New treatment for recurrent metastatic nasopharyngeal carcinoma! Professor Chen Mingyuan's team proposed a high-efficiency and low-toxicity triple GAT scheme Cell Press dialogue scientists

medicine

Medicine

Recently, the team of Professor Chen Mingyuan of the Cancer Prevention and Treatment Center of Sun Yat-sen University proposed a triple GAT program with more efficient and low toxicity potential, which provides a new treatment direction
for recurrent and metastatic nasopharyngeal carcinoma.
The study, titled "Gemcitabine combined with apatinib and toripalimab in recurrent or metastatic nasopharyngeal carcinoma," was published in
Cell Press cell publishing journal Med.
Professor Chen Mingyuan is the sole corresponding author
of the article.
You Rui, Zou Xiong, Ding Qian, Zhang Weijing, Sun Yat-sen University Cancer Prevention and Treatment Center, and Wang Xiao of Beijing Nuohe Zhiyuan Co.
, Ltd.
are the co-first authors
of the article.

▲Long press the picture recognition QR code to read the original text

Nasopharyngeal carcinoma is one of the most common malignant tumors in China, with a higher degree of malignancy than other head and neck malignant tumors, and is prone to local recurrence and distant metastasis
.
At present, gemcitabine plus cisplatin (GP) combined with PD-1 monoclonal antibody has become the standard regimen for recurrent and metastatic nasopharyngeal carcinoma, but there are still shortcomings
such as heavy cisplatin toxicity, poor tolerability, and low effective rate of PD1 monotherapy.
Therefore, it is urgent to find a low-toxicity drug to replace cisplatin, and at the same time can be combined with PD-1 and maintained for a long time to achieve synergistic effect
.

Tumor angiogenesis is the hallmark feature of tumors, tumor neovascularization morphology disorder, high leakage, slow blood flow, poor perfusion, aggravate tumor hypoxia, promote tumor recurrence and metastasis
.
Antiangiogenic drugs can induce tumor vascular normalization, improve intratumoral perfusion, increase chemotherapy sensitivity, and become a new direction
in tumor treatment.
In addition, antiangiogenic drugs can also reverse the immunosuppressive microenvironment in the tumor to an immune-promoting state, which has a synergistic effect
with immunotherapy.
Antiangiogenic drugs are mainly focused on the VEGF(R) pathway, including monoclonal antibodies against VEGF(R) and small molecule TKIs
that primarily target VEGFR-2.
In the clinical application of a variety of solid tumors, anti-vascular TKI has significant efficacy, low toxicity, high tolerability, and long-term maintenance when
combined with immunotherapy.

Therefore, we pioneered the use of apatinib (antiangiogenic TKI) instead of cisplatin during induction chemotherapy for nasopharyngeal carcinoma, namely: gemcitabine (chemotherapy) + apatinib (antiangiogenic therapy) + trepilimab (immunotherapy) (GAT regimen), while also using apatinib in combination with immunotherapy instead of immunotherapy monotherapy for long-term maintenance
.
The specific regimen of this study is as follows: first use GAT regimen to induce chemotherapy for 6 courses, and then use apatinib + trepilimab to continue long-term maintenance
.
A total of 41 patients with
recurrent and metastatic nasopharyngeal carcinoma were enrolled.
The ORR was as high as 90.
2%, the CR rate was 34.
1%, and the median PFS was 25.
8 months, all slightly higher than the previous GP+PD-1 regimen (CR rate: 5-19.
2%, mPFS: 9.
6-11.
7 months [updated data 21.
4 months]).

The incidence of toxicity associated with ≥ level 3 treatment was 56.
1%, lower than the 87-94%
of GP+PD-1 standard regimens.
Of note were the adverse events specific to this regimen, with a grade 3 incidence of nasopharyngeal necrosis ≥ as high as 21.
9%.

