Recent advances in targeted therapy for pancreatic adenocarcinoma

Table 1 Molecular targets for pancreatic cancer treatment

Target	Frequency of mutation/expression, %
KRAS	95
VEGF	93
Sonic hedgehog	70
Notch3	69-74
TP53	70
NF-kB	70
IGF-1R	64
CDKN2A	60
EGFR	43-69
Akt/mTOR	40
SMAD	40
BRCA1/2	1-3
NRG1 fusion	0.5
NTRK fusion	0.3

Akt: Akt serine/threonine kinase; BRCA1/2: Breast cancer susceptibility gene 1/2; CDKN2A: Cyclin-dependent kinase inhibitor 2A; EGFR: Epidermal growth factor receptor; KRAS: Kirsten rat sarcoma oncogene; IGF-1R: Insulin-like growth factor receptor; mTOR: mammalian target of rapamycin NF-κB: Nuclear factor kappa B; Notch3: Notch receptor 3; NRG1: Neuregulin 1; NTRK: Neurotrophic receptor tyrosine kinase; SMAD: Mothers against decapentaplegic homolog; TP53: Tumor suppressor 53; VEGF: Vascular endothelial growth factor.

Table 2 Clinical trials evaluating the impact of chemotherapeutic agents against specific targets

Target	Study treatment	Phase	Population	No. of patients	mPFS	mOS	Ref.
EGFR	GEM + Erlotinib	III	Locally advanced or metastatic PDAC	285	3.75	6.24	Moore et al[10], 2007
	GEM + Placebo			284	3.55	5.91
EGFR	GEM + Nimotuzumab	IIb	Locally advanced or metastatic PC	96	5.1	8.6	Schultheis et al[50], 2017
	GEM + Placebo			96	3.4	6
EGFR	GEM + Nimotuzumab	III	K-Ras wild-type, locally advanced or metastatic PC	46	4.2	10.9	Qin et al[51], 2022)
	GEM + Placebo			46	3.6	8.5
ERB2	GEM + Afatinib	II	Metastatic PC	79	3.9	7.3	Haas et al[57], 2021
	GEM + Placebo			40	3.9	7.4
VEGF	GEM + axitinib	II	Advanced PC	69	4.2	6.9	Spano et al[67], 2008
	GEM			34	3.7	5.6
VEGF	GEM + axitinib	III	Advanced PDAC	314	4.4	8.5	Kindler et al[68], 2011
	GEM + Placebo			316	4.4	8.3
VEGF	GEM + aflibercept	III	Metastatic PC	271	3.7	6.5	Rougier et al[69], 2013
	GEM + Placebo			275	5.1	7.8
PARP	Veliparib	II	BRCA-mutated PDAC	16	3.1	1.7	Lowery et al[101], 2018
PARP	Olaparib	III	gBRCA1 or BRCA2 mutation and metastatic PC	92	7.4	18.9	Golan et al[103], 2019
	Placebo			62	3.8	18.1
PARP	Cisplatin and GEM + Veliparib	II	Untreated gBRCA/PALB2+ PDAC with measurable stage III to IV PDAC	27	10.1	15.5	Sohal et al[40], 2020
	Cisplatin and GEM			23	9.7	16.4
RET	GEM + Vandetanib	II	Locally advanced or metastatic PC	72	NA	8.83	Middleton et al[107], 2017
	GEM + Placebo			70		8.95
Hedgehog	GEM + Vismodegib	II	Metastatic PC	53	4	6.9	Catenacci et al[160], 2015
	GEM + Placebo			53	2.5	6.1
Hyaluronic acid	mFOLFIRINOX + PEGPH20	II	Metastatic PDAC	55	4.3	7.7	Ramanathan et al[169], 2019
	mFOLFIRINOX			59	6.2	14.4
MMP	GEM + Marimastat	NA	Advanced PC	120	NA	5.51	Bramhall et al[172], 2002
	GEM + Placebo			119		5.47
MMPs	Tanomastat	III	Advanced or Metastatic PDAC	138	1.68	3.74	Moore et al[173], 2003
	GEM			139	3.5	6.59
NOTCH	RO4929097	II	Previously treated metastatic PDAC	18	1.5	4.1	De Jesus-Acosta et al[190], 2014
NOTCH	GEM + Tarextumab	II	Untreated metastatic PC	89	3.7	6.4	Hu et al[193], 2019
	GEM + Placebo			88	5.5	7.9
Wnt	GEM and nab-paclitaxel + Ipafricept	Ib	Untreated stage IV PC	26	5.9	9.7	Dotan et al[196], 2020
Autophagy	GEM and nab-paclitaxel + Hydroxychloroquine	II	Advanced PC	55	5.7	11.1	Karasic et al[209], 2019
	GEM and nab-paclitaxel			57	6.4	12.1

EGFR: Epidermal growth factor receptor; ERBB2: Erb-B2 receptor tyrosine kinase 2; GEM: Gemcitabine; mFOLFIRINOX: Modified fluorouracil plus leucovorin, oxaliplatin and irinotecan; MMPs: Matrix metalloproteinases; mOS: Median overall survival; mPFS: Median progression-free survival; NOTCH: Notch receptor; PARP: Poly (ADP-ribose) polymerase; PC: Pancreatic cancer; PDAC: Pancreatic adenocarcinoma; RET: Ret proto-oncogene; VEGF: Vascular endothelial growth factor.