Pancreatic · PDAC

ESPAC-1 established for the first time that adjuvant systemic chemotherapy improves OS after PDAC resection, while adjuvant chemoradiation may actually harm survival. This divergence from the contemporaneous US GITSG doctrine reshaped European practice away from adjuvant chemoRT.

Population: Resected PDAC, European multicenter, early enrollment (1994-2000), 2x2 factorial design for chemoradiation (yes/no) and chemotherapy (yes/no).

ESPAC-3 showed gemcitabine and 5-FU/folinic acid are equivalent in OS for adjuvant PDAC therapy, but gemcitabine has a better safety profile. Gemcitabine became the preferred monotherapy backbone globally and the reference control for every adjuvant trial through PRODIGE-24.

Population: Resected PDAC, R0/R1, post-surgery within 8 weeks, ECOG PS 0-2, 159 centers in Europe/Australasia/Japan/Canada.

CONKO-001 was the first trial to demonstrate a clear DFS and OS benefit for adjuvant gemcitabine monotherapy vs observation after PDAC resection. Established adjuvant chemotherapy (specifically gemcitabine) as the new global standard; served as the control arm for every subsequent adjuvant trial for the next decade.

Population: Resected PDAC (R0 or R1), German/Austrian multicenter, enrolled 1998-2004, long-term follow-up to 2012.

SCALOP showed capecitabine-based chemoradiation improves OS over gemcitabine-based chemoradiation after induction GemCap in locally advanced PDAC. Established capecitabine (not gemcitabine) as the preferred radiosensitizer in LA-PDAC when chemoRT is used.

Population: Histologically proven locally advanced PDAC, tumor ≤6 cm, WHO PS 0-1, 28 UK centers. All patients received 12 weeks induction GemCap, then randomized if stable/responding.

JASPAC-01 established oral S-1 as the Japanese/East Asian standard adjuvant regimen, nearly doubling 5-year OS vs gemcitabine. The effect size is unprecedented and has not been replicated in Western populations, likely due to CYP2A6 pharmacogenomic differences affecting S-1 metabolism.

Population: Resected PDAC (R0/R1), post-surgery within 10 weeks, ECOG PS 0-1, Japanese multicenter (33 hospitals).

LAP07 showed neither consolidative chemoradiation (after 4 months of stable disease on induction chemo) nor added erlotinib improves OS in locally advanced PDAC. Consolidative chemoRT did improve local control without translating to survival benefit. The trial refocused LA-PDAC practice on systemic therapy intensification.

Population: Locally advanced, unresectable PDAC, ECOG 0-2, French/European multicenter, 2 sequential randomizations.

ESPAC-4 established adjuvant gemcitabine + capecitabine (GemCap) as a new standard of care for resected PDAC patients, outperforming gemcitabine monotherapy. GemCap remains the preferred adjuvant regimen for patients unable to tolerate mFFX (the subsequent PRODIGE-24 winner).

Population: Resected PDAC (R0/R1), post-surgery within 12 weeks, ECOG PS 0-2, UK/European multicenter.

PRODIGE-24 established adjuvant mFOLFIRINOX as the new standard of care for fit patients after PDAC resection, nearly doubling 5-year OS vs gemcitabine. Results adopted immediately into NCCN/ESMO guidelines and remain the reference regimen for fit (ECOG 0-1) resected patients.

Population: Resected pancreatic ductal adenocarcinoma (PDAC), R0 or R1, post-surgery within 3-12 weeks, ECOG PS 0-1, French-Canadian multicenter.

PACT-15 signalled that perioperative multi-agent chemotherapy nearly doubles median OS vs adjuvant gemcitabine in resectable PDAC (38.2 vs 20.4 mo). Phase 3 part was halted because the standard of care shifted mid-trial (PRODIGE-24 published), making gemcitabine arm ethically untenable.

Population: Resectable PDAC, ECOG 0-1, Italian single-country multicenter (Milan-based), enrolled 2010-2015.

