Every trial that matters this week, distilled to a single call — act on it, watch it, or keep it on the radar.
Practice-shapingRectal · high-risk LARC
TNTCRT
A positive phase III in high-risk locally advanced rectal cancer: an intensified doublet (CAPOX) total neoadjuvant therapy built on long-course radiotherapy improved disease-free survival and nearly tripled pathologic complete response versus conventional chemoradiotherapy-then-surgery. More neoadjuvant toxicity, but no excess surgical complications — a genuine new option in the TNT paradigm.
· 3-yr DFS 74.8% vs 66.0% (HR 0.674, 0.489–0.929; p=.016)· pCR 26.4% vs 9.8% (p<.001)· MFS HR 0.655· n=458
Pathologic complete response · 0–100% scale
26.4%Doublet CAPOX + long-course RT (TNT)
9.8%Conventional chemoradiotherapy
050100%
Go deeper
This multicenter Chinese phase III trial (NCT03177382) randomized 458 patients with stage II/III rectal cancer and at least one high-risk feature (cT4a-b, cN2, mesorectal fascia involvement, or cT3c-d with extramural vascular invasion) to doublet-LC TNT — induction, concurrent, and consolidation capecitabine plus oxaliplatin integrated with long-course radiotherapy — versus conventional neoadjuvant chemoradiotherapy followed by surgery and adjuvant chemotherapy. At a median 51 months, doublet-LC TNT improved 3-year disease-free survival to 74.8% from 66.0% (HR 0.674, 95% CI 0.489–0.929; p=.016), improved metastasis-free survival (77.7% vs 67.6%; HR 0.655), and nearly tripled the pathologic complete response rate (26.4% vs 9.8%; p<.001), while locoregional failure stayed low and comparable (~6% in both arms). Grade ≥3 adverse events during the neoadjuvant phase were higher with the doublet regimen (27.6% vs 8.6%), but severe toxicity across the whole treatment course (28.0% vs 24.3%) and major postoperative complications (4.0% vs 2.9%) were similar. The open question is how doublet-LC TNT compares with short-course-radiotherapy-based or non-doublet-concurrent TNT regimens — not against the older chemoradiotherapy backbone used here.Full daily entry →
The 5-year update of STELLAR shows the overall-survival advantage of short-course radiotherapy followed by consolidation chemotherapy (a TNT strategy) over long-course chemoradiotherapy is durable — 78.1% vs 69.7% at five years. Be precise: disease-free survival did not separate significantly and local control was similar; the survival benefit, concentrated in high-risk patients, is the enduring signal. For a shorter, less resource-intensive radiotherapy course, that matters.
· 5-yr OS 78.1% vs 69.7% (HR 0.739, 0.550–0.993)· 5-yr DFS 62.0% vs 58.7% (HR 0.849, NS)· high-risk OS HR 0.663· median f/u 68.7 mo
5-year overall survival · 0–100% scale
78.1%Short-course RT-based TNT
69.7%Long-course chemoradiotherapy
050100%
Go deeper
STELLAR was one of the first randomized studies to test whether short-course radiotherapy (SCRT) followed by consolidation chemotherapy — a total neoadjuvant therapy strategy — could match or beat standard long-course chemoradiotherapy (CRT) in locally advanced rectal cancer, and this update reports the durable 5-year picture. Patients with distal or middle-third disease were randomized to SCRT-based TNT or long-course CRT; at a median follow-up of 68.7 months, 5-year overall survival was significantly higher with TNT (78.1% vs 69.7%; HR 0.739, 95% CI 0.550–0.993). The co-primary disease-free survival endpoint did not reach significance (62.0% vs 58.7%; HR 0.849, 95% CI 0.662–1.089), and distant metastasis and locoregional recurrence rates were similar — so the OS advantage, not local control or DFS, is the story. The benefit concentrated in ESMO high-risk patients (OS HR 0.663, 95% CI 0.469–0.937), and even among those who recurred, TNT was associated with better postrecurrence progression-free survival (HR 0.691) and postrecurrence survival (HR 0.698). The authors position SCRT-based TNT as a durable, viable alternative to long-course CRT, particularly for high-risk disease. Full daily entry →
A prespecified economic analysis of the CHALLENGE trial found a 3-year structured exercise program after adjuvant chemotherapy for colon cancer was 'dominant' — cheaper AND more effective than health-education alone. Roughly $1,589 CAD saved per patient over five years while adding quality-adjusted life-years, driven by fewer recurrences. One of the very few oncology interventions that improves outcomes while lowering total cost of care — a fundable, reimbursable standard for survivorship care.
