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Professor Xu Ruihua: 2022 Top 10 Digestive Tract Tumor Clinical Research Progress and Outstanding Problems

 Last Update: 2023-02-03
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In 2022, digestive tract tumors will make progress
in immunotherapy, precision targeted therapy, and ctDNA to guide treatment decisions.
"NEJM Medical Frontiers" invited the team of Professor Xu Ruihua of the Department of Internal Medicine of Sun Yat-sen University Cancer Prevention and Treatment Center to write an article to review the progress and problems
to be solved in the treatment of esophageal, gastric and colorectal cancer.

NEJM Medical Frontiers is a collaboration between Jiahui Medical Research and Education Group (J-Med) and the New England Journal of Medicine (NEJM
).
For the fifth consecutive year, we have launched a clinical research inventory of all important disease areas, so stay tuned
.

LUO Huiyan,HE Ye,XU Ruihua*

Department of Internal Medicine, Cancer Center, Sun Yat-sen University

*Corresponding author

If esophageal cancer

treatment ushered in the era of immunotherapy in 2021, then immunotherapy combined with radiotherapy/chemotherapy neoadjuvant therapy made further progress
in 2022.
The position of immunotherapy combined chemotherapy in the first-line treatment of advanced esophageal cancer has been consolidated again, the selection of PD-1 monoclonal antibody has become increasingly diversified, and the initial efficacy of immune combination therapy in advanced second-line therapy is remarkable
.

The optimal treatment mode in the perioperative period continues to be explored, and neoadjuvant chemoradiotherapy combined with surgery is currently the standard treatment for locally advanced operable esophageal cancer, but its recurrence rate is still high, and the mode of neoadjuvant therapy has been controversial
。 The JCOG 1109 study is a randomized controlled phase 3 clinical trial comparing neoadjuvant chemotherapy CF (cisplatin + fluorouracil [5-FU]), neoadjuvant chemotherapy DCF (docetaxel + cisplatin + 5-FU), neoadjuvant chemotherapy CF plus radiotherapy for locally advanced esophageal cancer, with the primary endpoint of overall survival (OS), the results of which were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Oncology Symposium (ASCO GI) [1].

。 Compared with the neoadjuvant chemotherapy CF group, the median overall survival (mOS; not achieved vs.
4.
6 years) and median progression-free survival (mPFS; not reaching vs.
2.
7 years) are significantly extended
.
There were no significant differences
in OS and PFS between the neoadjuvant chemotherapy CF group and the neoadjuvant chemotherapy CF plus radiotherapy group.
The study also presents new challenges
to the standard treatment model of neoadjuvant chemoradiotherapy before surgery for esophageal cancer.

For locally advanced resectable esophageal squamous cell carcinoma, there have been more and more research on perioperative immunotherapy combined with chemotherapy or chemoradiotherapy, which has also become the key research direction
of locally advanced esophageal cancer.
The results of the Phase 1b SCALE-1 trial [2] presented at the 2022 American Society of Clinical Oncology (ASCO) Congress showed that teripulimab + short-cycle neoadjuvant chemoradiotherapy (paclitaxel + carboplatin) had a major pathological response (MPR) rate of 80% and a complete pathological response (pCR) rate of 55%
in patients with locally advanced resectable esophageal squamous cell carcinoma.
Another teripulimab + neoadjuvant chemoradiotherapy (paclitaxel + cisplatin) in the treatment of locally advanced incisible esophageal squamous cell carcinoma had similar results [3], with an MPR rate of 77% and a pCR rate of 54%.

The 2022 European Society of Medical Oncology (ESMO) Annual Meeting reported a phase 2 clinical trial of a new drug sotigalimab (CD40 agonist) combined with chemoradiotherapy (paclitaxel + carboplatin) neoadjuvant therapy for esophageal cancer [4], with a pCR rate of 36%, including adenocarcinoma pCR rate of 30%, squamous cell carcinoma pCR rate of 60%, and total MPR rate of 64%.

It is worth noting that most of the above neoadjuvant immunotherapy studies are small sample studies, and the pCR rate between the studies has certain differences, and the best combination therapy strategy, combination therapy timing and combination therapy sequence are still unclear, and more large samples and randomized controlled trials are needed to explore and confirm, and long-term survival results need to be further determined
.

