onc brain

About · curated by Nick Boehling, MD · @nb2276

    2026-05-31

    digest generated 2026-09-15

    CAN-2409: intraprostatic aglatimagene + EBRT, DFS HR 0.70 (0.52-0.94), 2y biopsy persistence/recurrence 19.6% vs 36.4%, intermediate/high-risk localised prostate; no OS/PCSM difference.
    TL;DR
    Prostate RT carried the day: intraprostatic CAN-2409 cut 2y biopsy persistence/recurrence (19.6% vs 36.4%), 24mo enzalutamide added no MFS in high-risk localised disease (ENZARAD, HR 0.88), and protons showed no GI toxicity advantage over IMRT (COMPPARE). Outside RT, RASolute 302 daraxonrasib gave mOS 13.2 vs 6.6 mo (HR 0.40) in previously treated RAS G12 metastatic pancreatic cancer.

    GI Lower

    HFRT/SBRT plus tislelizumab tested in MSS rectal cancer, outside the MSI-H/dMMR setting where PD-1 benefit is established.

    Early signal

    MIRACLE-2

    For1L MSS rectal cancer ≤10 cm from AV, synchronous unresectable mets

    TL;DRORR 68.0%, mOS 23.2 mo, 18% NED with HFRT/SBRT then chemo-biologic + tislelizumab in 1L MSS rectal cancer with synchronous unresectable mets.

    Why it mattersRadiation oncology

    HFRT went to the primary and HFRT or SBRT to metastases before PD-1, but no dose, fractionation or target volume is reported, so the RT component cannot be reproduced. G3/4 lymphopenia 36.7% (all-grade 95.9%) is worth weighing when multisite RT precedes PD-1 blockade. Upfront RT to all sites in MSS disease stays investigational.

    MIRACLE-2
    Best overall responsen (%)95% CI
    CR1 (2.0%)n/a
    PR33 (66.0%)n/a
    SD10 (20.0%)n/a
    PD6 (12.0%)n/a
    ORR34 (68.0%)53.6%-80.0%
    DCR44 (88.0%)76.0%-95.2%
    ETS rate38 (76.0%)62.4%-86.8%
    10 details 1 trial watching
    Design

    Prospective, single-arm, phase I. Efficacy data for N=50 as of December 31, 2025; median follow-up 19.9 mo (95% CI 16.4-23.4). Reassessment every 8 weeks.

    Population & inclusion

    MSS rectal cancer, primary ≤10 cm from anal verge on MRI, with synchronous unresectable metastases, first-line. 76.0% male, median age 57 (range 30-73); liver mets 52.0%, lung 8.0%, both 40.0%; RAS/BRAF mutant 56.0%.

    Radiotherapy

    HFRT to the primary and HFRT or SBRT to metastases, delivered before systemic therapy. Dose, fractionation and target volumes not reported in source.

    Regimen

    RAS/BRAF-mutant: FOLFOX-bevacizumab-tislelizumab; wild-type: FOLFIRI-cetuximab-tislelizumab, tislelizumab 200mg Q2W per flowchart. Median 8 courses (range 3-12). Resectable disease went to primary resection plus metastasectomy/local ablation; watch-and-wait considered for primary cCR when the sphincter could not be preserved.

    Endpoints

    Primary: ETS rate (≥20% target lesion reduction at 8 wks after systemic start). Secondary: DCR, DOR, OS, PFS, safety.

    Results

    18% (9/50) reached NED; how many got there via resection, ablation or watch-and-wait is not reported.

    EndpointMedian (95% CI)1-yr rate
    PFS9.3 mo (7.1-11.5)33.4%
    OS23.2 mo (15.1-31.3)93.3%
    DOR (34 CR/PR)8.0 mo (5.2-10.8)20%
    Safety

    No grade 5 TRAEs. G3/4: lymphopenia 36.7%, neutropenia 26.5%, leukopenia 20.4%. All-grade lymphopenia 95.9%, anemia 91.8%.

    vs leading data

    PD-1 benefit in mCRC rests on MSI-H/dMMR disease (KEYNOTE-177), not MSS. This single arm cannot show RT converts MSS IO resistance, because the doublet plus bevacizumab or cetuximab backbone is itself active first-line.

