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*For medical professionals only, looking forward to bringing new treatment hope
to MSS CRC patients, the 2022 Chinese Society of Clinical Oncology (CSCO) Annual Meeting included a "Envolimab combined with recombinant human vascular endothelial statin continuous intravenous pumping therapy for prospective, single-arm, prospective, single-arm, Multicenter clinical trials" [1].
On this occasion, the Medical Oncology Channel is honored to invite Professor Li Enxiao of the First Affiliated Hospital of Xi'an Jiaotong University to have an in-depth discussion
on the original intention and design of this research, as well as the exploration direction of future MSS-type CRC.
The important contents are summarized below for the readers
.
The "intestine" road is long, and there are few breakthroughs: the current situation of MSS CRC immunotherapy
: Professor Lee Eun Hyo
to MSS CRC patients, the 2022 Chinese Society of Clinical Oncology (CSCO) Annual Meeting included a "Envolimab combined with recombinant human vascular endothelial statin continuous intravenous pumping therapy for prospective, single-arm, prospective, single-arm, Multicenter clinical trials" [1].
On this occasion, the Medical Oncology Channel is honored to invite Professor Li Enxiao of the First Affiliated Hospital of Xi'an Jiaotong University to have an in-depth discussion
on the original intention and design of this research, as well as the exploration direction of future MSS-type CRC.
The important contents are summarized below for the readers
.
The "intestine" road is long, and there are few breakthroughs: the current situation of MSS CRC immunotherapy
According to the latest statistics of the National Cancer Center, the incidence of CRC in China ranks second in malignant tumors, and the overall incidence rate is on the rise, but the mortality rate ranks fourth [2].
Professor Li Enxiao said, "The early screening and early diagnosis and treatment of CRC must be effective, and this gratifying result
has appeared.
"At present, the first- and second-line treatment of advanced CRC is mainly based on chemotherapy combined with targeting, and the transition from monotherapy to the era of combination therapy has significantly improved the survival benefits
of patients.
For third-line therapy after the advanced first- and second-line standard therapy, the drugs available include two small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drug TAS-102, and the overall efficacy still has room for
improvement.
With the continuous progress of immune checkpoint inhibitors in the field of colorectal cancer treatment, the survival of colorectal cancer patients has improved by leaps and
bounds.
A series of studies such as CheckMate 142, KEYNOTE-164 and KEYNOTE-177 have confirmed that patients with microsatellite highly unstable/mismatch repair deficiency (MSI-H/dMMR) CRC are the dominant population
for immune checkpoint inhibitor (ICI) therapy.
Immunotherapy has not only shown surprising efficacy in advanced first, second and later line therapy, but its good efficacy in neoadjuvant therapy has also been confirmed
by the NICHE study.
AND BASED ON THE SIGNIFICANT EFFICACY OF THE KEYNOTE-177 STUDY, ICI SINGLE-AGENT FIRST-LINE TREATMENT OF ADVANCED CRC IN MSI-H/DMMR HAS BEEN INCLUDED IN THE CSCO GUIDELINES
AS THE HIGHEST LEVEL OF CLASS I RECOMMENDATION.
However, in CRC patients, who account for up to 95 percent of MSS/pMMR, immunologic agents alone have limited efficacy [3].
MSS CRC is known in the industry as "cold tumors", and previous studies such as KEYNOTE-016 and KEYNOTE-028 studies have confirmed that monotherapy has little effect
on this type of CRC.
Basic research suggests that there are a variety of negative immune modulators in the "cold tumor" microenvironment, which makes tumor cells have an inhibitory effect on the autoimmune response, and therefore the response to ICI is weak
.
How to improve the immune microenvironment and transform "cold tumor" into "hot tumor" has become the biggest bottleneck
of immunotherapy for advanced colorectal cancer.
The treatment model of immunity combined with antiangiogenic drugs seems to bring some light to MSS CRC
.
Anti-angiogenic drugs can not only promote the normalization of tumor blood vessels, but also regulate negative regulatory factors, increase lymphocyte infiltration of tumor microenvironment, and transform the tumor microenvironment in the "immunosuppressive" state into an "immune-sensitive" state, thereby enhancing the efficacy
of immunotherapy.
The REGONIVO study reported at the 2019 ASCO Annual Meeting showed that the ORR of nivolumab combined with regorafenib in patients with MSS-type colorectal cancer who had failed standard therapy reached 33% [4], opening a new mode
of treatment of MSS CRC immunity combined with antiangiogenic drugs.
However, the treatment benefit
of the Japanese study was not replicated in the follow-up North American REGNIVO phase II study.
A number of domestic studies such as REGOMUNE, REGOTORI, Geptanolimab combined with fruquintinib, fruquintinib combined with sindilimab, etc.
have confirmed the effectiveness of immune combined with antiangiogenic drugs in the treatment of MSS CRC, with an objective response rate (ORR) of about 7-33%, and a median progression-free survival (PFS) of about 3-7 months [5-8].
。 However, the treatment differences generated by these studies are thought-provoking, and how to find the potential beneficiaries of the MSS population, and whether common biomarkers such as TMB and PD-L1 expression have the potential to predict efficacy, etc.