The status of advanced first-line immune combination therapy has been consolidated, and the selection of PD-1 monoclonal antibody CheckMate 648, KEYNOTE-590, JUPITER-06, ESCORT-1, and ORIENT-15 studies have clearly shown that first-line immune combination chemotherapy can bring significant survival benefits to patients with advanced esophageal cancer [ 5-9], PD-1 antibody combined with chemotherapy has become the new standard regimen for first-line treatment of advanced esophageal cancer (related reading: "The Year of the Tiger Opens the Door: Immunotherapy Prolongs the Survival of Patients with Advanced Esophageal Squamous Cell Carcinoma, Chinese Team is the Main Member of the NEJM Paper").

The 2022 ASCO Annual Meeting updated the CheckMate 648 study [10], nivolumab in combination with chemotherapy, The nivolumab plus ipilimumab dual immunotherapy group achieved longer second-line progression-free survival (PFS2) and duration of response (DOR) than chemotherapy alone, further supporting the use of immunotherapy in the first-line standard of
treatment for esophageal cancer.
In addition, the positive results of double exemption treatment in CheckMate 648 also suggest that some specific esophageal cancer patients are expected to receive "dechemotherapy" treatment
.

RATIONALE 306 is a randomized, global, placebo-controlled, double-blind Phase 3 clinical trial that explored the first-line treatment of advanced/metastatic esophageal squamous cell carcinoma with tislelizumab plus chemotherapy versus chemotherapy alone, with the primary endpoint being overall survival in the intention-to-treat population (ITT
).
。 The 2022 European Society of Medical Oncology-World Congress on Gastrointestinal Oncology (ESMO-WCGI) released data from RATIONALE 306 interim analysis [11], with an mOS of 17.
2 vs.
10.
6 months (hazard ratio [HR], 0.
66) and an mPFS of 7.
3 vs.
5.
6 months (HR, 0.
62)
for tislelizumab plus chemotherapy and a control group, respectively.
Regardless of PD-L1 expression, patients can benefit
from immunotherapy regimens.

The 2022 ESMO Asia Annual Meeting reported data from the Asian subgroup of the study [12], which was consistent
with the population-wide results.
The mOS of tislelizumab plus chemotherapy versus chemotherapy alone was 18.
3 vs.
11.
5 months (HR, 0.
67) and mPFS was 7.
2 vs.
5.
6 months (unstratified HR, 0.
62)
in the Asian subgroup.

The ASTRUM-007 study is a randomized, controlled, double-blind, multicenter phase 3 clinical trial led by Professor Huang Jing of Cancer Hospital of the Chinese Academy of Medical Sciences, which explores the efficacy and safety of domestic PD-1 monoclonal antibody serplulimab combined with chemotherapy alone for the first-line treatment of PD-L1-positive (comprehensive positive score [CPS]≥1) locally advanced/metastatic unresectable esophageal squamous cell carcinoma.
The chemotherapy regimen used a dose-intensive FP (cisplatin + 5-FU) regimen, with the primary endpoints of OS and PFS
in the ITT population.

The study was presented orally at the 2022 Chinese Society of Clinical Oncology (CSCO) Congress and ESMO ASIA 2022 [13], and the results showed significant improvements in OS and PFS in the serplulimab plus chemotherapy alone group, with mOS of 15.
3 vs.
11.
8 months (HR, 0.
68) and mPFS of 5.
8 vs.
5.
3 months (HR, 0.
60), respectively to achieve study double-endpoint efficacy
.
Subgroup analysis showed that patients with high CPS scores benefited more significantly, with mPFS of 7.
1 vs.
5.
3 months (HR, 0.
48; P<0.
0001) and mOS of 18.
6 vs.
13.
9 months (HR, 0.
59; P=0.
0082) in the ≥serplulimab group versus chemotherapy alone
, respectively.

The RATIONALE 306 and ASTRUM-007 studies add strong evidence to the first-line treatment of advanced esophageal squamous cell carcinoma in combination with chemotherapy, providing a new PD-1 antibody drug option
.
We also saw that in these seven studies, not all patients benefited from long-term survival with first-line immunotherapy plus chemotherapy
.
How to further expand the population benefiting from immunotherapy so that more patients can benefit from long-term survival is a problem
that we should pay close attention to and urgently solve in the future.

In the second-line treatment of advanced esophageal cancer, KEYNOTE-181, ATTRACTION-3, RATIONALE 302 and other studies have laid a solid foundation
for second-line immunotherapy to become the standard program.
Considering the limited efficacy of monotherapy immunotherapy, models such as immunotherapy combined with anti-angiogenesis, targeted therapy and chemotherapy are also actively being explored in 2022
.
Compared with monotherapy, combination therapy has improved its efficacy, but more research is needed to verify these preliminary results, explore the best combination approach, and reverse immune resistance
.