We further analyzed and found that the risk factors for nasopharyngeal necrosis caused by GAT regimens included re-radiotherapy and less than 12 months from the end of the previous radiotherapy, which was safe for GAT
regimens.
To identify the population benefiting from this protocol and explore the mechanism of benefit, we performed whole-exome (WES) and transcriptome sequencing on fresh tissue samples from patients prior to treatment, as well as monitoring of plasma EBV DNA and ctDNA dynamics before
and after treatment.
It was found that the amplification of the genomic 11q13.
3 segment and the high expression of MRGPRF in this segment were markers of poor prognosis of GAT regimens, and the underlying resistance mechanism was that the amplification of this segment activated epithelial-mesenchymal transformation, further inhibiting the anti-tumor immune response
in the tumor microenvironment.
In addition, we have found that dynamic detection of ctDNA is more effective than EBV-DNA in monitoring tumor progression
.

Therefore, this study proposes a triple GAT regimen with more efficient and low toxicity potential, which provides a new treatment direction
for recurrent and metastatic nasopharyngeal carcinoma.

This work is supported
by the National Natural Science Foundation of China, the Guangdong Science and Technology Major Project, and the Guangzhou Science and Technology Key Project.

Interview with the author

The public account of Cell Press specially invited Professor Chen Mingyuan to accept an exclusive interview on behalf of the research team and asked him to further explain
it in detail.

CellPress：

Gecitabine and cisplatin (GP) plus PD-1 inhibitors are the standard of care
for patients with recurrent/metastatic nasopharyngeal carcinoma.
What are the current problems with the program?

Professor Chen Mingyuan:

Indeed, the data of a number of large phase III clinical trials suggest that GP+PD-1 regimen has become the standard treatment for
recurrent and metastatic nasopharyngeal carcinoma.
However, we believe that there are two aspects of the solution that can be further optimized: First, the security aspect
.
It is well known that cisplatin is highly toxic and poorly tolerated, and its more significant toxicities include severe hematotoxicity, gastrointestinal toxicity, and hepatorenal toxicity
.
Thus, we can see multiple studies reporting severe acute toxicity rates of up to 87% to 94%
with GP chemotherapy plus PD-1 regimens.
Second, effectiveness
.
We know that PD-1 alone is less effective; However, this regimen uses PD-1 alone maintenance therapy after the first 4-6 stages of GP chemotherapy ends, which may affect long-term tumor control
.
Therefore, this study pioneered the use of apatinib instead of cisplatin to reduce the toxicity of its combination therapy, and after the end of induction chemotherapy, continue to use apatinib in combination with PD-1 and maintain it for a long time to achieve synergistic effects
.

CellPress：

What are the main concerns of gemcitabine, apatinib, and trepilimab (GAT)?

Professor Chen Mingyuan:

The protocol uses three types of drugs at the same time - chemotherapy drugs, targeted drugs and immunotherapy drugs, which is a completely new treatment idea
.

However, these three drugs are not randomly combined, gemcitabine is a commonly used standard chemotherapy drug for nasopharyngeal carcinoma, which has the characteristics of fast onset and wide applicability of chemotherapy; Apatinib is a vascular inhibitor targeting VEGFR, which can promote the normalization of intratumoral blood vessels and improve intratumor blood perfusion when used at low doses (250mg), on the one hand, it assists chemotherapy drugs to better enter the tumor, on the other hand, it improves the hypoxic state in the tumor, and increases the sensitivity of tumor cells to chemotherapy; Trepilimab is a PD-1 monoclonal antibody that synergistically works synergistically with apatinib for long-term maintenance of these two drugs than conventional PD-1 monoclonal antibody monotherapy
.
Based on the above theory, we can see from the study data that the complete response rate after three-drug treatment is as high as 34.
1%, suggesting that the scheme is widely applicable and has obvious anti-tumor effects; The median progression-free survival was 25.
8 months, suggesting that two-agent maintenance resulted in longer progression-free survival
.

However, it must be clear that this regimen is mainly suitable for patients
with recurrent and metastatic nasopharyngeal carcinoma who are not suitable for local treatment or who have lost the opportunity to undergo local radical treatment.