· SEP $31,957 vs $33,546 CAD (−$1,589/pt)· +0.05 LY, +0.10 QALY· dominant in 53% of bootstraps· <$50k/QALY in 80%· n=889
Go deeper
The phase III CHALLENGE trial (CCTG CO.21) had already shown that a 3-year structured exercise program (SEP) improved disease-free and overall survival versus health-education materials in stage III or high-risk stage II colon cancer after surgery and adjuvant chemotherapy. This prespecified economic evaluation, using prospectively collected data from all 889 participants, asked whether it is worth paying for. From a Canadian public-payer perspective over a 5-year horizon, it clearly is: despite an up-front delivery cost of $2,917 CAD per participant, the SEP strategy was less expensive overall ($31,957 vs $33,546 CAD; −$1,589 per participant) and more effective (+0.05 life-years, +0.10 QALYs) — a 'dominant' result. SEP was dominant in 53% of 1,000 bootstrap samples and fell below a $50,000 CAD/QALY threshold in 80%, with downstream savings coming from fewer recurrences and less anticancer therapy; 10-year and societal-perspective scenarios were consistent. Structured exercise is fundable, reimbursable survivorship care — not a nice-to-have.Full daily entry →
AstraZeneca's topline announcement makes sonesitatug vedotin the first anti-CLDN18.2 antibody-drug conjugate to significantly improve overall survival in 2nd-and-later-line CLDN18.2-positive advanced gastric/GEJ/esophageal cancer. Promising and potentially important — but topline only: no effect size released, and progression-free survival was not met. Worth watching for the full data, not yet actionable.
· Met dual primary OS in 3L+· Met key secondary OS in 2L+ overall· PFS (co-primary) not met· CLDN18.2 ≥25%, 175 sites / 19 countries· numbers pending
Go deeper
AstraZeneca reported positive topline results from CLARITY-Gastric01, the first phase III trial to show an overall-survival benefit with an anti-CLDN18.2 antibody-drug conjugate — a milestone for a target previously exploited only with the monoclonal antibody zolbetuximab. Sonesitatug vedotin (Sone-Ve), which pairs an anti-CLDN18.2 antibody with a protease-cleavable linker and an MMAE cytotoxic payload, was tested against investigator's choice of therapy in second- and later-line locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma with CLDN18.2 expression on ≥25% of tumor cells at any intensity. The trial met its dual primary endpoint of overall survival in the 3rd-and-later-line setting (statistically significant and, per the company, highly clinically meaningful) and a key secondary endpoint of overall survival in the overall 2L+ population; the other component of the dual primary, progression-free survival, did not reach statistical significance. No quantitative data (hazard ratios, median OS) have been released — AstraZeneca states full results will be presented at a forthcoming medical meeting, so this entry is a verified topline with the effect size still unknown. If the magnitude holds when the numbers land, Sone-Ve could become a new 2L+ option in CLDN18.2-positive disease and the first of AstraZeneca's wholly owned ADCs to reach a pivotal survival readout. Full daily entry →
The biomarker-focused counterweight to adjuvant-aspirin enthusiasm in colorectal cancer. Within ASCOLT's own tissue, aspirin showed no significant DFS benefit in any molecular subgroup — but the subgroups were small with wide confidence intervals, so this is underpowered, not proof of absence. The signal that survives is in the pooled data: across three trials, aspirin reduced DFS events specifically in PIK3CA exon 9/20 mutants (HR 0.61). The biomarker, not the drug broadly, is the story.
