The transition and current pattern of drug therapy for advanced gastric cancer

Ran Xue,Xin-Ran Song

1Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Department of Early Drug Development Center,Peking University Cancer Hospital&Institute,Beijing 100142,China.2School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China.

Ran Xue and Xin-Ran Song are the co-first authors of this paper.

Abstract Gastric cancer is one of the most common malignant tumors in the world.Its incidence ranks fifth among all malignant tumors worldwide and is the third leading cause of death among cancer patients.Surgery is currently considered to be the only radical treatment.However,the low rate of early diagnosis means that most patients have an advanced-stage disease at diagnosis which lost the chance of surgery.Therefore, the main treatment for advanced gastric cancer includes chemotherapy, targeted therapy, immunotherapy.The purpose of this study is to review the transition and current patterns of drug therapy for advanced gastric cancer and to provide assistance for subsequent clinical studies in advanced gastric cancer.

Keywords:advanced gastric cancer; treatment; perspectives

Background

Gastric cancer is one of the most common malignant tumors of digestive system.Globally, there are at least 950,000 new cases of gastric cancer every year, and gastric cancer ranks third in tumor-related mortality [1].In China, gastric cancer ranks second in incidence and mortality rate among malignant tumors and poses a serious threat to human health.Surgery remains the most effective treatment for gastric cancer.However, patients with advanced gastric cancer have lost the opportunity to undergo surgery and have a poor long-term prognosis.Since the discovery in the 1960s that patients with advanced gastric cancer could benefit from chemotherapy,chemotherapy has continued to play an important role as the cornerstone treatment modality for advanced gastric cancer for decades, although several iterations of chemotherapy drugs have changed.However, it is difficult to further improve the survival time of patients with advanced gastric cancer with traditional chemotherapy drugs, and its therapeutic effect has reached a bottleneck.There is an urgent need for new treatment modalities to change the current dilemma of advanced gastric cancer drug treatment.In recent years, immunotherapy and targeted therapy have gradually entered the historical stage of malignant tumor treatment with the development and depth of related research.The following is a review and discussion of the development and current problems of drug therapy for advanced gastric cancer at this stage.

Changes in the international diagnostic criteria for advanced gastric cancer

With the update of the treatment concept, the diagnostic criteria of advanced gastric cancer have constantly changed.The 7th edition of the American Joint Committee on Cancer Cancer Stage Manual [2],2010, updated the diagnostic criteria for advanced gastric cancer to define it as gastric cancer with distant metastasis (stage).The 8th edition of American Joint Committee on Cancer Cancer Staging Standard launched in 2017 [3] classified advanced gastric cancer by clinical diagnosis and pathological diagnosis and was divided into locally advanced gastric cancer (clinical stage A) and gastric cancer with distant metastasis (clinical stage B), the latter is consistent with the definition of pathological advanced gastric cancer.

Epidemiological characteristics of advanced gastric cancer in China

The proportion and mortality rate of advanced gastric cancer in China is significantly higher than those of other countries with a high incidences of gastric cancer in East Asia.In the past decade, although the proportion of advanced gastric cancer has decreased with better diagnosis and treatment power in China,there is still a grand gap with Japan and South Korea.Moreover, the age distribution of advanced gastric cancer in China was younger than that in all gastric cancer patients.In China, there are more stages of gastric cancer in young people, and mainly gastric cancer.Moreover, there is a heterogeneous gender distribution in advanced gastric cancer.The overall incidence in men is 2 to 4 times that in women.However, it is worth noting that in the young population with advanced gastric cancer,female patients accounted for more than 50%, which may be related to the higher level of estrogen in young women.In recent years, the location of gastric cancer had an obvious upward trend, but the primary site of advanced gastric cancer is still more common in the gastric sinus [4,5].

