 1.10); durvalumab alone also failed to improve OS (HR 0.93). Neither strategy improved OS versus TACE alone, leaving clinicians to weigh whether PFS gains without OS benefit justify these combinations or whether patient selection is the central unresolved issue.

Discussed by: @MarioBalsaMD, @UOzkerim, @DrAngelaLamarca, @ArndtVogel

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HERIZON-GEA-01: zanidatamab-based therapy positioned as new 1L standard in HER2+ mGEA

Zanidatamab plus chemotherapy, with or without tislelizumab, improved outcomes without significant impact on quality of life, with diarrhoea consistent with the known safety profile and no new safety signals; an OS benefit was observed with zanidatamab plus tislelizumab. The HRQoL data and significant PFS benefit have prompted oncologists to position zanidatamab-based therapy as the new first-line standard of care in HER2-positive metastatic gastroesophageal adenocarcinoma.

Discussed by: @ArndtVogel, @DraMartinezLago

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PROACTIF: largest prospective Y-90 dataset supports personalized dosimetry in HCC

The PROACTIF dataset encompasses 989 HCC patients and 207 iCCA patients, with HCC tumors exceeding 5 cm in 68% of cases and portal vein thrombosis present in 35%; higher absorbed tumor dose was associated with longer OS, with a threshold of ≥400 Gy appearing particularly relevant, and VP1–VP3 portal vein thrombosis patients achieved survival approaching that of non-PVT patients at this dose level. The dataset is the largest real-world Y-90 series reported, with absorbed dose identified as a key determinant of outcome, directing attention to how personalized-dose Y-90 should be sequenced with systemic therapy or TACE.

Discussed by: @MarioBalsaMD, @Erman_Akkus, @Jkhileman

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eNRGy: zenocutuzumab active in NRG1 fusion-positive cholangiocarcinoma, driving FDA approval

Among 22 pretreated NRG1 fusion-positive cholangiocarcinoma patients, zenocutuzumab produced an ORR of 36.8% and a median PFS of 9.2 months. RNA NGS substantially outperforms DNA NGS for detecting NRG1 fusions, and the recommended practice is to order both for all cholangiocarcinoma patients, framing the question of whether RNA-based fusion testing should be universal in this disease.

Discussed by: @JamesClearyMD, @Erman_Akkus

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PICC-2: adding celecoxib to neoadjuvant toripalimab lifts pCR in dMMR/MSI-H locally advanced CRC

In PICC-2, pCR was 89% with toripalimab plus celecoxib versus 69% with toripalimab monotherapy (p=0.014), with surgery performed in 96% versus 93% of patients and grade ≥3 treatment-related adverse events occurring in only 5% versus 7%. Clinicians noted that a cheap oral drug pushes neoadjuvant immunotherapy pCR from approximately 60% to approximately 90% in dMMR colon cancer, centering discussion on whether COX-2 inhibition is a practical strategy to deepen these responses.

Discussed by: @DraMartinezLago, @DrAllanPereira

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PARERE: liquid-biopsy-guided anti-EGFR rechallenge beats regorafenib in chemorefractory mCRC

In ctDNA wild-type patients, panitumumab-first outperformed regorafenib, with PFS1 of 4.1 versus 2.4 months and PFS2 of 3.9 versus 2.7 months (p=0.03). Re-treatment with anti-EGFR agents after first-line progression prolonged OS compared with switching to an anti-VEGF/R agent, with an anti-EGFR-free interval of ≥4 months identifying potential candidates, directing debate toward whether ctDNA-guided hyperselection should replace unselected anti-EGFR rechallenge in RAS/BRAF wild-type chemorefractory mCRC.

Discussed by: @DrRishabhOnco, @p_ciracimd

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STAR-221: domvanalimab/zimberelimab fails in 1L HER2-negative gastroesophageal cancer

STAR-221 was a negative study, with no OS, PFS, or ORR benefit for the TIGIT/PD-1 combination of domvanalimab and zimberelimab versus nivolumab plus chemotherapy. There was no benefit for TIGIT and PD-L1 targeted therapy in this setting, and oncologists noted that TIGIT remains a difficult target in oncology, with the question of whether it represents a dead end in upper GI cancers now squarely in focus.

Discussed by: @Erman_Akkus, @ArndtVogel

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🔥 Top Ranked Tweets

OncoAlert @OncoAlert

RT @Dr_Ivanoncologo: A new era of precision oncology!

The European Commission has approved trastuzumab deruxtecan (ENHERTU®) as the first tumor-agnostic HER2-directed antibody-drug conjugate (ADC) for patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) solid tumors, regardless of the tumor's site of origin.

This landmark approval reinforces a key message: biomarker-driven treatment is reshaping cancer care, making comprehensive HER2 testing increasingly important across multiple solid tumors—not just breast or gastric cancer.

Link to read: https://t.co/BlDCsaDxdw

@OncoAlert @PortalOnconews
#Oncology #PrecisionMedicine #HER2 #ADC #ENHERTU #CancerResearch #TargetedTherapy

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