    Applies to
    first-line MSS rectal cancer with synchronous unresectable liver and/or lung metastases, primary ≤10 cm from the anal verge
    Does not represent MSI-H/dMMR disease, colon primaries, or metachronous or resectable metastatic presentations.
    Limitations

    Median OS 23.2 mo carries a wide CI (15.1-31.3) at 19.9 mo median follow-up. Primary endpoint ETS is an 8-week shrinkage measure, not a durable outcome.

    Discussion

    High early shrinkage (ETS 76.0%, ORR 68.0%) sits against short durability (1-yr PFS 33.4%, 1-yr DOR rate 20%), so durable immune conversion is not yet shown. The testable claim, that RT to all disease sites sensitizes MSS tumors to PD-1 blockade, needs a randomised design and biomarker selection, which the authors flag as a priority.

    Rationale

    Single-arm phase I, N=50, surrogate primary (ETS); no RT-free or IO-free control, so neither RT nor tislelizumab contribution is isolated.

    Open questions

    Sourced from @NiuSanford

    📚 Sources · 🐦 1 tweet

    Combined Phase 1 Early signal ASCO Annual Meeting 2026

    Prostate

    Intensification split by target in localised disease: local (CAN-2409, DFS HR 0.70) helped, systemic (ENZARAD enzalutamide, MFS HR 0.88) did not, while COMPPARE and PROTEUS bear on proton selection and PSMA PET-driven MFS.

    Early signal

    COMPPARE

    ForDe novo non-metastatic prostate cancer, excluding very high risk

    TL;DRBowel urgency 5.7% vs 6% (p=0.28), proton vs IMRT; no significant difference in G2+ GI toxicity or 3-yr biochemical control, localized prostate.

    Why it mattersRadiation oncology

    The RT variable that tracked with GI toxicity was the rectal spacer, not the particle: 2-yr cumulative G2+ GI was 4.4% IMRT and 4.7% proton with spacer vs 7.2% and 8.7% without (Gray's test p=0.009). Observed IMRT rates sat well below the hypothesized control rates, leaving little absolute room for a proton advantage.

    Monday clinic

    In de novo non-metastatic prostate cancer short of very high risk, this questions choosing protons over IMRT to reduce bowel urgency, bowel frequency, or G2+ GI toxicity; it does not address late toxicity or long-term disease control.

    COMPPARE
    +1 more figure
    COMPPARE
    Group2-yr cumulative CTCAE GI G2+
    IMRT, no spacer7.2% (5.0%, 9.9%)
    Proton, no spacer8.7% (5.0%, 14%)
    IMRT, spacer4.4% (2.8%, 6.4%)
    Proton, spacer4.7% (3.6%, 6.0%)
    Gray's test p-value0.009
    10 details 1 trial watching
    Design

    Prospective comparison of proton and photon cohorts, PCORI-funded, 51 PT and IMRT centers. 2524 accrued July 2018 to October 2022; schema lists a proton cohort of 1500 and a photon cohort of 1000. Source does not describe randomisation.

    Population & inclusion

    All de novo prostate cancer except very high risk and metastatic. Baseline characteristics and risk-group mix by cohort not reported in source.

    Radiotherapy

    Proton therapy vs photon IMRT, with rectal spacer use analysed as a stratum. Dose, fractionation, target volume and ADT use not reported in source.

    Endpoints

    Powered hypotheses (90% power): EPIC bowel urgency, EPIC bowel frequency, CTCAE v5 ≥G2 GI toxicity. Exploratory: freedom from PSA progression at 3 years.