CellPress：

What are the things that need to be paid attention to in GAT therapy?

Professor Chen Mingyuan:

From our study data, the overall toxicity incidence of GAT efficacy is low, and it is better tolerated and effective
.
Therefore, in order to promote the protocol widely in clinical practice, we believe that as long as GAT therapy is avoided as long as possible in patients with high-risk factors for nasopharyngeal necrosis, including patients with a history of re-irradiation therapy and less than 12 months from the end of the last radiotherapy, the incidence
of nasopharyngeal necrosis caused by GAT therapy can be reduced from the source.
Indeed, from this study, we found that only one patient (3.
7%, 1/27) developed grade 3 nasopharyngeal necrosis
excluding patients with these two risk factors.
In addition, patients with nasopharyngeal necrosis due to GAT therapy are promptly treated with endoscopic surgical debridement and vascular embolization intervention
.
In this study, the rate of nasopharyngeal necrosis above grade 3 was as high as 21.
9% (9/41), however, only 3 patients (7.
3%, 3/41) subsequently developed grade 3 nasopharyngeal bleeding; At the same time, none of the patients had death
due to nasopharyngeal necrosis or nasopharyngeal hemorrhage.
The reason is that we carried out timely interventional embolization treatment of the internal carotid artery involved in the necrotic foci of these patients with grade 3 or above nasopharyngeal necrosis, so as to avoid major bleeding caused by internal carotid artery rupture; In addition, we perform endoscopic debridement of necrotic lesions in time to remove all necrotic tissues and bone, and at the same time, use our own peduncated nasal mucosal flap for lesion repair, promote wound healing, and completely cure nasopharyngeal necrosis
.

CellPress：

How can I identify the patient groups that benefit from GAT therapy?

Professor Chen Mingyuan:

For GAT therapy, in addition to gemcitabine chemotherapy, apatinib and trepilimab have clear therapeutic targets, however, the mechanism of synergy is not clear
.
Indeed, in this study, we found that different patients responded to and prognostically different patients
.
We believe that the reason is due
to the heterogeneity of different tumor genomes and differences in the immune microenvironment.
Therefore, we first performed whole exome (WES), transcriptome and immunomicroenvironment pathomic analysis
of fresh tissue from this patient before treatment.
We found that the amplification of the 11q13.
3 segment of the genome and the high expression of the gene MRGPRF in this segment are innovative biomarkers with poor prognosis of
GAT regimens.
Its potential failure mechanism activates epithelial-mesenchymal transformation (EMT) for the amplification of this segment and inhibits the immune response
of the tumor microenvironment.
However, due to the variability and non-reproducibility of tumor tissue sampling before treatment, response to treatment is not taken into
account.
Therefore, we tried to use dynamic non-invasive tests, including EBV DNA and ctDNA, to monitor tumor progression
.
Surprisingly, ctDNA dynamic testing is more effective at monitoring tumor progression
than routine EBV DNA testing.

CellPress：

What is your next step in terms of the efficacy of GA?

Professor Chen Mingyuan:

We will further improve the application prospects
of GAT solutions from both clinical and basic research aspects.
First, in terms of clinical research, is the GAT program the optimal combination? We are conducting a small randomized controlled trial comparing two pairs of this three-drug regimen (gemcitabine + PD-1 monoclonal antibody, apatinib + PD-1 monoclonal antibody) and GAT regimen to demonstrate the efficacy of GAT
regimens 。 Second, in terms of basic research, what is the synergy mechanism of the GAT triple program? We will conduct relevant translational trials on the above small sample studies, and we believe that we can obtain more convincing evidence to explain the synergistic mechanism of GAT regimens under the premise of a control group; In addition, we have established a mouse model of humanized PBMC to explore the synergistic mechanism
of GAT regimens by comparing different drug combinations.
The biological mechanism of high expression of MRGPRF leading to poor efficacy of GAT regimens was further explored, and it was found that the target of action of this resistance mechanism could be
reversed.