Exploration and development of drug therapy for advanced gastric cancer

Chemotherapy

Before the 1960s,the treatment of advanced gastric cancer was mostly supportive therapy.It was not until 1960 that 5-FU started the chemotherapy road of advanced gastric cancer, and after gradual exploration, it was found that patients with advanced gastric cancer could benefit from single-agent chemotherapy.Single-agent effective drugs include fluorouracil, cisplatin, anthracycline (doxorubicin and epirubicin), mitomycin C, and etoposide.In order to further improve the efficacy of advanced gastric cancer, scholars began to gradually use the combination of two or three drugs for chemotherapy.Later,2006 V325 study established the status of docetaxil combined with fluorouracil and cisplatin, and then to the later EOX regimen(capecitabine+epirubicin+oxaliplatin;REAL 2 study)and the 2008 SPIRITS study (S1 + cisplatin) [6-8].Chemotherapy has become the basis of drug treatment for advanced gastric cancer.At present,regarding the application of chemotherapy in advanced gastric cancer,due to the low response rate of single-agent chemotherapy,single-agent chemotherapy is generally not recommended for advanced gastric cancer.However, given the low toxic response of single-agent chemotherapy, single-agent chemotherapy is still suitable for those patients with advanced gastric cancer with poor physical condition and unable to tolerate strong chemotherapy.Moreover, the more feasible application mode of single-agent chemotherapy is intermittent maintenance therapy with intense chemotherapy.Due to its high objective response rate (ORR), three-drug combination chemotherapy has become the priority for these patients with the best option for these patients to prioritize to achieve better response efficiency and the longest survival time with improved quality of life.

Advanced gastric cancer has undergone a long period of chemotherapy exploration.Although a number of clinical studies established with yew or platinum combined fluorouracil drug strategy, different choices will increase the survival of advanced gastric cancer patients from 3 to 4 months to 13 months, but the chemotherapy platform always cannot surpass, today, simple traditional chemotherapy drugs are difficult to make advanced gastric cancer patients have further improved survival time, its treatment effect has reached the bottleneck.It is urgent for a new treatment mode to change the dilemma of drug treatment for advanced gastric cancer.With the continuous progress of molecular biology research,molecular targeted therapy and immunotherapy have gradually stepped onto the historical stage of anti-tumor therapy, and become the hot spot of comprehensive treatment of advanced gastric cancer.

Targeted therapy

Nowadays, targeted therapy has become an indispensable part of advanced gastric cancer treatment.Currently, the mainstream therapeutic targets for advanced gastric cancer include human epidermal growth factor receptor-2 (HER-2), fibroblast growth factor receptor 2b (FGFR2b), gastric-specific membrane protein (Claudin 18.2), anti-vascular endothelial growth factor receptor, and amplification of MET, the gene encoding c-MET protein.

HER-2-positive gastric cancer accounts for approximately 20%of all gastric cancer patients, and in 2010, the ToGA trial [9] published in The Lancet suggested that trastuzumab could be a new option in the treatment of HER-2-positive gastric cancer.In subsequent studies,trastuzumab in combination with chemotherapy was found to be significantly better than chemotherapy alone in terms of efficacy and safety,with first-line treatment with trastuzumab in combination with different chemotherapeutic agents [10, 11] increasing the ORR of HER-2-positive gastric cancer to more than 60% and achieving an OS of 16.0 to 20 months.Trastuzumab has also been used to varying degrees in second-line therapy [12], cross-line therapy [13],conversion and neoadjuvant chemotherapy [14, 15].