A021501 showed neoadjuvant mFFX alone is feasible and meets the efficacy threshold in borderline resectable PDAC (18-mo OS 67.9%), whereas adding hypofractionated RT/SBRT does NOT improve outcomes and may be detrimental (47.3%). Arm B was halted early for futility.

Population: Borderline resectable PDAC (central radiographic review), ECOG 0-1, US Alliance cooperative group multicenter.

PREOPANC-1 long-term follow-up (2022) showed neoadjuvant gemcitabine-chemoradiation significantly improves OS vs upfront surgery in combined resectable + borderline PDAC, driven primarily by the borderline-resectable subgroup. R0 resection rate 71% vs 40% in favor of neoadjuvant arm.

Population: Resectable or borderline resectable PDAC, ECOG 0-1, 16 Dutch centers, enrolled 2013-2017, long-term follow-up 2022.

APACT missed its DFS primary endpoint on blinded-independent review, although investigator-assessed DFS (HR 0.82, p=0.02) and OS (HR 0.82, p=0.045) favored the combination. The trial is widely cited as a cautionary tale on endpoint-assessment method; not adopted as new adjuvant standard.

Population: Resected PDAC (R0/R1), post-surgery within 12 weeks, ECOG PS 0-1, global multicenter.

ESPAC-5F provided the first UK-German randomized evidence that any neoadjuvant therapy — particularly FOLFIRINOX or GemCap — dramatically improves 1-year OS over immediate surgery in borderline resectable PDAC, despite similar resection rates (55% vs 68%). Small N (90) limits strength but signal is consistent with US A021501 and Dutch PREOPANC data.

Population: Borderline resectable PDAC, UK/German multicenter (16 centers), ECOG 0-1, randomized 1:1:1:1 to 4 arms.

SCALOP-2 showed neither dose-escalated chemoradiation (60 Gy vs 50.4 Gy) nor the addition of nelfinavir improves outcomes in locally advanced PDAC after induction gem+nab-pac. Both primary endpoints failed. Reinforces LAP07's message that consolidative chemoRT intensification yields no OS gain in LA-PDAC.

Population: Locally advanced PDAC, stable/responding after 4 cycles gemcitabine + nab-paclitaxel induction, UK multicenter.

Alliance A021806 is the most important ongoing phase 3 trial addressing whether perioperative (neoadj + adj) mFFX improves OS over adjuvant-only mFFX in strictly resectable PDAC. Results will directly inform the NCCN framework for resectable disease; readout expected ~2027-2028.

Population: Strictly resectable PDAC (not borderline), ECOG 0-1, US + Canadian multicenter. Accruing from 2020; enrollment ~145 as of 2023 update.

NORPACT-1 is the first phase 2 RCT to show neoadjuvant FOLFIRINOX in strictly resectable (not borderline) PDAC fails to improve 18-month OS and numerically harms it vs upfront surgery. Implementation of neoadjuvant FFX proved challenging (~20% could not receive surgery).

Population: Strictly resectable pancreatic head cancer, ECOG 0-1, Danish/Finnish/Norwegian/Swedish 12-center trial.

PREOPANC-2 showed total neoadjuvant FOLFIRINOX does not improve OS vs neoadjuvant gemcitabine-chemoradiation + adjuvant gemcitabine in resectable/borderline PDAC. Both arms delivered similar outcomes, supporting either approach but failing to establish FOLFIRINOX-only neoadjuvant as clearly superior.

Population: Resectable or borderline resectable PDAC, ECOG 0-1, Dutch multicenter, enrolled 2018-2021.

PRODIGE-4/ACCORD-11 (Conroy 2011 NEJM) redefined first-line metastatic PDAC with a nearly 4.3-month OS gain over gemcitabine — the largest single-trial OS improvement in the history of metastatic PDAC. Established FOLFIRINOX as new 1L standard for fit patients (ECOG 0-1, age ≤75).