Preliminary data from a Phase 2 study published by ESMO 2022 [14] showed that the targeted combination regimen of regorafenib combined with nivolumab had an objective response rate (ORR) of 43%, a disease control rate (DCR) of 73.
3%, and an mPFS of 6.
9 months in the second-line treatment of advanced esophageal squamous cell carcinoma
。 The ORR in PD-L1-positive people (tumor ratio score [TPS] ≥1%) was 83%, suggesting that regorafenib in combination with nivolumab has good efficacy in patients with esophageal squamous cell carcinoma and is worthy of continued validation
in larger studies.

A Phase 1b trial explored the safety and efficacy of the FGFR inhibitor futibatinib in combination with pembrolizumab in the treatment of advanced or metastatic solid tumors, with primary endpoints of dose-limiting toxicity at the feasibility stage and ORR
in the dose-expansion phase.
Among them, esophageal cancer cohort data were presented at the 2022 ESMO Annual Meeting [15].

The results showed that no dose-limiting toxicity
was observed with futibatinib (20 mg once daily) in combination with pembrolizumab (200 mg once every 3 weeks) in esophageal cancer patients.
In the cohort (Cohort A) that did not receive immunotherapy, the ORR was 44% and the DCR was 78%; In the immunotherapy relapsed refractory cohort (cohort B), the ORR was 20% and the DCR was 60%.

Of note, cohorts A and B both included patients
with esophageal adenocarcinoma and squamous cell carcinoma.
The study preliminarily showed that futibatinib combined with pembrolizumab has good tolerability and antitumor activity, and is suitable for patients with esophageal cancer (whether adenocarcinoma or squamous cell carcinoma) who are refractory to immunotherapy
.

In terms of immune + targeted + chemotherapy triple therapy, a phase 2 trial reported by ASCO GI in 2022 evaluated the efficacy of carrelizumab combined with apatinib and irinotecan in the second-line treatment of advanced esophageal squamous cell carcinoma [16], and in 16 patients with efficacy evaluation, the ORR reached 56.
25% and the DCR reached 81.
25%, and mPFS and mOS data were not mature
.
The efficacy data are encouraging, and we look forward to subsequent data releases
.

Gastric cancer immunotherapy rewrites the first-line treatment model for advanced gastric cancer

.

With the rapid development of new anti-HER2 drugs, the whole treatment pattern of HER2-positive gastric cancer is also changing, and the survival prognosis of such patients is expected to be further improved
.
Emerging therapies such as antibody-drug conjugate (ADC) drugs and chimeric antigen receptor T cell (CAR T cell) therapy have made significant progress in the precision treatment of gastric cancer, but more translational studies and clinical trials are needed to confirm their mechanisms and efficacy, and more trials are needed to develop new targets/drugs to further improve survival benefits
.

The status of first-line immunotherapy for advanced gastric cancer has been consolidated, and the optimization of the regimen has become a new standard first-line treatment for advanced gastric cancer, regardless of HER2-negative or HER2-positive gastric cancer
.
Clinical studies such as CheckMate 649, ORIENT-16, and KEYNOTE-811 have shown that immunotherapy combined with chemotherapy can significantly improve the survival benefit of patients [17-19].

。 In 2022, Nature published updated 2-year follow-up data on CheckMate 649 [20], mPFS in patients with PD-L1 CPS≥5 after nivolumab was added (8.
1 vs.
6.
1 months; HR, 0.
70) and mOS (14.
4 vs.
11.
1 months; HR, 0.
70) significantly lengthened
.
Results were similar for all randomized patients, mPFS (7.
7 vs.
6.
9 months; HR, 0.
79) and mOS (13.
8 vs.
11.
6 months; HR, 0.
79) was also significantly prolonged
in the nivolumab plus chemotherapy group.
In the data of 208 Chinese subgroup patients updated at the 2022 ESMO GI Conference, significant benefits were seen in the nivolumab combination chemotherapy group in OS, PFS, and ORR [21].