, more research data are needed to support
.
The 2022 CSCO Congress included a prospective, single-arm, multicenter clinical trial
of envolimab combined with continuous intravenous pumping of recombinant human vascular endostatin for relapsed or metastatic microsatellite stabilization (MSS) colorectal cancer (CRC) after failure of second-line standard therapy.
The study planned to include 30 patients
with CRC with pathologically and histologically confirmed advanced relapsed or metastatic MSS who had previously failed second-line standard therapy (including fluorouracil or its derivatives, oxaliplatin, irinotecan and bevacizumab, and cetuximab).
。 Eligible patients will receive envolimab (subcutaneous, 300 mg) combined with recombinant human vascular endostatin (210 mg, continuous intravenous pumping for 72 hours) for a treatment cycle every three weeks, clinical tumor imaging evaluation using RECIST v1.
1 during the treatment of envolimab, every 6 weeks for the first year of treatment, and every 8 weeks thereafter; safety assessment with NCI-CTCAE 5.
0 every 3 weeks until disease progression, Participants withdrew informed consent, lost to follow-up, or died
.
The primary endpoint was ORR, and the secondary studies were PFS, disease control rate (DCR), and safety
.
Envolimab is the world's first subcutaneously injected PD-L1 antibody using humanized anti-PD-L1 monodomain antibody
and human immunoglobulin (IgG1) Fc fragment.
Professor Li Enxiao talked about the reason for choosing envolimab for this study, "Envolimab can be administered by subcutaneous injection, which is simple and
easy.
In combination with recombinant human vascular endothelial instatin, it does not increase the burden
of intravenous infusion in patients.
And after clinical observation, the adverse reactions of envolimab are very small
.
”
Recombinant human vascular endostatin is a pan-targeted anti-angiogenic drug whose antitumor effects have been confirmed
in non-small cell lung cancer.
Some basic studies believe that recombinant human vascular endothelial instatin can downregulate a variety of angiogenic factors, effectively inhibit tumor angiogenesis, and promote tumor vascular normalization
.
Moreover, it can improve the hypoxic state of tumors, reduce leakage and interstitial pressure, improve drug delivery, and improve drug efficacy
.
In addition, recombinant human vascular endostatin can improve the inhibitory state
of the tumor immune microenvironment.
From the perspective of combination therapy, anti-angiogenic drugs and ICI can work together on the tumor microenvironment, reshape the tumor vascular microenvironment and immune microenvironment, transform the immunosuppressive state into an immune-promoting state, increase the invasion of tumor by T cells, and play a synergistic anti-tumor effect
.
Therefore, the combination regimen of envolimab and recombinant human vascular endostatin was selected to further evaluate the efficacy
of immune combined with antiangiogenic drugs.
Professor Li Enxiao said, "Through this study, we evaluate the efficacy and safety of envolimab combined with recombinant human vascular endostatin in the backline treatment of MSS CRC, and expect that envolimab combined with antiangiogenic drugs can bring survival benefits to MSS CRC patients, and its efficacy is not inferior to the existing third-line standard treatment regimen
.
" Of course, it is also hoped that the OS benefit of this study can provide more than 50%, further enriching the evidence-based data
of immune combined with anti-angiogenic drugs for MSS CRC.
”
When talking about the exploration direction of MSS CRC, Professor Li Enxiao said, "In the future, there will be more and more exploratory studies related to ICI treatment of MSS CRC, and the research design will be more and more optimized
.
First of all, the most important direction is to explore
the treatment model of different combination regimens with existing cytotoxic drugs and antiangiogenic drugs.
Secondly, dual immune combination therapy, including bi-antibody drugs, PD-1 inhibitors + PD-L1 inhibitors and PD-1 + CTLA-4 dual inhibitors, can be used as new exploration directions
.
In addition, whether cytotoxic drugs combined with topical treatment regimens such as targeted drugs TKI and radiotherapy can improve the overall efficacy through the 'distant effect' of local therapy and increase antigen release will also be the main direction
of future exploration.
”
Professor Li Enxiao also introduced some ongoing research to inspire ideas for future exploration
.
He noted that "in 2020, there are two studies worth considering
.
The positive results of the KEYNOTE-651 study evaluating ICI combined with first-line standard chemotherapy for the treatment of metastatic CRC suggest that the addition of ICI to further improve the clinical efficacy of standard first-line therapy can be considered in first-line therapy, and similar explorations can be carried out in MSS CRC.
FOLFOX+dulvalumab + Tremelimumab was used first-line for MSS metastatic CRC with untreated RAS mutations, with an ORR of 62.
5%, which exceeded the benefit of FOLFOX combined with targeted tumor remission [9], and could also be used as a reference
for MSS CRC first-line study design 。 In 2022, there are also two studies, the CAVE study of anti-EGFR monoclonal antibody rechallenge combined immunization and the TRAP study of TKI rechallenge combined immunization, which provide new ideas
for the use of rechallenge combination immunization strategy in MSS CRC patients.