Population: Metastatic PDAC, first-line, ECOG PS 0-1, age ≤75, bilirubin ≤1.5x ULN, French multicenter.

GEST confirmed oral S-1 is non-inferior to gemcitabine in East Asian advanced PDAC, with better convenience (all-oral) and tolerability. GS combination failed to show superiority over gem monotherapy for OS, though numerically better in locally advanced subgroup (median OS 15.9 vs 12.7 mo).

Population: Chemo-naive locally advanced or metastatic PDAC, ECOG 0-1, Japanese + Taiwanese multicenter (enrolled 2007-2009).

MPACT established nab-paclitaxel + gemcitabine as a new 1L metastatic PDAC standard, particularly for patients unable to tolerate FOLFIRINOX (older, ECOG 2, or fragile). The regimen remained the preferred alternative to FFX through NAPOLI-3 (2023), which used it as the control arm.

Population: Metastatic PDAC, first-line, KPS ≥70, global multicenter (including patients unfit for FOLFIRINOX — ECOG 2 allowed).

CCTG PA.7 was the largest randomized test of PD-L1 + CTLA-4 dual blockade added to chemotherapy in unselected metastatic PDAC. No OS or PFS benefit in the full population — reinforces that pancreatic adenocarcinoma is a 'cold' tumor essentially unresponsive to combination checkpoint blockade without biomarker selection or other immune-engagement strategy.

Population: Treatment-naive metastatic PDAC, ECOG 0-1, unselected for biomarkers, Canadian/multicenter (CCTG network).

NAPOLI-3 is the first trial in a decade to beat nab-pac+gem in the 1L metastatic space. NALIRIFOX became a new preferred 1L option per NCCN 2024 for fit patients and was FDA-approved February 2024. The triplet partially substitutes for FOLFIRINOX in regions where lipo-IRI is accessible.

Population: Treatment-naive metastatic PDAC, ECOG PS 0-1, global multicenter (187 sites, 18 countries).

CONKO-003 showed addition of oxaliplatin to 5-FU/FA improves OS in gemcitabine-refractory advanced PDAC by ~2.6 months. Established oxaliplatin-based regimens (OFF, later FOLFOX) as a viable 2L choice — though contradicted by PANCREOX. Never FDA-labeled but NCCN-recognized.

Population: Advanced PDAC with progression on prior gemcitabine, ECOG 0-2, German multicenter.

NAPOLI-1 established nal-IRI + 5-FU/LV as the first FDA-approved (October 2015) and guideline-endorsed 2L regimen after gemcitabine-based failure in metastatic PDAC. OS gain of ~2 months is modest but meaningful in this heavily pretreated population.

Population: Metastatic PDAC after progression on prior gemcitabine-based therapy, ECOG KPS ≥70, global multicenter (76 sites, 14 countries).

PANCREOX is the puzzling inverse mirror of CONKO-003: adding oxaliplatin to 5-FU/LV showed no PFS benefit and a detrimental OS effect in 2L metastatic PDAC. Hypotheses include imbalanced post-progression therapy and small N (108). The conflict with CONKO-003 prevents oxaliplatin-based 2L from being a category 1 recommendation.

Population: Advanced PDAC with progression on prior gemcitabine-based therapy, ECOG 0-2, Canadian multicenter.

Provided the pivotal evidence that led to FDA tissue-agnostic approval of pembrolizumab for MSI-H/dMMR solid tumors (2017 initial, KN-158 confirmed). For PDAC specifically, 18% ORR with remarkable durability (median DoR 13.4 mo) in a small subset — demonstrating that the rare MSI-H PDAC patient can achieve durable benefit that standard chemo cannot deliver. Supports universal MMR/MSI testing at PDAC diagnosis.

Population: Previously treated unresectable/metastatic PDAC with MSI-H or dMMR status (rare in PDAC, ~1%); pancreatic cohort n=22 within 233-pt non-CRC MSI-H analysis (Marabelle JCO 2020).