In addition, a global multicenter phase 3 clinical trial, RATIONALE-305, explored the efficacy of tislelizumab in combination with chemotherapy in the first-line treatment of HER2-negative advanced gastric cancer, and the interim analysis data obtained positive results
。 The KEYNOTE-859 trial published positive top-line results that significantly prolong OS in
patients with HER2-negative locally advanced unresectable/metastatic gastric cancer regardless of PD-L1 expression level.
It can be seen that the dominant position of immunotherapy combined chemotherapy in the first-line treatment of advanced gastric cancer has been affirmed again, and it is also expected to bring new PD-1 monoclonal antibody options
to patients.

In 2022, the optimization and efficacy improvement of gastric cancer immunotherapy are still being explored, including dual immunotherapy, double immunization combined chemotherapy, immune combination targeting or other immunomodulators, etc.
, and whether the effect of immune combined with other types of treatment can be better than the current standard treatment remains to be confirmed
by more phase 3 clinical trial results.

In the CheckMate 649 study, the combination of anti-PD-1 and anti-CTLA-4 drugs (nivolumab + ipilimumab) failed to improve treatment outcomes
compared with conventional chemotherapy.
The AIO-STO-0417 (Moonlight) study is a four-arm phase 2 clinical trial for HER2-negative metastatic/locally advanced gastric or gastroesophageal junction adenocarcinoma [22].

。 In this study, enrolled patients were randomized to nivolumab + ipilimumab + FOLFOX (calcium folinate + 5-FU + oxaliplatin) concurrent chemotherapy (A/A1) or FOLFOX induction chemotherapy followed by sequential nivolumab + ipilimumab (A/A2 group) or FOLFOX chemotherapy (B group) or non-randomized to FLOT (5-FU + calcium folinate + oxaliplatin + docetaxel) + nivolumab (group C), The primary endpoint was the half-year PFS rate
.

The 2022 ASCO Annual Meeting presented analysis data from groups A and B [22], and there was no difference
in PFS (5.
7 vs.
6.
6 months), OS (10 vs.
12 months), or ORR (45% vs.
48%) between chemotherapy and chemotherapy alone.
The 2022 ESMO Annual Meeting further announced relevant clinical data for the A1/A2 group [23].

The results showed that the half-year PFS rate was 57% in the double-free combination chemotherapy group (A1 group), 28% in the chemotherapy sequential double-exemption group (A2 group) (P=0.
012), and the median PFS was 8.
4 vs.
4.
0 months (P=0.
006),
respectively.
The median OS was not yet reached in the A1 group and 9.
1 months in the A2 group, with an ORR of 47% vs.
30%,
respectively.
However, in this study, the incidence of grade 3 or above adverse reactions in the A1 group was 70%, and the A2 group was 43.
3%, although the toxicity of the sequential treatment group was low, but considering the efficacy, the first-line chemotherapy sequential double-exemption treatment
was not supported for the time being.

The combination of lenvatinib + pembrolizumab + chemotherapy has been explored
in a phase 2, multicluster, open-label LEAP-005 trial.
Results from the gastric cancer cohort showed that in patients with gastric cancer who had previously received at least two lines of therapy, the ORR was 10 percent and the DCR was 48 percent, and toxicity was tolerated [24].

LEAP-015 is a global, randomized controlled, open-label, two-part Phase 3 clinical trial exploring the safety and efficacy
of lenvatinib + pembrolizumab + chemotherapy (mFOLFOX [calcium folinate + 5-FU + oxaliplatin] or CAPOX) as first-line treatment for advanced/metastatic gastroesophageal adenocarcinoma.

Preliminary data from Part 1 (safety lead-in phase) of the LEAP-015 study were reported at the 2022 ESMO Annual Meeting [25], with a controllable safety profile of lenvatinib + pembrolizumab + chemotherapy with preliminary antitumor activity (ORR, 73%; DCR，93%）
。 Part 2, which is recruiting patients, will evaluate the efficacy and safety
of lenvatinib + pembrolizumab + chemotherapy versus first-line chemotherapy.

Novel anti-HER2 drugs for advanced gastric cancer are in full bloom, HER2 is an important target for gastric cancer treatment, and ToGA studies [26] and KEYNOTE-811 [19] have rewritten the first-line treatment guidelines
for HER2-positive advanced gastric cancer 。 In recent years, new targeted drugs against HER2 have developed rapidly, and monoclonal antibodies (such as margetuximab), new bispecific antibodies (such as ZW25, KN026), ADC (such as T-DXd, disitamab vedotin) and other drugs are prescribedA series of studies and encouraging results are a potential new option
for patients with HER2-positive gastric cancer.