    Results

    No significant difference on any powered GI endpoint or on 3-yr biochemical control (see table).

    EndpointPTIMRTHypothesized PT vs IMRTp
    Bowel urgency (EPIC)5.7%6%7% vs 15%0.28
    Bowel frequency (EPIC)3.5%4%4% vs 10%0.43
    GI toxicity (CTCAE ≥G2)5.2%5.6%20% vs 29%0.60
    3-yr freedom from progression (PSA)98.0%97.9%91% vs 89% (exploratory)0.90
    Safety

    GI G2+ toxicity point estimates were lower with a rectal spacer in both cohorts (Gray's test p=0.009). GU toxicity not reported in source.

    vs leading data

    PARTIQoL randomised the same proton vs IMRT question in localized prostate cancer and also found no bowel-function advantage for protons. COMPPARE adds a larger multicentre cohort read in the same direction.

    Applies to
    de novo non-metastatic prostate cancer below very high risk treated with protons or IMRT
    Does not represent very high-risk or metastatic disease.
    Limitations

    Control event rates came in far below the powering assumptions, so the hypothesized absolute differences were never plausible at observed rates. Spacer use by cohort is not reported, so the modality comparison may be confounded by rectal sparing strategy.

    Discussion

    The null holds across patient-reported and physician-graded GI endpoints, and the spacer stratum suggests GI toxicity tracks rectal sparing more than particle type. It does not settle late toxicity or long-term outcomes.

    Rationale

    Source calls these early results; late toxicity and long-term control immature. No randomisation described, so the null GI comparison carries cohort selection bias.

    Open questions
    • Proton vs IMRT late GI toxicity beyond early follow-up
      active Protons vs. Photons for High-risk Prostate Cancer Phase NA
      n=102 · primary completion 2028-12 · late GI tox, protons vs photons, high-risk pelvic RT
    • Long-term disease control with protons vs IMRT
    • Does a rectal spacer erase any residual proton GI advantage?

    Sourced from @QianJanieQin

    📚 Sources · 🐦 1 tweet

    Radiation Curative Early signal ASCO Annual Meeting 2026

    Unclear

    PROTEUS

    TL;DRNo primary effect size in source; most distant mets were PSMA PET-detected (53.0% apalutamide group, 60.7% in the other group).

    Why it mattersRadiation oncology

    MFS here is largely a PET endpoint: most distant metastases were identified by PSMA PET (53.0% apalutamide group, 60.7% in the other group). Any MFS difference needs reading against conventional-imaging MFS endpoints with that ascertainment shift in mind.

    Also covered Oct 24 Aug 29

    9 details 1 trial watching
    Design

    Design not stated in source. Commentary frames the comparison as an ADT + apalutamide arm vs ADT alone; results published in NEJM alongside ASCO 2026.

    Endpoints

    Source names EFS and MFS. Primary endpoint and its effect size are not reported in source tweets.

    Results

    Most distant metastases were identified by PSMA PET: 53.0% of those in the apalutamide group and 60.7% in the second group (label truncated in source).

    Limitations

    The BCR counts (60 vs 50 per 100) come from a hypothetical thought experiment, not trial data. The arm attribution of the 60.7% figure is truncated in the source tweet.

    Discussion

    A PET-dominated MFS event mix means the endpoint is not interchangeable with conventional-imaging MFS. Whether the result is a benefit or a negative trial, as the commentator frames the debate, cannot be settled from the source.

    Rationale

    Source tweets give no primary endpoint result, design, phase or population; only the imaging mode of distant-met detection is stated.