Another interesting study is CheckMate 9X8, which compares the efficacy and safety of immunization plus mFOLFOX6/BEV with mFOLFOX6/BEV in the first-line treatment of
metastatic CRC.
Although the study did not meet the primary endpoint, the 12-month PFS rate was higher in the immune combination group, demonstrating the 'tailing effect' of immunotherapy [10], laying the foundation
for further exploration of immunotherapy benefit populations.
Finally, Professor Li Enxiao emphasized that circulating tumor DNA (ctDNA) detection can distinguish which patients can benefit from immunotherapy, so as to guide the implementation of MSS CRC immunotherapy, which can be one of the
important directions for future exploration.
In recent years, the immune combination therapy model has made continuous progress in the field of MSS CRC treatment, and it is believed that with the release of more research data, it will further enrich the clinical treatment decisions
of MSS patients.
Among them, envolimab, as the world's first subcutaneous PD-L1 inhibitor, expects the immune combination regimen based on it to bring new therapeutic hope
to MSS CRC patients.
: Professor Lee Eun Hyo
Leader of the Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University
Chief physician, professor, medical doctor, doctoral supervisor
Chairman of the Tumor Biotherapy Professional Committee of Shaanxi Anti-Cancer Association
CSCO Board of Trustees
Vice Chairman of CSCO Biliary Tract Tumor Committee, Member of CSCO Pancreatic Cancer Professional Committee,
Member of the Standing Committee of the GP-NET Special Committee and the Standing Committee of the Special Committee of Integrated Traditional Chinese and Western Medicine
Member of the National Health Commission Capacity Building and Continuing Education Oncology Committee
Member of the Standing Committee of the Cancer Rehabilitation Committee of the Chinese Association of Rehabilitation Medicine
Member of the Standing Committee of the Tumor Molecular Targeted Therapy Professional Committee of the Chinese Society of Biomedical Engineering
Member of the Standing Committee of the Tumor Molecular Targeted Therapy Professional Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of the Precision Medicine and Oncology MDT Professional Committee of the China Research Hospital Association
Editorial Board Member, Modern Oncology Medicine
References:
1] Li Enxiao, et al.
A prospective, single-arm, multicenter clinical trial of envolimab combined with recombinant human vascular endothelial instatin (Endo) continuous intravenous pumping in the treatment of recurrent or metastatic MSS-type colorectal cancer after failure of second-line standard therapy.
2022 CSCO
[2]Zheng RS, Zhang SW, Zeng HM, et al.
Cancer incidence and mortality in China, 2016, Journal of the National Cancer Center, 2022; 2(1):1-9.
[3]Ho WW，Gomes - Santos IL，Aoki S，et al.
Dendritic cell paucity in mismatch repair - proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy.
Proc Natl Acad Sci U S A.
2021 Nov 9; 118(45):e2105323118.
[4]Fukuoka S, Hara H, Takahashi N, et al.
Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose - Escalation，and Dose - Expansion Phase Ib Trial（REGONIVO，EPOC1603）.
J Clin Oncol.
2020 Jun 20；38（18）：2053-2061.
[5]Cousin S, Cantarel C, Guegan JP, et al.
Regorafenib - Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer （REGOMUNE）：A Single - arm，Open - label，Phase II Trial.
Clin Cancer Res.
2021 Apr 15；27(8)：2139-2147.
[6]F.
Wang，M.
H，e，Y.
Yao，et al.
A phase Ib / II clinical trial of tolerability，safety and efficacy of regorafenib in combination with toripalimab（a PD - 1 antibody）in patients with relapsed or metastatic colorectal cancer.
2020 ESMO Abstract 433P
[7]Bai YX, Xu N, An S, et al.
A phase ib trial of assessing the safety and preliminary efficacy of a combination therapy of geptanolimab （GB226） plus fruquintinib in patients with metastatic colorectal cancer （mCRC）.
2021 ASCO.
Abstract e15551.
[8]W.
Zhang, Y.
Sun，Z.
Jiang，et al.
Fruquintinib plus sintilimab in refractory repair - proficient（pMMR） / microsatellite stable（MSS）metastatic colorectal cancer（mCRC）：Preliminary clinical results and biomarker analyses from a phase II study.
2022 ESMO Abstract 423P.
[9]François Ghiringhelli，Benoist Chibaudel，Julien Taieb，et al.
Durvalumab and tremelimumab in combination with FOLFOX in patients with RAS-mutated, microsatellite - stable，previously untreated metastatic colorectal cancer（MCRC）：Results of the first intermediate analysis of the phase Ib / II MEDETREME trial.
2020 ASCO.
Abstract 3006.
[10]Heinz - Josef Lenz，Aparna Raj Parikh，David R.
Spigel，et al.
Nivolumab （NIVO） + 5 - fluorouracil / leucovorin / oxaliplati（mFOLFOX6） / bevacizumab（BEV）versus mFOLFOX6 / BEV for first - line（1L）treatment of metastatic colorectal cancer（mCRC）：Phase 2 results from CheckMate 9 X 8.
2022 ASCO GI.
Abstract 8.