Supported FDA tissue-agnostic approval of larotrectinib for NTRK fusion-positive advanced solid tumors (2018). In PDAC specifically, the signal is limited by ultra-rare NTRK fusion prevalence (<0.5% of PDAC); data from case reports + registries (not the pooled trial) have since confirmed deep and durable responses in individual PDAC pts with NTRK fusions. Rationale for comprehensive fusion testing at PDAC diagnosis.

Population: TRK fusion-positive locally advanced/metastatic solid tumors pooled across NAVIGATE (NCT02576431), SCOUT pediatric (NCT02637687), and phase 1 (NCT02122913); overall N=159, pancreatic subset n=3 (NTRK fusion in PDAC is ultra-rare, <0.5%). Hong/Drilon Lancet Oncol 2020.

Supported FDA tissue-agnostic approval of entrectinib for NTRK fusion-positive advanced solid tumors (Aug 2019). Small PDAC subset (n=3) with 2 responders mirrors the general TRK-inhibitor class activity in fusion-positive tumors. CNS penetration is a differentiator vs larotrectinib for PDAC pts with brain mets (rare in PDAC but occasional).

Population: NTRK fusion-positive locally advanced/metastatic solid tumors pooled across STARTRK-2 (NCT02568267), STARTRK-1 (NCT02097810), ALKA-372-001; overall N=54 efficacy-evaluable; pancreatic subset n=3 (ultra-rare). Doebele Lancet Oncol 2020.

First positive biomarker-selected phase 3 in PDAC: significant PFS improvement (HR 0.53) led to FDA approval (Dec 2019) of olaparib maintenance for gBRCA+ metastatic PDAC — the first molecularly-targeted therapy approved in PDAC. Final OS null (HR 0.83, p=0.35) despite numerical direction favoring olaparib. Long-term survivor subset and extended chemo-free interval remain clinical benefits.

Population: Metastatic PDAC with deleterious/suspected deleterious germline BRCA1 or BRCA2 mutation (~4-7% of PDAC), disease not progressed after ≥16 weeks of 1L platinum-based chemotherapy. Olaparib n=92, placebo n=62. Global (12 countries).

Second KRAS G12C inhibitor to demonstrate single-agent activity in previously treated KRAS G12C PDAC (NEJM 2023). ORR 21% + DCR 84% vs single-digit chemo benchmark confirmed the class effect first seen with adagrasib. Toxicity was mostly low-grade (diarrhea, fatigue). Confirmed that biomarker-matched KRAS G12C therapy is active across pan-tumor settings including PDAC.

Population: Previously treated (≥1 prior line) locally advanced or metastatic PDAC with KRAS p.G12C mutation (rare, ~1-2% of PDAC); 38 evaluable PDAC pts across phase 1 + 2 of CodeBreaK-100 (Strickler NEJM 2023).

First prospective cohort to show clinical activity of a selective KRAS G12C inhibitor in previously treated PDAC. ORR 33% in a disease where 2L historical ORR is single-digit. Manageable safety (mainly GI toxicity, no grade 4-5 TRAEs). Validated the biomarker-matched precision approach in PDAC for the G12C subset (a small slice of the KRAS-mutant PDAC population, but the first to be addressable).

Population: Previously treated unresectable/metastatic PDAC with KRAS G12C mutation (a rare variant, ~1-2% of PDAC); pancreatic cohort n=21 within the 64-pt non-NSCLC/non-CRC cohort of KRYSTAL-1 (Bekaii-Saab JCO 2023).

First clinical evidence that a lymph node-targeted mKRAS peptide vaccine can elicit robust mKRAS-specific T-cell responses (84% of pts) and correlate with relapse-free and overall survival in MRD+ PDAC/CRC. Safety profile favorable (no grade 3-4 vaccine TRAEs). Led to ongoing randomized phase 2 AMPLIFY-7P (NCT05726864) with expanded 7-peptide formulation covering G12D/G12R/G12V/G12C/G12A/G12S/G13D.