    Open questions

    Sourced from @DrSpratticus, @seanmmcbride

    📚 Sources · 🐦 3 tweets
    📝 Note until the trial is released later this is preview
    📝 note add commentary to proteus discussion
    📝 add to proteus data

    Systemic Unclear ASCO Annual Meeting 2026

    Confirmatory

    CAN-2409 NCT01436968

    ForIntermediate or high-risk localised prostate cancer, EBRT candidates, ECOG 0-2

    Disease-free survival surrogate

    HR 0.70

    95% CI 0.52-0.94, p=0.016; median NR vs 86.1 mo

    TL;DRDFS HR 0.70 (0.52-0.94), 2y biopsy persistence/recurrence 19.6% vs 36.4%, adding intraprostatic aglatimagene to EBRT in intermediate/high-risk localised prostate cancer.

    Why it mattersRadiation oncology

    The effect is local: 2y post-treatment biopsy persistence/recurrence 19.6% vs 36.4% (p=0.0015), while OS and PCSM were not different (1 PCSM event per arm). That places it beside ADT, SIB and brachy boost as a local-intensification option; the discussant's RTOG 9408 benchmark, 4mo ADT added to 66.6 Gy, showed 2y positive biopsy 40% vs 20%.

    Monday clinic

    In intermediate or high-risk localised prostate cancer planned for 78 Gy in 2 Gy, 60 Gy in 3 Gy or 70 Gy in 2.5 Gy fractions, this supports intraprostatic aglatimagene as a DFS-improving addition; it does not extend to pts whose EBRT includes a brachytherapy or SIB boost. The longer read

    CAN-2409
    TrialArmsLocal endpointControl vs intensified
    RTOG 9408RT 66.6Gy vs + 4m ADT2yr post-Rx biopsy positive40% vs 20%
    ASCENDE-RT46Gy + DE-EBRT 23Gy vs 46Gy + LDR-BT10y local failure7.1% vs 1.5%
    FLAMERT 77Gy vs + SIB 95GyCrude local failure7.7% vs 2.7%
    CAN-2409RT 78Gy + placebo vs + CAN-24092yr post-Rx biopsy positive36.4% vs 19.6%
    8 details
    Design

    Phase 3, randomised 2:1, double-blind, placebo-controlled at 51 US and Puerto Rico centres (26 community, 25 institutional or military). Accrual Feb 2012 to Sept 2021; median follow-up 50.3 mo (IQR 35.2-63.3).

    Population & inclusion

    Intermediate or high-risk localised prostate cancer planned for EBRT, age ≥18, ECOG 0-2. N=745 (496 vs 249); 591 (79%) White, 121 (16%) Black.

    Regimen

    Three courses of intraprostatic aglatimagene (5 × 10^11 viral particles) plus valacyclovir vs placebo plus valacyclovir. Stratified by risk category and ADT use; ADT optional.

    Radiotherapy

    78 Gy in 2 Gy fractions, or hypofractionated 60 Gy in 3 Gy or 70 Gy in 2.5 Gy fractions. No boost regimen described in source.

    Endpoints

    Primary: DFS, time from randomisation to prostate cancer recurrence or death, ITT. Safety in all pts receiving ≥1 injection.

    Results

    Per the discussant, the DFS gain was driven mainly by 2y post-treatment biopsy pCR; OS and PCSM not significantly different.

    EndpointAglatimagene + valacyclovirPlacebo + valacyclovirEffect
    Median DFSNR (95% CI 121.78-NR)86.1 moHR 0.70 (0.52-0.94), p=0.016
    2y post-Rx biopsy pCR80.4%63.6%not stated
    2y biopsy persistence/recurrence19.6%36.4%p=0.0015
    Safety

    G3+ TEAEs 8% vs 7%; most common G3+ event AKI (2% each). SAEs 6% vs 7%, treatment-related SAEs 2% each. No treatment-related deaths.

    vs leading data

    The discussant set it against established local-intensification strategies: ADT in RTOG 9408, LDR brachy boost in ASCENDE-RT and focal SIB in FLAME. None was tested head-to-head or in combination with aglatimagene.