After establishing its use in HER-2-positive advanced gastric cancer,the choice of anti-HER 2 agents after first-line therapy has been uncertain.The quest for the best treatment option for HER-2-positive gastric cancer has not stopped.Several antibody-drug couples (ADCs)and bispecific antibody drugs have emerged in recent years.In early 2021, the US Food and Drug Administration approved the antibody-coupled drug Enhertu (DS-8201) for extended indications in patients with HER2-positive locally advanced or metastatic gastric cancer and gastroesophageal junction adenocarcinoma treated with trastuzumab.The DESTINY-Gastric01 study [16] showed that DS-8201 significantly improved the objective remission rate(51%:14%,P＜0.001) and overall survival time (12.5 months:8.4 months,P= 0.01) in patients with HER-2-positive gastric cancer in the third line and beyond compared to the investigator’s choice of treatment regimen.DS-8201 officially entered China in 2021 to begin a bridging trial for efficacy validation in the Chinese population.Disitamab vedotin(RC48-ADC)is also a novel antibody-drug coupling.Studies have shown [17] that the ORR was 24.8% in patients with HER-2 overexpression, locally advanced or metastatic gastric or gastroesophageal junction cancer.The median progression free survival (PFS) and overall survival (OS) were 4.1 months and 7.9 months.This study concluded that RC-48 is a targeted drug with efficacy and safety, and on June 9, 2021, RC-48 became the first Chinese ADC approved for marketing in China.ARX788 is an HER-2 targeted coupled ADC drug, currently granted orphan drug status by the FDA, in studies [18], HER-2-positive patients with advanced gastric/gastroesophageal junction adenocarcinoma were ineffective to prior standard treatment with trastuzumab.The confirmed objective response rate is 37.9% and the disease control rate is 55.2%.With a median follow up of 10 months, the median progression-free survival and overall survival are 4.1 and 10.7 months.ARX788 was well tolerated and had good antitumor activity in patients.Zanidatamab(ZW25) is an HER-2 targeting bispecific antibody that doubly blocks HER-2 signaling.In the study[19],the trialists treated HER2+gastric cancer patients (90% were treated with HER2-targeted therapy) for 3/4 lines.The results showed that ZW25 monotherapy in HER-2-positive gastric cancer patients had an ORR of 33% and a disease control rate(DCR)of 61%,with better efficacy in combination with chemotherapy, with an ORR of 54% and an even higher DCR of 79%.

FGFR2b is overexpressed in approximately 30% of patients with HER-2-negative gastroesophageal cancer, making FGFR2b an equally interesting therapeutic target.Bemarituzumab is the first and only investigational therapy targeting FGFR2b positive tumors.The results of the study [20] showed a significant prolongation of PFS in the Bemarituzumab combined with chemotherapy group compared to the chemotherapy alone group, with median OS not reached in the combination group and 12.9 months in the chemotherapy group, in addition to an objective remission rate ORR of 53% and 40% in the two groups, respectively.

Claudin 18.2, a gastric-specific membrane protein, is considered a potential therapeutic target for advanced gastric cancer as Claudin 18.2 target expression is present in 50%-80% of gastric cancer patients.Zolbetuximab (IMAB362), a class of monoclonal antibody drugs against the Claudin 18.2 target, in the 2019 phase II clinical results [21] showed that Zolbetuximab in combination with chemotherapy in first-line treatment of Claudin 18.2-positive advanced gastric/gastroesophageal junction adenocarcinoma met the important primary endpoint in the phase II clinic.mPFS was prolonged by 3 months and OS by 7 months compared to the control group, especially for the CLDN18.2 high expression group.CT041 is a humanized anti-Claudin 18.2 autologous CAR-T cell injection to be developed for the treatment of advanced gastric/esophagogastric junction adenocarcinoma with positive Claudin 18.2 expression and progression or recurrence after previous systemic therapy, among other indications.The study results [22] showed that the ORR and DCR reached 48.6%and 73.0%,respectively.The 6-month duration of response rate was 44.8%.The 6-month duration of response rate was 44.8%.In patients with gastric cancer , the ORR and DCR reached 57.1% and 75.0%.In August 2020, the product was first approved in China for the indication of Claudin18.2 positive solid tumors.

