📬 GI Cancer Intelligence Digest — Week 2026-W34

Nature Medicine maps acquired resistance to daraxonrasib in pancreatic cancer, BEACON-HCC redefines HCC treatment allocation, TNTCRT and 5-year STELLAR reshape rectal cancer TNT, and NETTER-2/COMPETE strengthen first-line PRRT in GEP-NETs.

⚡ TL;DR

🐦 Twitter / 🦋 Bluesky

Nature Medicine maps acquired resistance to daraxonrasib in pancreatic cancer and points to combination strategies — ctDNA profiling of 44 PDAC patients found RAS pathway alterations in 59%, with KRAS amplification most frequent at 36%
COMPETE phase III puts PRRT ahead of everolimus in progressive SSTR-positive GEP-NET, reshaping the NET treatment roadmap — COMPETE included 309 patients and PRRT prolonged progression-free survival to 23.9 vs 14.1 months (HR 0.67)
TNTCRT phase III: doublet chemotherapy delivered before, during and after long-course radiotherapy improves DFS in high-risk rectal cancer, but clinicians question the comparator — TNTCRT randomized 458 patients with high-risk LARC and reported 3-year DFS 74.8% vs 66.0% (HR 0.67) and MFS 77.7% vs 67.6% (HR 0.66)
Depth of response proposed as a new efficacy endpoint in HCC immunotherapy trials — In IMbrave150, DRR60 (at least 60% shrinkage) was achieved in 21% with atezolizumab plus bevacizumab
Histotripsy for liver tumors in US practice: 30-day mortality of 11.1% prompts warnings about hype — In 972 patients, 30-day mortality after histotripsy was 11.1%

Full details below ↓

📄 What's Being Published

Manuscripts:

A Phase II Trial of Pembrolizumab plus Granulocyte-Macrophage Colony-Stimulating Factor in Advanced Biliary Cancer. — Kelley Robin Kate et al., Clin Cancer Res

Among 42 patients enrolled, the confirmed objective response rate was 12% (95% CI 4, 26), including two complete responses, and 26% had progression-free survival ongoing at 6 months. Treatment-related grade 3–4 events occurred in 7% and treatment-related serious adverse events in 10%. Tumor PD-L1 expression was present in 46% and was associated with a higher rate of 6-month progression-free survival, though the combination did not meet the pre-specified response rate for efficacy.

Clinical bottom line: GM-CSF added to pembrolizumab does not rescue checkpoint inhibitor monotherapy in pretreated biliary cancer, and this combination should not move forward without a biomarker-selected design.

Read full article →

🗣️ 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).

Nature Medicine maps acquired resistance to daraxonrasib in pancreatic cancer and points to combination strategies

ctDNA profiling of 44 PDAC patients found RAS pathway alterations in 59%, with KRAS amplification most frequent at 36%, as part of a phase 1/2 trial of the RAS(ON) multi-selective inhibitor daraxonrasib; preclinical translational modeling was used alongside these analyses to identify mechanisms of acquired resistance to monotherapy. Resistance biology converges on KRAS amplification, MAPK reactivation, PI3K signaling, MYC and cell-state plasticity, providing a rationale for mechanism-based combination strategies. RAS(ON) inhibition can induce or upregulate cell-surface RTKs including HER2 — creating a therapeutic vulnerability rather than simply another resistance mechanism — with a RAS(ON) inhibitor doublet of daraxonrasib plus zoldonrasib and RTK-targeting biologics such as T-DXd and amivantamab identified as key proposed combination approaches. The central debate is whether combination partners should be selected by ctDNA-detected resistance mechanism at progression, or built into frontline RAS(ON) inhibitor regimens from the start.

Discussed by: @EladSharonMD, @OncBrothers, @jgong15, @HHorinouchi, @HHorinouchi, @OncoAlert, @OncUpdates

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COMPETE phase III puts PRRT ahead of everolimus in progressive SSTR-positive GEP-NET, reshaping the NET treatment roadmap

COMPETE, which included 309 patients with progressive, SSTR-positive, well-differentiated G1–2 GEP-NET, demonstrated superior progression-free survival with PRRT over everolimus at 23.9 vs 14.1 months (HR 0.67), published in The Lancet 2026. The tolerability advantage was substantial: grade 3–4 treatment-related adverse events occurred in 18% with PRRT versus 40% with everolimus, and treatment discontinuation due to toxicity was 6% versus 23%. A proposed GI-NET roadmap positions SSTR-positive higher-grade G2 or bulky disease needing response toward 177Lu-DOTATATE plus SSA based on NETTER-2, with progression on SSA directing appropriate patients to PRRT per NETTER-1. The clinical question is whether any role remains for everolimus before PRRT in SSTR-positive GEP-NET, given COMPETE's PFS, quality-of-life, and tolerability findings.