    Applies to
    intermediate or high-risk localised prostate cancer receiving 78 Gy or hypofractionated EBRT with optional ADT
    Does not represent pts treated with brachytherapy or SIB boost regimens.
    Limitations

    Long accrual (Feb 2012 to Sept 2021). Safety population (479 and 232) smaller than randomised arms (496 and 249). MFS and biochemical recurrence not presented; funded by Candel Therapeutics and NIH.

    Discussion

    A positive blinded phase 3 of an oncolytic-viral agent with RT and no toxicity penalty, but the benefit currently rests on biopsy-defined local persistence. Whether that converts to MFS or PCSM, and whether it holds against boost-level dose intensification, is unsettled.

    Enrolment
    CONSORT flow
    Randomized745
    ↓
    Aglatimagene + valacyclovir
    allocated 496
    analyzed 496
    mDFS not reached
    Placebo + valacyclovir
    allocated 249
    analyzed 249
    mDFS 86.1 mo
    Rationale

    Blinded phase 3 met DFS at 50.3mo, but gain driven by 2y biopsy persistence; OS/PCSM not different, and no boost-level dose intensification in control.

    Open questions
    • Does the biopsy-driven DFS gain translate into MFS or PCSM benefit?
    • Added value over brachytherapy boost or focal SIB dose intensification
    • Interaction with ADT use and duration

    Sourced from @MikeSerzanMD, DeWeese, Theodore L et al.

    📚 Sources · 🐦 1 tweet · 📄 1 paper
    📄 PAPER DeWeese, Theodore L; Manzanera, Andrea; Sylvester, John et al. · The Lancet Oncology (2026-06)
    Aglatimagene besadenovec (CAN-2409) with radiotherapy for patients with localised prostate cancer: a phase 3, multicentre, randomised, double-blind, placebo-controlled trial
    doi
    Abstract
    Background About 30% of men with localised prostate cancer undergoing radiotherapy with curative intent have disease recurrence associated with progression-related symptoms and substantial toxicity of salvage therapies. Previous studies with aglatimagene besadenovec (CAN-2409, hereafter referred to as aglatimagene) showed synergy with radiation and immune-mediated cytotoxicity in patients with prostate cancer. We aimed to assess whether addition of aglatimagene plus prodrug (valacyclovir) to standard-of-care external beam radiation therapy (EBRT) could improve disease-free survival in this population. Methods We conducted a phase 3, randomised, double-blind, placebo-controlled trial at 51 medical centres (26 community and 25 institutional or military) across the USA and Puerto Rico in patients with intermediate or high-risk prostate cancer. Patients aged at least 18 years who were planning to undergo EBRT and with an Eastern Cooperative Oncology Group score of 0-2 were eligible. Patients were randomly assigned (2:1) via central block-randomisation to receive either three courses of intraprostatic aglatimagene (5 × 10 11 viral particles) plus valacyclovir or placebo plus valacyclovir, with randomisation stratified by risk category and androgen deprivation therapy (ADT) use. Patients received standard-of-care EBRT (78 Gy in 2 Gy fractions) or hypofractionated EBRT (60 Gy in 3 Gy fractions or 70 Gy in 2·5 Gy fractions) with optional ADT. The primary endpoint was disease-free survival, defined as time-from-randomisation to prostate cancer recurrence or death in the intent-to-treat population (all randomly assigned patients). Safety was assessed in all individuals who received at least one injection. The trial is registered at ClinicalTrials.gov, NCT01436968, and long-term follow-up is ongoing. Findings Between Feb 21, 2012, and Sept 9, 2021, 745 men (591 [79%] White, 121 [16%] Black) were randomly assigned to receive aglatimagene plus valacyclovir (n=496) or placebo plus valacyclovir (n=249). After a median follow-up of 50·3 months (IQR 35·2-63·3), median disease-free survival was not reached (95% CI 121·78 to not reached) in the aglatimagene plus valacyclovir group versus 86·1 (IQR 29·7-143·0) months in the placebo plus valacyclovir group (hazard ratio 0·70, 95% CI 0·52-0·94; p=0·016). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 40 (8%) of 479 patients in the aglatimagene group and 17 (7%)of 232 patients in the placebo group. The most common TEAE of grade 3 or worse was acute kidney injury in both the aglatimagene group (nine [2%] of 479 patients) and the placebo group (four [2%] of 232 patients). Serious adverse events occurred in 28 (6%) of 479 patients in the aglatimagene group and 17 (7%) of 232 in the placebo group. Treatment-related serious adverse events occurred in eight (2%) patients in the aglatimagene group (four acute kidney injury, two pyrexia, and one each influenza-like symptoms and urinary retention) and five (2%) in the placebo group (four acute kidney injury, and one each increased creatinine levels and skin rash; one patient reported two serious adverse events). No treatment-related deaths were reported. Interpretation Aglatimagene plus valacyclovir was associated with longer disease-free survival than placebo plus valacyclovir when added to standard of radiotherapy for the treatment of localised prostate cancer, offering a meaningful benefit without increasing clinically significant toxicity. Funding Candel Therapeutics and US National Institutes of Health.
    📝 https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(26)00071-9/fulltext