Margetuximab is an anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab, but its Fc segment has a higher affinity for CD16A after special modification, which can recruit CD16A-expressing natural killer cells, macrophages and monocytes, further promoting antibody-dependent cell-mediated cytotoxicity (ADCC).

。 The MAHOGANY study explored the efficacy of margetuximab in combination with the anti-PD-1 antibody retifanlimab in first-line therapy in patients with advanced gastroesophageal adenocarcinoma [27], in which data from cohort A showed that the ORR was 53% and the DCR was 73%
in the margetuximab combined with retifanlimab treatment group.

ZW25 (zanidatamab) is a HER2-targeted bispecific antibody that binds
to both HER-2 extracellular domains II (ECD2) and IV (ECD4).
In a phase 2 trial of patients with advanced/metastatic HER2-positive gastric adenocarcinoma, first-line treatment with ZW25 plus chemotherapy (CAPOX or FP) resulted in an ORR of 75 percent, mDOR of 16.
4 months, and mPFS of 12.
0 months [28].

The 2022 ASCO Annual Meeting announced the results of a Phase 1b/2 clinical trial of ZW25 combined with tislelizumab and CAPOX chemotherapy for the first-line treatment of HER2-positive advanced gastric cancer, with an ORR of 75.
8%, a DCR of 100%, and an mPFS of 10.
9 months [29].

A global phase 3 study, HERIZON-GEA-01, is ongoing to evaluate the efficacy and safety of ZW25 in combination with chemotherapy plus or without tislelizumab versus trastuzumab in patients with metastatic HER2-positive gastroesophageal adenocarcinoma in the first line [30].

KN026 is another HER2-targeted bispecific antibody that also binds
to HER2 extracellular domains II and IV 。 Preliminary data from a Phase 2 trial presented at the 2022 ESMO Annual Meeting suggest that KN026 in combination with KN046 (PD-L1 and CTLA-4 bispecific antibodies) has a significant efficacy and tolerable safety profile in patients with HER2-positive gastric/gastroesophageal junction cancer who have not previously been treated [31], but further evidence of the efficacy
of KN026 plus KN046 versus standard care is needed in larger samples.
The exploration of anti-HER2 bi-antibody and immune bi-antibody combination therapy mode provides the possibility
of first-line chemotherapy for gastric cancer in the future.

DESTINY-Gastric01 [32] and RC48-C008 [33] laid the foundation
for the application of ADC drugs DS8201 and vedicitumab in the post-line treatment of advanced gastric cancer 。 The 2022 ESMO Annual Meeting published updated data from the DESTINY-Gastric02 study [34], DS-8201 second-line monotherapy for HER2-positive Western advanced gastric cancer with positive results with a confirmed objective response rate (cORR) of 41.
8%, mPFS and mOS of 5.
6 and 12.
1 months
, respectively 。 Currently, the DESTINY-Gastric06 bridging trial in China and the second-line randomized controlled trial of DESTINY-Gastric04 are ongoing, and the DS8201 first-line combination chemotherapy or combination chemotherapy and immunotherapy randomized controlled trial is also underway
.

The above research suggests that the development of new anti-HER2 drugs has brought new hope for the treatment of advanced positive gastric cancer, ADC drugs have broken the dilemma of late-line treatment of advanced HER2-positive gastric cancer, achieved a breakthrough in OS for one year, and new antibody drugs are also exploring whether the use of first-line combined immunity can bring better therapeutic effects and survival benefits
.

With the continuous application and popularization of genetic testing, clinical trials of biomarker-guided precision targeted therapy are also actively being carried out
.
In addition to HER2 targets, new target drugs such as Claudin-18.
2, FGFR, and VEGFR are used as targeted therapies for the treatment of gastric cancer, and clinical efficacy has gradually emerged
.

Targeted therapy for Claudin 18.
2 (CLDN18.
2) has great potential and value
in gastric cancer.
Previous phase 2 FAST trials have shown [35] that zolbetuximab, a CLDN18.
2 chimeric IgG1 monoclonal antibody combined with standard first-line chemotherapy, significantly improves PFS and OS in patients with CLDN18.
2-positive
gastric or gastroesophageal junction cancer 。 Currently, two Phase 3 studies, SPOTLIGHT (NCT03504397) and GLOW (NCT03653507), evaluate the efficacy
of zolbetuximab in combination with mFOLFOX6 and zolbetuximab in combination with CAPOX as first-line treatments for CLDIN-18.
2-positive and HER2-negative advanced gastric cancer or gastroesophageal junction cancer, respectively.
Recently, positive top-line results have been reported in SPOTLIGHT and GLOW studies, which further support CLDN18.
2 monoclonal antibody as a new and effective targeted therapy
for gastric cancer.