Discussed by: @ChandrakanthMv, @ChandrakanthMv, @ChandrakanthMv, @ArndtVogel

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TNTCRT phase III: doublet chemotherapy delivered before, during and after long-course radiotherapy improves DFS in high-risk rectal cancer, but clinicians question the comparator

TNTCRT randomized 458 patients with high-risk locally advanced rectal cancer to conventional long-course chemoradiotherapy followed by surgery and adjuvant chemotherapy versus CAPOX before, during, and after long-course radiation; the doublet strategy improved 3-year DFS to 74.8% vs 66.0% (HR 0.67), metastasis-free survival to 77.7% vs 67.6% (HR 0.66), and pCR to 26.4% vs 9.8%. Critics note the control arm does not reflect how high-risk rectal cancer is treated in the US, and that consolidation FOLFOX/CAPOX in OPRA yielded a 3-year DFS of 76% — essentially the same as the 74.8% seen in TNTCRT — while OPRA also carries a TME-free survival of 54%. The central debate is whether TNTCRT adds anything over consolidation-chemotherapy TNT regimens such as OPRA, given the nearly identical 3-year DFS and the absence of an organ-preservation endpoint.

Discussed by: @JCO_ASCO, @GIMedOnc, @Dr_ElvinaA, @ASCOPost

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Depth of response proposed as a new efficacy endpoint in HCC immunotherapy trials

Data from IMbrave150 show that DRR60 — at least 60% tumor shrinkage — was achieved in 21% of patients receiving atezolizumab plus bevacizumab, while HIMALAYA data indicate that patients achieving at least 75% shrinkage reached 83.3% 5-year OS compared with 11.1% in those with less than 30% shrinkage. BEACON-HCC integrates biomarkers including AFP above 1000 ng/mL alongside size and number in its treatment allocation framework. Specialists are debating whether depth of response should be adopted as a co-primary or surrogate endpoint in HCC immunotherapy trials, or whether it simply re-identifies patients who were always going to do well.

Discussed by: @hongjaechon, @hongjaechon

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Histotripsy for liver tumors in US practice: 30-day mortality of 11.1% prompts warnings about hype

First US practice data on histotripsy for liver tumors, drawn from 972 patients, show a 30-day mortality of 11.1% — outcomes that oncologists are describing as very concerning. Clinicians report that many patients are requesting histotripsy as a perceived "safe" treatment, creating a counseling challenge at a time when the early outcome data are at odds with that perception. The question facing multidisciplinary teams is how to counsel patients requesting histotripsy when the first US practice data show an 11.1% 30-day mortality.

Discussed by: @ArndtVogel, @hongjaechon

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🔥 Top Ranked Tweets

OncoAlert @OncoAlert

RT @OncoAlert: Can short-course radiotherapy followed by chemotherapy deliver durable survival benefits for patients with locally advanced rectal cancer.

Article 👉 https://t.co/QkU8evLrf4

Five-Year Outcomes of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy for Locally Advanced Rectal Cancer: Updated Results of the STELLAR Trial💫

The 5-year STELLAR trial results show that short-course radiotherapy☢️ followed by chemotherapy🧪 as total neoadjuvant therapy (TNT) offers a durable overall survival benefit compared with standard long-course chemoradiotherapy in locally advanced rectal cancer.

Although disease-free survival, distant metastasis, and locoregional recurrence were similar, TNT significantly improved overall survival, particularly in high-risk patients, and outcomes after recurrence, supporting TNT as an effective alternative to conventional CRT.

@CathyEngMD
@BenWestphalen
@graokane
@NiuSanford
@AndresC27622123
@GillSharlene
@pashtoonkasi
@DrVilmaPBarcia
@Erman_Akkus
@GIMedOnc
@UOzkerim
@MarioBalsaMD
@p_ciracimd
@DraMartinezLago
@DaisukeKotani
@Aiims1742
@ARosen380
@realbowtiedoc
@KoheiShitara
@MarioBalsaMD

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