    Combined Curative Phase 3 RCT Confirmatory ASCO Annual Meeting 2025

    GI Upper

    A RAS-directed agent beats chemo on OS in previously treated metastatic pancreatic cancer (RASolute 302).

    Practice-changing

    RASolute 302

    ForPreviously treated metastatic pancreatic cancer, RAS G12-mutant

    TL;DRMedian OS 13.2 vs 6.6 mo, HR 0.40 (95% CI 0.30-0.54), P<0.001, daraxonrasib over chemo in previously treated RAS G12 metastatic pancreatic cancer.

    Monday clinic

    In previously treated metastatic pancreatic cancer with a RAS G12 mutation, this supports daraxonrasib over investigator's choice chemotherapy on OS; it does not extend to treatment-naive or non-metastatic disease.

    RASolute 302
    PopulationArmNEvents, n (%)mOS, mo (95% CI)HR for death (95% CI)
    RAS G12Daraxonrasib22872 (32)13.2 (10.0-NR)0.40 (0.30-0.54), P<0.001
    RAS G12Chemotherapy231127 (55)6.6 (5.4-8.2)ref
    OverallDaraxonrasib24879 (32)13.2 (10.0-NR)0.40 (0.30-0.53), P<0.001
    OverallChemotherapy252141 (56)6.7 (5.8-8.0)ref
    8 details 2 trials watching
    Design

    Phase, randomization and primary endpoint not stated in source. HRs came from a stratified Cox model and P values from a stratified log-rank test. Presented at ASCO as abstract LBA5.

    Population & inclusion

    Previously treated metastatic pancreatic cancer. OS reported in a RAS G12 population (228 vs 231) and an overall population that also includes G13 or Q61 mutations or no RAS mutation identified (248 vs 252).

    Regimen

    Daraxonrasib vs investigator's choice chemotherapy. Dose, schedule and the chemo options allowed are not stated in source.

    Results

    OS favored daraxonrasib in both populations with HR 0.40, P<0.001; per-arm values are in the figure table.

    vs leading data

    Second-line metastatic pancreatic cancer has been a chemotherapy space, with NAPOLI-1 establishing a nal-IRI based option. An OS benefit for a RAS-directed agent over chemo is a different class of result; no cross-trial numbers are reported in source.

    Applies to
    previously treated metastatic pancreatic cancer, principally RAS G12-mutant disease
    Does not represent treatment-naive or non-metastatic disease, and gives no separate estimate for G13, Q61 or no-RAS-mutation tumors.
    Limitations

    Safety and follow-up duration not reported in source; the daraxonrasib median OS upper CI is not reached. Composition of the investigator's-choice control is unknown, which bears on comparator strength.