The parent ASCOLT trial randomized 1,587 patients to aspirin versus placebo and found no significant disease-free survival benefit overall; other modern trials (including ALASCCA) that did show benefit did so specifically in PI3K-pathway-altered tumors, so this preplanned translational analysis tested whether ASCOLT's own tissue told the same story. Among 397 tumors assessable for PIK3CA, aspirin was not significantly associated with improved DFS in any molecularly defined subgroup: PIK3CA mutation of any exon (HR 0.93, 95% CI 0.35–2.47), exon 9/20 specifically (HR 0.72, 0.21–2.46), PIK3CA or PTEN mutation (HR 1.23, 0.47–3.19), or COX-2/PTGS2 overexpression, present in 69% of tumors (HR 0.99, 0.60–1.63) — though every estimate carried wide confidence intervals because the mutant subgroups were small (only 69 patients had any PIK3CA mutation). The pivotal result is the accompanying meta-analysis: pooling three completed adjuvant-aspirin trials in patients with PIK3CA exon 9/20 mutations yielded a significant reduction in DFS events (HR 0.61, 95% CI 0.39–0.96). ASCOLT alone was underpowered to confirm the biomarker signal and should not be over-interpreted as negating it; the pooled data continue to point to exon 9/20 PIK3CA mutation as the group most likely to benefit from a cheap, widely available drug.Full daily entry →
Two phase III trials this week point the same direction in locally advanced rectal cancer (reorganize the neoadjuvant phase) but they 'disagree' on how.
1- The updated STELLAR trial reported 5-year outcomes for short-course radiotherapy followed by consolidation chemotherapy (a TNT strategy) versus the 'old' standard long-course chemoradiotherapy. At a median 68.7 months, OS was significantly higher with the short-course TNT: 78.1% vs 69.7% (HR 0.739).
Worth being precise about what did and didn't move: DFS did not separate significantly, and local control was similar. The survival advantage, concentrated in higher-risk patients, is what held up over five years.
Remember that the RAPIDO 5-year update did show a significantly higher locoregional recurrence (LRR) rate with SCRT-based TNT compared to long-course CRT (10% vs. 6%, p = 0.027 among R0/R1 resected patients), and this finding appears to conflict with STELLAR's report of similar locoregional recurrence between arms. However:
RAPIDO exclusively enrolled defined high-risk patients (cT4, cN2, EMVI, involved MRF, enlarged lateral lymph nodes): the very population most vulnerable to inadequate local control.
In RAPIDO, patients in the SCRT arm were more often treated with 3D-conformal RT rather than IMRT.
In the RAPIDO, the excess LRR was concentrated in patients who underwent sphincter-preserving surgery (12.1% vs. 4.8%, HR 2.60), not abdominoperineal resection (8.5% vs. 7.5%).
Adjuvant chemo was optional in the RAPIDO trial, while STELLAR's control arm mandated 6 cycles of adjuvant CAPOX.
RAPIDO raises a legitimate concern about local control with SCRT in the highest-risk patients, particularly when sphincter-preserving surgery is performed without careful attention to the original (pre-treatment) tumor extent.
The second is an intensification study from the other end of the radiotherapy spectrum. The TNTCRT trial tested an intensified doublet (CAPOX) TNT built on long-course radiotherapy against conventional chemoradiotherapy in high-risk disease, and it improved 3-year DFS (74.8% vs 66.0%, HR 0.674) while nearly tripling the pCR rate (26.4% vs 9.8%). More neoadjuvant toxicity, but no excess surgical complications.
Remember the past: of the major phase III trials testing oxaliplatin added to concurrent fluoropyrimidine-based CRT, only CAO/ARO/AIO-04 demonstrated a statistically significant DFS benefit (with more toxicity). All the others failed.
And a reminder that curative-intent care doesn't end at surgery: the CHALLENGE cost-utility analysis found that a structured post-treatment exercise program in colon cancer was not just survival-improving but "dominant" health-economically — roughly $1,589 cheaper per patient over five years while adding quality-adjusted life-years, driven by fewer recurrences. Exercise is one of the very few oncology interventions that improves outcomes while lowering total cost of care. That is a fundable, reimbursable finding, not a wellness aside.
Let's prescribe 'exercizumab' 🏃 🏃♀️
Also on my radar: AstraZeneca reported positive topline results from CLARITY-Gastric01, making sonesitatug vedotin the first anti-CLDN18.2 antibody-drug conjugate to significantly improve overall survival in second-line-and-later CLDN18.2-positive gastric cancer.
GI Oncology Weekly · curated by Dr. Allan Pereira, Moffitt Cancer Center. Educational summaries for practising oncologists — not medical advice; verify against primary sources before acting.