In addition, the mid-phase analysis data of CLDN18.
2-specific CAR T cells in the treatment of gastrointestinal tumors by Professor Shen Lin's team of Peking University Cancer Hospital showed that its ORR and DCR in gastric cancer patients reached 57.
1% and 75.
0%, respectively, and the 6-month OS rate was 81.
2%.

CLDN18.
2 CAR T-cell therapy achieved considerable ORR improvement in gastric cancer, becoming a landmark event
for solid tumor cell immunotherapy.

Fruquintinib is a highly selective VEGFR family kinase inhibitor originally developed in China, and its targets are VEGFR1, 2 and 3
.
Fruquintinib was approved by China's National Medical Products Administration in September 2018 for the third-line treatment
of patients with metastatic colorectal cancer.
In a phase 1b/2 trial, fruquintinib in combination with paclitaxel was used as a second-line treatment for advanced gastric cancer to achieve mPFS at four months and mOS at 8.
5 months [37].

Recently, the Chinese phase 3 FRUTIGA study led by the author's team led by fruquintinib combined with paclitaxel versus paclitaxel single-agent second-line treatment for gastric cancer achieved positive top-line results, in which fruquintinib combined with paclitaxel group PFS was significantly improved, and fruquintinib is expected to provide a potential new oral treatment option
for second-line gastric cancer patients.
The detailed results of the study are to be published at a later date
.

Colorectal Cancer

In 2022, the research data of immunotherapy in DNA mismatch repair defect/high-frequency microsatellite instability (dMMR/MSI-H) locally advanced colorectal cancer are encouraging
.
Circulating tumor DNA (ctDNA) detection is expected to assist the postoperative clinical treatment decision of locally advanced colorectal cancer, but the detection method still needs to be optimized and matured
.
First-line immunotherapy for microsatellite stability (MSS) metastatic colorectal cancer has not yielded satisfactory results
.
With the gradual deepening of the research on backline molecular targeted therapy, the efficacy of precision therapy is initially apparent, and more follow-up research results are expected
.

Significant efficacy of perioperative immunotherapy for dMMR colorectal cancer The 2022 ASCO Annual Meeting reported a prospective, single-arm, phase 2 clinical trial for stage II.
/III.
dMMR rectal cancer, in which patients received PD-1 antibody dotarimab monotherapy neoadjuvant therapy for 6 months, followed by standard concurrent chemoradiotherapy and surgery.
If complete clinical remission is achieved after completion of dotalimab therapy, chemoradiotherapy and surgery are not required [38] (Related reading: "Xu Ruihua, Wang Feng Review: NEJM publishes ctDNA to guide adjuvant chemotherapy for colon cancer| Rome is not built in one day").

。 At the time of ASCO data, 18 patients had received 6 months of neoadjuvant therapy with dotalimab, and the results showed that at a median follow-up of 12 months, 14 evaluable patients achieved 100% complete clinical response without chemoradiotherapy or surgery
.
The results of this study are surprising, providing patients with advanced rectal cancer with dMMR with potential new options, which may change the treatment model
of locally advanced rectal cancer.
However, the sample size was small and the follow-up time was insufficient, and the results need to be further tested in studies with larger populations, wider geographies, and longer follow-up periodsCertificate
.

The NICHE study is the first Phase 2 clinical trial to explore neoadjuvant immunotherapy for non-metastatic colon cancer, including patients
with dMMR and mismatch repair gene intact (pMMR) colon cancer 。 The final efficacy data announced at the 2022 ASCO Annual Meeting showed that 32 patients with dMMR colon cancer achieved a pathological response rate of 100% after receiving neoadjuvant nivolumab combined with ipilimumab, of which the MPR rate was 95% and the pCR rate was 69%.

In 30 patients with pMMR colon cancer, pathologic response rates were 29 percent and pCR rates were 10 percent [39].

NICHE-2 is a further non-randomized, multicenter trial of immunoneoadjuvant therapy for nonmetastatic dMMR colon cancer [40], in which enrolled patients received one dose of ipilimumab (1 mg/kg on day 1) and two doses of nivolumab (3 mg/kg, given on days 1 and 15), with surgery within six weeks of initiation
.
Primary endpoints included safety and 3-year disease-free survival (DFS), with secondary endpoints MPR and pCR.