    Discussion

    The identical HR 0.40 in both populations reflects that the overall population is almost entirely RAS G12, not a demonstrated benefit beyond G12. Events of 32% vs 55% and 56% mean the daraxonrasib median of 13.2 mo rests on fewer events and may move with maturity.

    Rationale

    OS HR 0.40 vs investigator's-choice chemo, P<0.001, consistent in RAS G12 and overall populations; source frames it as historic. Tweet omits phase and design.

    Open questions

    Sourced from @GIMedOnc

    📚 Sources · 🐦 1 tweet

    Systemic Palliative Practice-changing ASCO Annual Meeting 2026

    Thoracic / Lung

    Retrospective registry signal favouring sequential over concurrent RT+ICI in newly diagnosed advanced NSCLC; no trial has randomised RT-ICI timing.

    Caveats dominate

    OCEANUS

    ForAdvanced NSCLC receiving RT with ICI, newly diagnosed or ICI-refractory

    TL;DRSequential RT+ICI mOS 20.3 vs 16.0 mo for concurrent, aHR 0.68 (0.47-0.99), in newly diagnosed advanced NSCLC; retrospective registry.

    Why it mattersRadiation oncology

    The RT-relevant gap is the exposure itself: the source text neither defines the sequential window nor reports dose, fractionation or target, so the timing signal cannot yet guide SBRT versus palliative-course scheduling around ICI. In refractory disease, continuing ICI after RT gave 11.2 vs 6.7 mo rwOS (P=.20), limited to 90-day survivors.

    Monday clinic

    In newly diagnosed advanced NSCLC starting ICI with an RT indication, this adds observational support for sequencing RT rather than overlapping it; it does not extend to unresectable locally advanced disease, and in ICI-refractory disease the maintenance signal is non-significant. The longer read

    9 details 2 trials watching
    Design

    Territory-wide retrospective cohort from the Hong Kong Hospital Authority CDARS database (more than 90% population coverage), NSCLC diagnosed 2010 to 2021. Overlap weighting was the primary propensity method, IPTW the sensitivity analysis; RMST was specified where proportional hazards failed.

    Population & inclusion

    Of 3522 ICI-treated pts, 335 received RT: 155 newly diagnosed advanced and 180 refractory NSCLC. 247 (73.7%) male, median age 64 (range 34-90).

    Radiotherapy

    RT dose, fractionation, modality, target site and the interval separating sequential from concurrent delivery are not reported in source text.

    Endpoints

    Primary: real-world OS after landmark, via weighted Kaplan-Meier and Cox models. Exposures: sequential vs concurrent RT+ICI (newly diagnosed), RT with vs without ICI maintenance (refractory), and receipt of chemotherapy.

    Results

    Chemotherapy tracked with longer rwOS in newly diagnosed disease but not in refractory disease; no chemotherapy effect size in source text. IPTW estimates were similar to the primary analysis.

    CohortExposure armReference armEffect
    Newly diagnosed advanced (n=155)Sequential RT+ICI: 20.3 mo (13.3-NR)Concurrent RT+ICI: 16.0 mo (8.3-30.0)aHR 0.68 (0.47-0.99), P=.045
    Refractory (n=180)RT + ICI maintenance: 11.2 mo (7.9-20.6)RT without ICI maintenance: 6.7 mo (4.4-17.4)P=.20
    vs leading data

    The source notes randomized data on RT+ICI sequencing are limited. PEMBRO-RT tested SBRT before pembrolizumab in advanced NSCLC, and PACIFIC placed ICI after concurrent chemoRT in unresectable locally advanced disease; neither randomized timing as this cohort compares it.

    Applies to
    advanced or ICI-refractory NSCLC receiving RT alongside ICI in a Hong Kong public-system population
    Does not represent unresectable locally advanced disease treated with curative chemoRT, or refractory pts who died within 90 days.
    Limitations

    Undefined timing window and unreported RT parameters make the exposure heterogeneous, possibly mixing consolidative and palliative courses. The 2010 to 2021 window spans shifting first-line ICI practice, and any RMST estimates are not reported in source text.