With a positive expression rate of approximately 17.6% for vascular endothelial growth factor and 32.2% to 52.9% for anti-vascular endothelial growth factor receptor in gastric cancer tissues,respectively,blocking tumor angiogenesis has become one of the goals to achieve anti-tumor therapy.Based on the results of the global priority registration clinical trials REGARD and RAINBOW studies,the anti-angiogenic drug ramucirumab (Ramucirumab) became the first and so far the only targeted drug approved for second-line treatment of advanced gastric cancer in 2014 and was included in the first class of recommended drugs in global treatment guidelines [23, 24].In addition, based on the results of the RAINBOW-Asia trial, it was approved as a second-line treatment for advanced gastric cancer by the Chinese State Drug Administration (NMPA) in March 2022, and the study found that this + paclitaxel second-line treatment had a significant PFS benefit for patients with advanced gastric cancer in the Chinese population, and the OS benefit was consistent with the global population [25].The 2022 Chinese Society of Clinical Oncology guidelines for second-line gastric cancer treatment added ramucirumab in combination with paclitaxel (Class 1A evidence and Class I recommendation).Anti-angiogenic targeted therapies represented by ramucirumab are gradually taking over in advanced gastric cancer.

Amplification of MET, the gene encoding the c-MET protein, is present in only 5%-10% of gastric cancer patients.cMet inhibitor TPX-0022 was granted orphan drug status by the Food and Drug Administration, but clinical trial results of targeted drugs against this pathway in gastric cancer patients have been unsatisfactory [26].

During the study of molecularly targeted drugs related to gastric cancer, investigators have typed the gastric cancer genome and therapeutic targets.We recognize that gastric cancer has high molecular heterogeneity [27], which leads to the emergence of drug resistance [28] in patients and variation in therapeutic targets [29]after successive treatments.Therefore, the breakthrough of drug resistance, the evaluation of molecular targets, and the study of drugs targeting low expression of the targets in the backline therapy will be the breakthrough point in the treatment of advanced gastric cancer.On the basis of theory first, researchers should compare around clinical treatment results.After opening the door of molecular targeted therapy in 2010, a large number of researchers have poured in.However, there are many failures and few successes in gastric cancer research.Now, molecular-targeted therapy has entered a new era.How to arrange the troops and find a breakthrough is an important factor to be considered in the design of subsequent clinical studies.

Immunization therapy

The KEYNOTE-012 study published by Lancet Oncology in June 2016 officially opened the road of immunotherapy for advanced gastric cancer.KEYNOTE-012 was shown for the first time to demonstrate the considerable antitumor activity and controlled treatment-related adverse effects of pabolizumab monotherapy in advanced gastric cancer [30].In view of the considerable efficiency of immunotherapy in posterior line treatment, scholars gradually explored the third-line and further-line treatment of advanced gastric cancer.Since then,clinical research has shifted to front-line application and combined therapy strategies.

In 2017 KEYNOTE-059 study [31], Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment.Objective response rate was 11.6%, with complete response at 2.3%.Median (range)response duration was 8.4 months.Objective response rate and median (range) response duration were 15.5% and 16.3 months and 6.4% and 6.9 months in patients with PD-L1-positive and PD-L1-negative tumors, respectively.In the concurrent clinical trial ATTRACTION-2 [32], 12-month overall survival rates were 26.2%with nivolumab and 10.9% with placebo.Based on the study data of KEYNOTE-059 and ATTRACTION-2 reported in 2017, the US Food and Drug Administration (FDA) approved the indication [33, 34] of pabizzumab and Nulumab for the treatment of advanced gastric cancer in September 2017.

But immunosuppressants in advanced gastric cancer forward to the second line of clinical trials, KEYNOTE-061 research [33] suggests that single-agent immunotherapy in advanced gastric cancer result is not ideal.Median overall survival was 9.1 months with pembrolizumab and 8.3 months with paclitaxel.Median progression-free survival was 1.5 months with pembrolizumab and 4.1 months with paclitaxel.So the scholars to further mining double immune combination effect in the second line of advanced gastric cancer treatment, based on Checkmate 032 research data show that single-agent immune or double immune have certain antitumor activity, 12-month OS rates were 39% (single-agent immune), 35%(double immune) [34].

