The most complete summary of the top ten targets and drugs for precision treatment of pancreatic cancer in 2021

Pancreatic cancer can be called the "king of cancer".

In recent years, as the basis of precision treatment, genetic testing has made significant progress in the treatment of a variety of solid tumors

(Source: Author)

POLO Study: Start a new journey of precision treatment of pancreatic cancer

The 2019 American Society of Clinical Oncology (ASCO) annual meeting announced the most important POLO study in the field of pancreatic cancer.

Preliminary results showed that metastatic pancreatic cancer patients with germline BRCA gene mutations (gBRCAm) received platinum-based first-line chemotherapy better than wild-type patients; based on the better safety of PARP inhibitors, this study will target the PARP of gBRCAm The inhibitor olaparib was used in the maintenance treatment of pancreatic cancer.

(Source: Reference)

Based on this study, olaparib was approved by the U.

(Source: Reference)

KRAS mutation : AMG510KRAS

Although mutations are common, targeted drugs are lacking

After 30 years of research, AMG 510 is the first KRAS G12C inhibitor to reach the clinical stage! Studies have shown that AMG 510 is well tolerated in advanced KRAS G12C mutant solid tumors.

At present, the US FDA has approved AMG 510 for KRAS G12C positive non-small cell lung cancer and colorectal cancer

In addition, basic research has found that the combination of autophagy inhibitor hydroxychloroquine and MAPK inhibitor trametinib can slow down tumor growth and prolong survival in mice transplanted with human pancreatic tumors with KRAS mutations

The effect of this combination therapy was also confirmed in a patient with advanced pancreatic cancer.

NTRK fusion: larotinib or emtratinib

NTRK fusion gene accounts for about 0.

In the NAVIGATE study, the remission rate of Larotrectinib for NTRK fusion patients (55 cases) reached 75%, including 1 case of pancreatic cancer (partial remission)

In addition, the STARTRK-2 study evaluated the efficacy of Entrectinib.

In 2018, larotinib became the first pan-tumor tissue small molecule targeted drug approved by the FDA for NTRK fusion.

MSI-H/dMMR: Immunotherapy

Immune checkpoint inhibitors have achieved amazing results in multiple cancers

In addition, anti-cytotoxic T-lymphocyte associated protein 4 (cytotoxic T-lymphocyte associated protein 4, CTLA4) inhibitors and anti-programmed cell death receptor 1 (programmed cell death protein 1, PD-1) inhibitors combined with standard gemcitabine chemotherapy Clinical trials are ongoing

EGFR mutation : Erlotinib

30 to 89% of pancreatic cancers have EGFR overexpression
.
In a phase III, double-blind, placebo-controlled clinical study, 569 patients with advanced or metastatic pancreatic cancer were randomized to receive erlotinib combined with gemcitabine and gemcitabine monotherapy.
The overall survival and progression-free of patients in the combined treatment group The survival time was significantly improved.
The median survival time was 6.
24 months, and the 1-year survival rate was 23%; the median survival time of the control group was 5.
91 months, and the survival rate was 17%
.

VEGFR : sunitinib

VEGFR is highly expressed in more than 90% of pancreatic cancers and is involved in a variety of angiogenesis processes, including vascular penetration, endothelial cell proliferation, migration and survival
.
A phase II clinical study showed that sunitinib for maintenance treatment of metastatic pancreatic cancer can improve the prognosis
.

Notch access : MK-0752

Both Notch ligands and receptors are highly expressed in pancreatic cancer tissues
.
The Notch pathway can induce epithelial-mesenchymal transition (EMT) to play an important carcinogenic role in pancreatic carcinogenesis
.

At present, most of the studies on NOTCH pathway inhibitors such as Demcizumab, Tarextumab and RO4929097 have negative results
.
A phase I multi-center study from the United Kingdom showed promising results.
The study included 44 patients with metastatic pancreatic cancer who were treated with gemcitabine and MK-0752 as first-line or second-line treatment.
One patient obtained a definite partial remission.
13 The patient has stable disease
.

MEK sudden change : qumei imatinib

Changes in the structure of MEK and its expression level are related to the occurrence of many diseases such as tumors.
At present, a variety of MEK inhibitors have been discovered, and some of them have been used in the treatment of tumors
.

A randomized, double-blind, phase II trial evaluated the efficacy of gemcitabine plus trametinib in 160 patients with metastatic pancreatic cancer, and found that compared with gemcitabine plus placebo group, the overall survival of the patients (8.
4 months vs 6.
7 Months) and progression-free survival (16.
1 weeks vs 15.
1 weeks) were not statistically significant; and clinical trials of other MEK1/2 inhibitors such as Selumetinib also ended in failure
.

Another phase I/II clinical study (NCT02703571) evaluating the efficacy of trametinib combined with ribosomes in locally advanced pancreatic cancer or metastatic pancreatic cancer is ongoing
.

IGF mutation : Ganitumab

Ganitumab is an anti-IGF1R monoclonal antibody that blocks the binding of IGF-1 and IGF-2 to their receptors
.
A phase II clinical study evaluated the safety and efficacy of gemcitabine combined with Ganitumab in the treatment of metastatic pancreatic cancer, and found that compared with the gemcitabine combined with placebo group, the treatment group tolerated the treatment well and achieved a longer overall survival This is the only clinical trial with positive results so far
.

mTOR inhibitors : everolimus and temsirolimus

The main mTOR inhibitors currently used in clinical practice are everolimus and temsirolimus
.
A phase II study evaluated the efficacy of everolimus monotherapy in patients with metastatic pancreatic cancer resistant to gemcitabine, but the clinical efficacy was not obvious
.
Another phase I/II study from the Greek Cancer Collaboration Group in combination with gemcitabine and temsirolimus for locally advanced pancreatic cancer or metastatic pancreatic cancer also failed
.

Although the research on pancreatic cancer-related genes, molecular pathways and other mechanisms has been intensified in recent years, the currently available genomic data has become the basis for conducting biomarker-driven clinical trials, but currently very few targeted drugs have been approved, such as TP53, There are no effective targeted drugs for common mutations such as CDKN2A and SMAD4
.

As more and more new potential therapeutic targets are discovered, a large number of studies are needed to verify the clinical application prospects of new biomarkers
.

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