    Discussion

    A sequential advantage cuts against the common assumption that overlap maximises RT-ICI interaction, but urgent symptomatic RT given during ICI could explain it equally well. Whether continuing ICI after RT helps refractory disease remains open.

    Rationale

    Retrospective propensity-weighted registry cohort; residual confounding by indication likely, upper CI bound 0.99 in n=155, and authors frame it as hypothesis generating.

    Open questions

    Sourced from Zhou et al.

    📚 Sources · 📄 1 paper
    📄 PAPER Zhou; Wang; Lee et al. · JAMA oncology (2026-05)
    Combination of Radiotherapy and Immunotherapy in Advanced Non-Small Cell Lung Cancer.
    PMID 41885834 → doi full text (PMC)
    Abstract
    IMPORTANCE: The optimal sequencing of radiotherapy (RT) combined with immunotherapy (iRT) and the value of chemotherapy remain undefined for advanced non-small cell lung cancer (NSCLC), where randomized data are limited.<br/><br/>OBJECTIVE: To compare real-world overall survival (OS) between sequential and concurrent iRT in newly diagnosed advanced NSCLC, assess the effect of immune checkpoint inhibitor (ICI) maintenance after RT in refractory disease, and evaluate the association of chemotherapy with survival.<br/><br/>DESIGN, SETTING, AND PARTICIPANTS: This is a territory-wide study (OCEANUS) based on the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (more than 90% population coverage). Patients with NSCLC diagnosed from January 1, 2010, to December 31, 2021, who subsequently received iRT for advanced or refractory disease were included. Overlap weighting was the primary propensity score-weighted method, with inverse probability of treatment weighting used for sensitivity analysis. Data were analyzed from December 2024 to April 2025.<br/><br/>EXPOSURES: Sequential vs concurrent iRT for newly diagnosed advanced NSCLC; RT with vs without ICI maintenance for refractory NSCLC; receipt of chemotherapy.<br/><br/>MAIN OUTCOMES AND MEASURES: The primary outcome was real-world OS after landmark, estimated with weighted Kaplan-Meier and Cox models. When proportional hazards were violated (per Schoenfeld residuals), treatment effects were summarized using restricted mean survival time.<br/><br/>RESULTS: Of 3522 patients who received ICIs, 335 received RT, including 155 with newly diagnosed advanced and 180 with refractory NSCLC. Of these, 247 (73.7%) were male, and the median (range) age was 64 (34-90) years. In newly diagnosed NSCLC, patients treated with sequential iRT had significant longer real-world OS than those treated with concurrent iRT (median, 20.3 months [95% CI, 13.3 to not reached] vs 16.0 months [95% CI, 8.3-30.0]; adjusted hazard ratio, 0.68; 95% CI, 0.47-0.99; P&#x2009;=&#x2009;.045). Chemotherapy was also associated with longer survival in patients with newly diagnosed advanced NSCLC. In refractory NSCLC, RT with ICI maintenance was associated with a numerically longer median real-world OS (11.2 months [95% CI, 7.9-20.6] vs 6.7 months [95% CI, 4.4-17.4]; P&#x2009;=&#x2009;.20). Addition of chemotherapy was not significant for real-world OS. Inverse probability of treatment weighting analyses produced similar estimates.<br/><br/>CONCLUSIONS AND RELEVANCE: In this cohort study, sequential iRT was associated with longer survival than concurrent iRT in patients with newly diagnosed advanced NSCLC, and chemotherapy was associated with longer survival. In patients with refractory NSCLC who survived at least 90 days, RT with ICI maintenance resulted in nonsignificantly longer survival and an unclear association with chemotherapy. These findings are hypothesis generating and support prospective randomized studies to define optimal sequencing of iRT and use of systemic treatment partners.
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    6 of 7 study clusters analyzed successfully.

    1 cluster dropped
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