Hepatobiliary and pancreatic tumors: immunotherapy becomes a trend ASCO 2021

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Liver cancer is a malignant tumor with high incidence and poor prognosis in China For one, a number of immunotherapies have been approved for treatment, and first-line combination therapies are being explored
.

Due to the high degree of malignancy and heterogeneity of pancreatic cancer and biliary system tumors, targeted and immune single-agent therapy can no longer achieve significant clinical benefits, and the combination of multiple programs is still in the early stage
.

At the 2021ASCO annual meeting, there were 25 abstracts submitted by Chinese companies for independent research and development products of liver cancer, pancreatic cancer and biliary tumors in the digestive system tumors, of which 16 were funded by enterprises
.

This article will briefly review the results of key clinical studies
.

For more detailed analysis of the 2021ASCO annual meeting, please contact mc@pharmaDJ.
com to purchase the first-line combination therapy for liver cancer.
The combination therapy of immune and targeted drugs has begun to show results and has been widely developed for the treatment of liver cancer
.

Among them, the first-line treatment field is the "T+A" combination of tislelizumab and bevacizumab, which has become a new first-line treatment for advanced hepatocellular carcinoma (HCC)
.

The remarkable therapeutic effect has also attracted domestic companies to compete for research on combination therapy
.

Chinese pharmaceutical companies released a total of 3 research results on immune checkpoint inhibitors combined with targeted drugs at the 2021ASCO annual meeting.
Although the research is still in phase II clinical phase, the preliminary data are already impressive
.

Among them, the faster pace is Hengrui's "Double AI" program "PD-1 antibody Carrelizumab (Erica) + TKI inhibitor Apatinib (Aitan)", which is a combination of two leading products The therapy updates the OS data
.

At last year’s ESMO (European Medical Oncology Society) annual meeting, the “Shuang Ai” combination has contributed more significant clinical data.
The ORR of the first-line treatment group was as high as 46%, the 1-year OS rate reached 75%, and the median OS reached 20.
3.
Month
.

In this update of ASCO data, patients with advanced HCC have achieved significant survival benefits.
In the first-line cohort, 58.
6% of patients achieved OS, with a median OS of 20.
1 months; in the second-line cohort, 60.
0% of patients achieved OS, with a median OS of 20.
1 months.
21.
8 months
.

It further verified the therapeutic potential of the "Shuang Ai" combination
.

Not only that, carrelizumab combined with apatinib has launched a phase III clinical trial for the treatment of advanced HCC, and subjects are being recruited (SHR-1210-III-310)
.

The other two combination treatments are still in the early stages
.

Innovent's PD-1 inhibitor Sintilimab and Chia Taiqing's Anlotinib combined program included 20 patients with an objective response rate (ORR) of 40.
4% and a disease control rate (DCR) Reached 95%
.

The other is Kangfang Bio's PD-1/CTLA-4 double antibody AK104 combined with lenvatinib in the treatment of unresectable hepatocellular carcinoma, ORR was 44.
4%, DCR reached 77.
8%, and the median progression-free survival has not yet been reached ( PFS)
.

Lenvatinib has been approved as a first-line drug for liver cancer, and the combination of lenvatinib and PD-1 antibody pembrolizumab has been shown to have a significant effect in the treatment of liver cancer
.

This time, Kangfang Biology uses a combined treatment plan of double antibodies and lenvatinib, which may contribute different data to the first-line treatment of HCC
.

Judging from the information released by ASCO this year, combination therapy has gradually become the mainstream treatment for hepatocellular carcinoma
.

According to incomplete statistics in ClinicalTrials.
gov, there are more than 180 clinical trials of immune combination (immunization + targeting, dual immunization, immune + radiotherapy and chemotherapy) for the treatment of HCC
.

Hengrui also announced the results of two clinical studies on the treatment of HCC with PD-1 antibody + radiotherapy, TKI inhibitor + radiotherapy
.

Among them, the results of apatinib combined with IMRT radiotherapy in the treatment of unresectable HCC showed that ORR and DCR were 15% and 82%, respectively, and the median PFS was 7.
68 months
.

The ORR of carrelizumab combined with radiotherapy for advanced HCC reached 47%
.

For the adjuvant treatment of hepatocellular carcinoma, ASCO also provided preliminary data this time
.

It is also the "double AI" combination of PD-1+TKI.
Hengrui initiated a clinical trial for the treatment of resectable hepatocellular carcinoma during the perioperative period.
Among the 17 evaluable patients, 5 cases (29.
4%) reached the main pathology Remission (MPR), of which 1 case (5.
9%) achieved pathological complete remission (pCR)
.

In addition, CP Tianqing's Anlotinib combined with TACE was used as an adjuvant treatment for HCC after surgery, and the median disease-free survival (DSF) reached 2.
4 months.
Among the 10 evaluable patients, 9 had no disease progression, 1 Patients relapsed
.

Preliminary testing of cell therapy for liver cancer For immunotherapy of liver cancer, in addition to immune and targeted therapy, Chinese companies are also preliminarily testing the waters in the field of CAR-T cell therapy
.

The GPC3 (glypican-3) target is highly expressed in hepatocellular carcinoma (HCC) and is a potential target for HCC cell therapy
.

At this year's ASCO meeting, Keji Pharmaceuticals announced for the first time the Phase I clinical data of GPC3 autologous CAR-T cell therapy CT011
.

In the primary endpoint, no dose-limiting toxicity (DLT) was observed, and the maximum tolerated dose (MTD) was not reached.
In the secondary endpoint, the overall objective response rate (ORR) reached 16.
7%, the DCR was 50%, and the mPFS was 4.
2 months
.