The 2022 ESMO Annual Meeting reported that all enrolled patients underwent negative margin (R0) surgical resection, and in the population with efficacy analysis (n=107), 95% of patients achieved MPR and a pCR rate of 67%.

After a median follow-up of 13.
1 months, no patients experienced disease recurrence
.
The incidence of grade 3~4 immune-related adverse events was 4%, and the DFS data was not yet mature
.

The above latest research data suggest that perioperative immunotherapy has a significant effect in locally advanced dMMR colorectal cancer, which is conducive to the preservation of organ function in patients with colorectal cancer with dMMR, and is expected to usher in treatment reform
.

ctDNA helps guide postoperative adjuvant therapy decisions Postoperative adjuvant chemotherapy for colorectal cancer can effectively reduce recurrence and metastasis and improve long-term survival of patients, but how adjuvant chemotherapy should be used, which groups of people should be used, and how to avoid overtreatment has been a topic
of debate for many years.
Early IDEA studies proposed the recommended regimen and duration of adjuvant chemotherapy based on different disease stages and risk [41].

As ctDNA testing continues to expand in clinical research, it plays an important role in assessing the risk of postoperative recurrence and predicting minimal residual disease (MRD), which may help screen out patients
who may benefit from adjuvant chemotherapy.

The CIRCULATE-Japan trial is a large-scale prospective, multicenter, MRD-guided adjuvant therapy platform trial for colorectal cancer in Japan, including three clinical trials
: GALAXY, VEGA and ALTAIR.
THE OBSERVATIONAL STUDY GALAXY [42]
WAS REPORTED AT THE 2022 ASCO GI CONFERENCE.
The study dynamically monitored postoperative ctDNA for stage II.
-IV colorectal cancer, using Signatera's customized tumor-informed ctDNA detection method, and analyzed the DFS rate
of patients at 6 months 。 The results showed that the patients were divided into four groups according to the dynamic changes of ctDNA from 4 weeks to 12 weeks after surgery, and the 6-month DFS rates were 98% (n=618 cases) in the "negative to negative" group, 59% (n=32 cases) in the "negative to positive" group, 100% (n=58) in the "positive to negative" group, and 45% (n=78 cases) in the "positive to positive" group, among which there was a significant difference between the "positive to positive" group and the "positive to negative" group, with an HR of 52.
3 (95%) CI, 7.
2~380.
5;P<0.
001).

DYNAMIC is a prospective study of postoperative adjuvant therapy for stage II colon cancer [43], in which enrolled patients are randomly assigned to "ctDNA-directed management group" or "standard management group"
on a 2:1 basis.
Patients in the ctDNA guidance group decided whether to undergo adjuvant chemotherapy based on ctDNA results at week 4 or 7 postoperatively, with oxaliplatin-based or 5-FU-based adjuvant chemotherapy if ctDNA positive, and ctDNA-negative patients not receiving adjuvant chemotherapy
.
The adjuvant chemotherapy strategy in the standard management group is consistent
with current clinical practice.
The primary endpoint was 2-year recurrence-free survival (RFS).

The results showed that the proportion of chemotherapy in the ctDNA-guided group was 15%, while the proportion of chemotherapy in the standard management group was 28%, and the 2-year recurrence-free survival rates of patients in the two groups were 93.
5% and 92.
4%, respectively, reaching the preset non-inferior endpoint
.
The study shows that ctDNA-guided treatment of stage II.
colon cancer can save nearly half of patients from adjuvant chemotherapy without affecting recurrence-free survival, which is expected to further expand the clinical application
of ctDNA detection.

At present, chemotherapy combined with anti-EGFR or anti-VEGF antibody has become the standard treatment for
metastatic colorectal cancer (mCRC).
The European FIRE-3 study [44] and the US CALGB/SWOG 80405 study [45] revealed survival advantages
in patients with left colorectal cancer.
However, in patients with RAS wild-type mCRC, no previous randomized controlled trials have determined the advantages of
the anti-EGFR antibody cetuximab over bevacizumab.
Retrospective studies have found that anti-EGFR antibodies have a better
effect in patients with RAS wild-type left half of mCRC.
The advantages and disadvantages of the first-line targeted regimen EGFR monoclonal antibody versus VEGF monoclonal antibody still need to be answered
by head-to-head clinical trials.

