Importance of landscape exploration and progress in molecular therapies and precision medicine for pancreatic ductal adenocarcinoma

Table 1 Phase II/III trials of first-line chemotherapy for pancreatic cancer published previously

Clinical trial identifier	Year	Patients	Clinical phase	Tumor stage	Treatment regimen	Median OS (months)	Median PFS (months)	Ref.
JCOG1407 UMIN000023143	2022	126	Phase II	LAPC	mFOLFIRINOX/gemcitabine + nab-paclitaxel	23.0 vs 21.3	11.2 vs 9.4	[48]
PREOPANC Eudra CT 2012-003181-40	2022	246	Phase III	rPC	Gemcitabine + surgery	15.7 vs 14.3	NA	[49]
NAPOLI 3 NCT04083235	2023	770	Phase III	mPDAC	NALIRIFOX vs nab-paclitaxel and gemcitabine	11.1 vs 9.2	7.4 vs 5.6	[53]
PRODIG-4 ACCO TD-11	2022	406	Phase III	PDAC	Gemcitabine plus nab-paclitaxel vs FOLFIRINOX	9.4 vs 7.5	Failure	[61]
MPACT NCT00844649	2013	861	Phase III	mPDAC	Nab-paclitaxel plus gemcitabine + gemcitabine	8.5 vs 6.7	5.5 vs 3.7	[57]
NEONAX NCT02047513	2023	127	Phase II	rPADC	Gemcitabine plus nab-paclitaxel	15.7 vs 14.3	11.5 vs 5.9	[62]
NAPOLI 3	2024	2581	Phase III	mPC	NALIRIFOX, gemcitabine plus nab-paclitaxel + FOLFIRINOX	11.1 vs 10.4 vs 11.7	7.4 vs 5.7 vs 7.3	[63]
PRODIGE 65 NCT03943667	2024	211	Phase III	mPDAC	Gemcitabine and paclitaxel vs gemcitabine (GEMPAX)	6.4 vs 5.9	3.1 vs 2.0	[64]

OS: Overall survival; PFS: Progression-free survival; LAPC: Locally advanced pancreatic cancer; rPC: Resectable pancreatic cancer; NA: Not available; mPDAC: Metastatic pancreatic ductal adenocarcinoma; NALIRIFOX: Liposomal irinotecan, oxaliplatin, leucovorin, and fluorouracil; PDAC: Pancreatic ductal adenocarcinoma; mPC: Metastatic pancreatic cancer; rPADC: Resectable pancreatic ductal adenocarcinoma.

Table 2 Summary of second-line therapies for pancreatic cancer and the results of phase III clinical trials

Clinical trial identifier	Year	Patients	Study phase	Tumor stage	Treatment regimen	Median OS (months)	Median PFS (months)	Ref.
NAPOLI-1 NCT01494506	2016	417	Phase III	mPDAC	Nanoliposomal irinotecan with fluorouracil and folinic acid	6.1 vs 4.2	NA	[66]
MPACT	2021	378	Phase III	mPDAC	Liposomal irinotecan + fluorouracil/leucovorin vs FOLFIRINOX	9.8 vs 6.6	3.7 vs 4.6	[68]
PANCREOX NCT01121848	2016	108	Phase III	LAPC	Nanoliposomal irinotecan + fluorouracil and folinic acid	6.1 vs 9.9	3.1 vs 2.9	[69]
MPACT	2015	57		mPDAC	Nab-paclitaxel plus gemcitabine	8.8	5.1	[71]
NCT05074589	2022	298	Phase III	mPDAC	Liposomal formulation of irinotecan plus 5-fluorouracil and folinic acid, or placebo plus 5-fluorouracil and folinic acid	7.39 vs 4.99	4.21 vs 1.48	[73]
NCT01834235	2023	78	Phase III	APDAC	Gemcitabine and nab-paclitaxel	6.6 vs 5.0	2.7 vs 3.4	[74]
NAPOLI-1	2024	115	Phase III	APDAC	Nanoliposomal irinotecan and 5-fluorouracil/leucovorin	8.4 vs 7.9	3.6 vs 3.4	[75]
NAPOLI-1	2023	296	Phase III	APDAC	Nanoliposomal irinotecan plus 5-fluorouracil/leucovorin	6 vs 12	12.4 vs NA	[76]

OS: Overall survival; PFS: Progression-free survival; mPDAC: Metastatic pancreatic ductal adenocarcinoma; NA: Not available; LAPC: Locally advanced pancreatic cancer; APDAC: Advanced pancreatic ductal adenocarcinoma.

Table 3 Previous phase II/III clinical trials of third-line therapeutic options for pancreatic cancer

Clinical trial identifier	Year	Patients	Study phase	Tumor stage	Treatment regimes	Median OS (months)	Median FPS (months)	Ref.
NAPOLI-1	2019	86	Retrospective	mPDAC	Nanoliposomal irinotecan + 5-fluorouracil and leucovorin	9.4	3.5	[77]
NAPOLI-1NCT01494506	2020	417	Phase III	mPDAC	Nanoliposomal irinotecan + 5-fluorouracil/leucovorin	5.8 vs 4.3	2.8 vs 1.4	[78]
NR	2023	29	Phase II/III	LA-mPC	Nanoliposomal irinotecan plus 5-fluorouracil/leucovorin	10.27 vs 9.33	2.90 vs 3.60	[80]

OS: Overall survival; PFS: Progression-free survival; mPDAC: Metastatic pancreatic ductal adenocarcinoma; LA-mPC: Locally advanced metastatic pancreatic cancer.

Table 4 Challenges and opportunities for recent targeted therapy options that have been approved and recommended by the Food and Drug Administration for treating pancreatic cancer

Targeted pathway	Frequency of mutation	Clinical phase	Targeted therapies approved by the FDA
KRAS [G12D, G12V, G12R, G12C, G13 (D, C, S, R)]	95%	Phase I-II	Sotorasib (AMG 510), adagrasib (MRTX849)
BRAF (V600E)	13.7%	Phase I-III	Dabrafenib, trametinib
NTRK fusion	0.3%	Phase II	Larotrectinib, entrectinib
NRG-1 fusion	0.5%	Phase I-II	Afatinib, zenocutuzumab
BRCA1/2/PALB2	3%	Phase I-III	Olaparib, cisplatin, niraparib
MSI-H/dMMR	4.7%	Phase I-II	Pembrolizumab
FGFR2	43%-69%	Phase II	Pemigatinib
MEK/ERK	1%	Phase II	Trametinib
RET fusion	1%	Phase II	Selpercatinib, pralsetinib (BLU-667)

FDA: United States Food and Drug Administration; KRAS: Kirsten rat sarcoma oncogene; BRAF: B-raf proto oncogene; NTRK: Neurotrophic receptor tyrosine kinase; NRG-1: Neuregulin-1; BRCA1/2: Breast cancer susceptibility gene 1/2; PALB2: Partner and localizer of breast cancer 2; MSI-H: Microsatellite instability high; dMMR: Mismatch repair deficient; FGFR2: Fibroblast growth factor receptor 2; MEK: Mitogen activated protein kinase; ERK: Extracellular signal regulated kinase; RET: Rearranged during transfection.