Population: Post-curative-intent resection + adjuvant therapy for KRAS G12D or G12R mutant PDAC (n=20) or CRC (n=5), with minimal residual disease (MRD) defined by persistent tumor biomarker (CA19-9/CEA) or ctDNA positivity after definitive therapy. Pant Nature Med 2024.

First-in-class pan-KRAS G12X RAS(ON) multi-selective tri-complex inhibitor. Proof-of-concept that a single agent can cover G12D/G12V/G12C/G12R simultaneously — covering ~90% of all KRAS-mutant PDAC. FDA Breakthrough Therapy Designation + Orphan Drug Designation granted for previously treated metastatic PDAC with KRAS G12X mutations. Anchor trial that opened the first crack in KRAS's 30-year undruggable wall for pancreatic cancer.

Population: Previously treated locally advanced/metastatic solid tumors with KRAS G12X mutation (G12D/G12V/G12C/G12R/G12A/G12S); PDAC monotherapy cohort n=127 at 300 mg QD; second-line PDAC KRAS G12X subgroup n=22 in updated analysis presented at ESMO 2023/ASCO GI 2024-2025. Global sites.

First selective KRAS G12D(ON) inhibitor to show clinical antitumor activity in PDAC (the dominant KRAS variant in pancreatic cancer, ~40%). Manageable safety (grade 1-2 GI + rash, no grade 4-5 TRAEs). FDA Breakthrough Therapy Designation granted (NSCLC initially; PDAC development accelerating). Complements pan-KRAS RMC-6236 by offering a selective option and potential for combination strategies.

Population: Previously treated advanced solid tumors harboring KRAS G12D mutation (confirmed by tumor or ctDNA); PDAC subgroup at RP2D (1200 mg QD or 600 mg BID) n=42 enrolled ≥14 weeks prior to Sep 2024 cutoff. Global sites.

FDA accelerated approval December 2024 for NRG1 fusion-positive advanced PDAC and NSCLC — the first biomarker-matched targeted therapy approved for PDAC that is not chemo (after olaparib). 42% ORR in a KRAS-WT, fusion-defined subset of PDAC where salvage chemo ORR is near zero. Validates the 'rare but actionable' fusion paradigm in PDAC that parallels NTRK, ROS1, ALK stories in other tumors.

Population: Advanced NRG1 fusion-positive solid tumors (158 pts primary efficacy population across 10 tumor types; PDAC cohort n=36 — second-largest after NSCLC n=94). NRG1 fusions occur in ~0.5-1.5% of PDAC, enriched in KRAS WT PDAC. Global.

FDA accelerated approval June 2024 for NTRK fusion-positive advanced solid tumors (tumor-agnostic) — the next-generation TRK inhibitor with activity after progression on 1st-gen (larotrectinib/entrectinib), including against solvent-front mutations (G595R/G667C). For PDAC pts with NTRK fusions who progress on 1st-gen TRK, repotrectinib provides a next-line precision option. CNS-active.

Population: Advanced solid tumors with NTRK1/2/3 fusion; NTRK-fusion tumor-agnostic cohort n=88 (TKI-naive n=19 + TKI-pretreated n=69). PDAC pts included within the broader NTRK cohort. Pancreatic case reports published separately.

First positive phase 3 in biomarker-selected KRAS-mutant metastatic PDAC. Near-doubling of median OS in ITT population vs SoC chemotherapy in the 2L setting where FOLFOX/NALIRIFOX-1 benchmark mOS is 5-7 mo. Selected for FDA Commissioner's National Priority Voucher pilot program. If confirmed in final analysis, establishes daraxonrasib as new 2L standard and validates pan-KRAS G12X as a therapeutic category.

Population: Previously treated (1 prior line metastatic) metastatic PDAC, ECOG 0-1, enrolled KRAS G12X + non-G12 RAS + RAS WT; primary efficacy population = KRAS G12X mutation (G12D/G12V/G12C/G12R/G12A/G12S) confirmed by local or central testing. Global sites.