About the author

Chen Mingyuan

professor

Professor Chen Mingyuan, Deputy Director of the Department of Nasopharyngeal Surgery, Minimally Invasive Surgery for Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Prevention and Treatment Center, former Vice President of Nanchang Hospital Affiliated to Sun Yat-sen University; He was selected as a national high-level talent, a young scientific and technological innovation leader in the Innovation Talent Promotion Program of the Ministry of Science and Technology, an "Outstanding Young Medical Talent" of Guangdong Province of the Ministry of Education, and a "Double Hundred Plan" of Nanchang High-level Scientific and Technological Innovation Talents; He is the vice chairman/secretary general of the Nasopharyngeal Carcinoma Prevention and Control Branch of the China Association for the Promotion of International Exchanges in Healthcare, the vice chairman of the Nasopharyngeal Carcinoma Professional Committee of the Chinese Health Science and Technology Promotion Association, and the chairman of the Nasopharyngeal Cancer Special Committee of Guangdong Anti-Cancer Association
.
He is good at multidisciplinary treatment and basic translational research
such as radiotherapy, chemotherapy and surgery for nasopharyngeal carcinoma.
He has published more than 100 SCI papers, including more than 50 communications/first author publications, 7 publications with an impact factor of more than 20 points, 24 papers with 10~20 points, and the highest IF: 54.
4, including Lancet Oncology, JAMA Oncology, Med and other international academic journals, and the results have been adopted by the United States NCCN, European ESMO international guidelines and China CSCO, CACA and other domestic guidelines for many times.
It has been funded by dozens of scientific research projects, including key projects of the National Natural Science Foundation of China, with a funding amount of more than 40 million
.
He is the chief editor of 2 monographs, authorized 10 invention patents, and has made keynote speeches at famous international academic conferences such as ASCO, ESMO, RWC for many times, and is Chinese mainland the first head and neck oncologist invited to the American Academy of Sciences for Otorhinolaryngology-Head and Neck Surgery Association to open courses
.
The research results were selected as one of the top 17 major advances in clinical oncology in the world by the American Society of Clinical Oncology ASCO in 2021, which was also the only research result in the field of head and neck cancer that year, and the only research result
from Chinese mainland.

Yurui

Associate Researcher

Dr.
You Rui is a nasopharyngeal physician, associate researcher, clinical postdoctoral fellow, master supervisor of Sun Yat-sen University Cancer Prevention and Treatment Center, secretary of the Youth Committee of the Nasopharyngeal Cancer Special Committee of Guangdong Anti-Cancer Association, won the excellent doctoral dissertation of Sun Yat-sen University, won the 35 under 35 national most potential young oncologist, won the special prize of the National Clinical Postdoctoral Research Competition, won the outstanding contribution award of the People's Daily "People's Good Doctor Golden Camellia Award", and was successfully selected into the first batch of special funding of the China Postdoctoral Science Foundation (in front of the station)
。 He has long focused on the clinical diagnosis and treatment of nasopharyngeal carcinoma and related translational research
.
By carrying out high-quality clinical trials, using multi-omics data integration mining, high-throughput sequencing, biological information analysis, molecular experiments and other technical means, the treatment mode of high-risk recurrent and metastatic nasopharyngeal carcinoma is optimized.
Innovate diagnosis and treatment strategies for recurrent and metastatic nasopharyngeal carcinoma; Discover new and efficient molecular targets for nasopharyngeal carcinoma recurrence and metastasis
.
A total of 12 first authors/authors have been published, including Med, Lancet Oncol, JAMA Oncol, Cancer Res, J Immunother Cancer, Theranostics, etc
.
The relevant research results have been adopted
by the Up to date clinical evidence-based medicine database and NCCN guidelines.
He has been invited to give oral reports and poster presentations
at international (AACR, ESMO-ASIA, etc.
) and domestic oncology conferences.

Related paper information

The original paper was published in Med, a journal owned by CellPress Cell Press.