CT011 is the first and only product in China to carry out a registered clinical trial of GPC3 CAR-T therapy for HCC
.

In addition, Yuanqi Biological also released the non-registered clinical results of G3-CAR-ori2 cells this time at ASCO
.

Among the 7 evaluable subjects, 3 had partial remission (PR), 2 had stable disease (SD), and 2 had disease progression (PD)
.

Pancreatic cancer exploratory immunotherapy + AG combination therapy.
Because pancreatic cancer is an immune "cold" tumor, tumor cells can easily achieve immune escape.
The existing clinical trial results show that single-agent immunotherapy has no benefit on the survival and prognosis of patients with pancreatic cancer, but immune combination The therapy has achieved certain results
.

[1] In this year's ASCO meeting, three Chinese companies submitted early data on immune checkpoint inhibitors and the AG program (gemcitabine combined with albumin-bound paclitaxel) in the first-line treatment of pancreatic cancer
.

The AG regimen is a classic regimen for the first-line treatment of pancreatic cancer
.

The three trials are all in the early stage, the research scale is small, and the sample size does not exceed 20%
.

The Phase II trial of the PD-L1/CTLA-4 dual-antibody KN046 combined with AG regimen in the treatment of pancreatic ductal adenocarcinoma (PDAC) conducted by Corning Jerry had an ORR of 55.
6% and a DCR of 88.
9%
.

Hengrui's combination of Karelizumab and AG has achieved ORR and DCR of 60% and 85%, respectively
.
The data on PFS and OS are not yet mature .

In addition, the Phase I data of the c-Met inhibitor AL2846 treatment of PDAC initiated by Zhengda Tianqing showed that the maximum tolerated dose reached 120mg
.

From the results, the preliminary effectiveness and safety data of the three first-line immunization + AG combined programs are good, but the long-term data is not yet mature, laying the foundation for later phase III clinical trials
.

In addition, what is more noteworthy is that Hutchison’s Sofatinib, with its excellent SANET-p phase III clinical data, has submitted an NDA application to the NMPA for the treatment of advanced pancreatic neuroendocrine tumors (pNET), and has entered the “in It is believed that it will be approved soon
.

Part of the Phase III clinical data (Ki-67 and CgA subgroups) supporting NDA were also released at this year's ASCO
.

Combined with the data released by ESMO in 2020, Sofatinib can significantly prolong the median PFS (10.
9 vs 3.
7 months) of Chinese patients with advanced pNET, and the overall objective response rate (ORR) reached 19.
2%
.

Sofatinib is a new kinase inhibitor independently developed by Hutchison Medicine, which can effectively inhibit the activities of VEGFR (1, 2, 3), FGFR1 and CSF1R, and enhance anti-tumor activity
.

On December 30 last year, Sofatinib (Sutaida) received NMPA approval for the first time for the treatment of non-pancreatic endocrine tumors
.

According to the CDE website, Sofatinib has carried out a total of 3 phase III registered clinical trials in China to treat pancreatic neuroendocrine tumors, non-pancreatic endocrine tumors, and biliary tract cancers, mostly in relatively difficult-to-treat tumors
.

The results of the second-line treatment of biliary tract tumors are quite satisfactory.
At present, most of the immunological and targeted therapy researches on biliary tract tumors are only in the clinical phase II and the second-line treatment is mostly used.
The first-line treatment is still chemotherapy with cisplatin combined with gemcitabine
.

Some studies suggest that this may be related to the heterogeneity of TRA in cholangiocarcinoma and the unique tumor microenvironment
.

[2] In this ASCO, a total of 2 second-line treatments for biliary tumors initiated by Chinese companies announced clinical results, showing preliminary anti-tumor activity
.

They are Sofatinib from Hutchison Medicine and TQB2450 from Chia Tai Tianqing and Anlotinib in combination therapy
.

Hutchison initiated the Phase II study of cholangiocarcinoma in 2017, and the Phase III study initiated the head-to-head clinical trial of Sofantinib versus capecitabine in the second-line treatment of cholangiocarcinoma in 2018
.

From the published phase II clinical results, the 16-week PFS rate of the primary endpoint reached 46.
33%, the median PFS of the secondary endpoint was 3.
7 months, and the median OS was 6.
9 months.
The data results are quite satisfactory, and the dose tolerance And the safety results are good
.

Further efficacy needs to be proven by phase III clinical data
.

In contrast, the results of another study of combination therapy are slightly impressive
.

This is a phase I/II study of anlotinib combined with PD-L1 monoclonal antibody TQB2450 initiated by Chia Tai Tianqing
.

The dose of phase I climbs to 12 mg to be tolerable
.

Among the 34 evaluable patients, the 12-month OS rate reached 64.
71%, the median follow-up time was 14.
9 months, the OS did not reach, and the median progression-free survival (mPFS) was 5.
95 months
.

Overall, combination therapy will become the trend of tumor immunotherapy in the future
.

Due to the heterogeneity and high malignancy of pancreatic cancer and biliary tract tumors, immunotherapy has not made substantial progress.
Therefore, it is necessary to continuously update clinical trial data to improve patient survival rate and reduce recurrence and metastasis
.

References: [1] Jia Shengnan, Zhang Chaolei, Cao Liping.
Progress in comprehensive treatment of pancreatic cancer[J].
Clinical and Education of General Medicine,2021,19(03):256-258.
[2]Guo Xueran,Zhong Fei.
Research progress in immunotherapy of cholangiocarcinoma[J].
Modern Oncology Medicine,2020,28(11):1969-1973.
[3] ASCO Meeting Library https://meetinglibrary.
asco.
org/[4] ClinicalTrials.
gov total For 1341 period, visit the R&D customer website to browse more articles