Although the results of the second-line study made us confused, the researchers did not abandon the attempt of immunosuppressive agents in the first-line treatment of advanced gastric cancer.Both KEYNOTE-059 in 2017 and KEYNOTE-062 in 2019 showed that the single-agent immunotherapy group was significantly better than the chemotherapy group in the first-line advanced gastric cancer population.In March 2020, Nevoluzumab was approved in China for advanced gastric cancer receiving second-line or above treatment,becoming the first PD-1 mmab approved in the field of gastric cancer in China.In addition, the combination treatment data of immunization and chemotherapy are constantly updated.The CheckMate-649 study of median follow-up for OS was 13.1 months(IQR 6.7-19.1) for nivolumab plus chemotherapy and 11.1 months(5.8-16.1)for chemotherapy alone[35].In the ATTRACTION-4 study,median overall survival at the final analysis was 17.45 months in the nivolumab plus chemotherapy group and 17.15 months in the placebo plus chemotherapy group [36].Their results affirm the role of immunocombination chemotherapy in the first-line treatment of gastric cancer.The 2021 ORIENT-16 study was presented at the European Society for Medical Oncology conference.The domestic cindilizumab also confirmed its role in the first-line treatment of gastric cancer.The overall ORR was 58.2%.Compared with the data of CheckMate-649, the OS time was even longer.In patients with PD-L1 CPS 5, the median PFS time and OS time were 7.7 months and 18.4 months, respectively, which were significantly prolonged compared with chemotherapy alone.

In addition to the exploration of immune single-agent or combination chemotherapy in the first, second and third lines,scholars have also begun to gradually begin to explore immunosuppressive agents and targeted combination chemotherapy.A series of data from REGONIVO 2019 study[37]and EPOC17062020 study [38] showed the prospect of immunocombination targeted therapy in advanced gastric cancer.Whether the combination of multiple models and the screening of effective population can further improve the efficacy is the future research direction of precision treatment.

How to arrange the troops for the treatment of advanced gastric cancer

Overall, the development of treatment strategies for patients with advanced gastric cancer should improve the quality of patient life and prolong survival time through the joint participation of multiple disciplines.With the establishment of the status of immunotherapy in the first-line treatment of advanced gastric cancer, the overall clinical layout of advanced gastric cancer has therefore undergone tremendous changes.In addition, the continuous emergence of innovative drug targets and cellular immunotherapy has also brought new major breakthroughs in the treatment of advanced gastric cancer,bringing hope to more patients with advanced gastric cancer.

Although these treatments have benefited many patients, we still face some difficulties and challenges.The existence of drug resistance in targeted therapies is a huge obstacle to the expansion of targeted therapies in clinical applications [39].The author suggests exploring the pharmacological and physical properties of the drugs themselves while studying the resistance of targeted drugs and combining the results of clinical trials to find mechanisms to overcome resistance.Screening for appropriate biomarkers is the key to achieving drug therapy and is also fundamental to achieving individualized treatment.Screening of therapeutic targets for targeted therapies is also one of them.The duration of immunotherapy and immune-related adverse events are not yet controllable.The duration of treatment for patients can vary from 4 cycles to 1-2 years, and treatment outcomes are variable.There is a need to explore the duration of treatment to obtain the maximum effect.The mechanisms of multiple immune-related adverse events are unclear.They need to be explored in clinical studies, and trialists need to be offered prophylactic interventions and treatments.

Nowadays, combination drugs and multi-target drugs are in the public eye They bring more comprehensive efficacy and are a popular direction of research today.However, as more clinical data are generated, they also reveal many problems.The increase in therapeutic agents can bring more adverse effects [40].The mechanism of action between therapeutic agents may lead to unexpected treatment outcomes.The introduction of small doses may be one of the solutions to the problem, but there will be reduced therapeutic effects that need to be explored in depth by researchers.

At present, a number of domestic drugs have also announced their high-quality research results, which marks that China’s drug research and development and gastric cancer research with Chinese patients has stepped on the international stage.And patient-centered translational research and high-throughput sequencing will provide more powerful basis for clinical drug resistance mechanism exploration and biomarker stratification screening of candidate groups.