The PARADIGM study, presented at the 2022 ASCO Annual Meeting, is an open-label, multicenter, randomized Phase 3 clinical trial of RAS wild-type mCRC [46] that compares the efficacy
of panizumab in combination with mFOLFOX6 versus bevacizumab plus mFOLFOX6 in RAS wild-type mCRC.
The primary endpoint was OS, and secondary endpoints included PFS, response rate (RR), DOR, and R0 excision rate
.
The results showed that in the overall cohort, the panitizumab group was overall superior to the bevacizumab group, with OS of 36.
2 months and 31.
3 months, RR of 74.
9% and 67.
3%, and R0 resection rates of 16.
5% and 10.
9%,
respectively.
For the left half of the mCRC cohort, panitumab was significantly more effective than bevacizumab with OS of 37.
9 months and 34.
3 months, RR of 80.
2% and 68.
6%, and R0 resection rate of 18.
3% and 11.
6%,
respectively.
No significant differences
were seen in the right half of the mCRC cohort.
This study has important implications
for the first-line treatment of FOLFOX in combination with EGFR monoclonal antibody (panitumab) for RAS wild-type left half of mCRC.

For advanced first-line immunotherapy, the KEYNOTE-177 study [47] has shown that 5% of mCRC populations with dMMR/MSI-H clearly benefit
from monotherapy.
Most patients with pMMR and MSS-type mCRC do not respond well
to immunotherapy.
Many clinical studies have explored combinations of immunotherapy with chemotherapy, targeted and other therapeutic modalities to improve the prognosis of MSS-type mCRC, but the efficacy is not satisfactory
.

The CheckMate 9X8 study presented at the 2022 ASCO GI Conference evaluated nivolumab in combination with mFOLFOX6/bevacizumab versus mFOLFOX6/bevacizumab first-line treatment of mCRC [48].

A total of 195 patients were randomized 2:1 to nivolumab + mFOLFOX6/bevacizumab or mFOLFOX6/bevacizumab
.
The primary endpoint was PFS
.
The results showed that the median PFS of both groups was 11.
9 months, and the HR was 0.
81 (95% CI, 0.
53~1.
23; P=0.
30), which did not meet the primary endpoint
.

AtezoTRIBE was a multicenter, open-label, randomized, controlled phase 2 trial [49] that enrolled 218 patients with mCRC and randomized 1:2 to a control and trial group to receive first-line FOLFOXIRI (calcium folinate + 5-FU + oxaliplatin + irinotecan) + bevacizumab and FOLFOXI, respectivelyRI+ bevacizumab + atezolizumab therapy
.
The primary endpoint was PFS
.
The results showed that the mPFS of atezolizumab group and control group were 13.
1 months and 11.
5 months (HR, 0.
69; 80% CI, 0.
56~0.
85; P=0.
012),
respectively.
However, post-hoc subgroup analysis found that in the pMMR subgroup, the mPFS of atezolizumab group compared with the control group was 12.
9 vs.
11.
4 months (HR, 0.
78; 80% CI, 0.
62~0.
97; P=0.
071), and no significant benefit
was observed.

For MSS mCRC patients with RAS/BRAF mutations, the immune + chemotherapy + targeted treatment mode shows certain efficacy
.
The NIVACOR study was an open-label, multicenter, single-arm, phase 2 clinical trial [50] that evaluated the efficacy and safety of nivolumab in combination with FOLFOXIRI/bevacizumab in first-line treatment of RAS/BRAF-mutant mCRC, with the primary endpoint being ORR
.
The results showed that the ORR of the ITT population was 76.
7%, the DCR was 97.
3%, the mDOR was 8.
4 months, and the mPFS was 10.
1 months
.
In the subgroup analysis of MSS patients, the ORR was 78.
9%, the DCR was 96.
2%, the mDOR was 7.
59 months, and the mPFS was 9.
8 months
.
In addition, the BBCAPX phase 2 trial conducted by the team of Professor Yuan Ying of the Second Affiliated Hospital of Zhejiang University School of Medicine explored the efficacy of sindilimab combined with CAPEOX (capecitabine + oxaliplatin) and bevacizumab in the first-line treatment of patients with RAS mutation and MSS mCRC [51].

The study showed encouraging initial efficacy and a good safety profile: 84% ORR and 100% DCR; By the time the results were announced, median PFS had not been reached
.

In general, first-line immunotherapy for MSS/pMMR mCRC patients is still being explored, and immunotherapy combined with chemotherapy and targeted therapy may not be suitable for all MSS-type mCRC patients, although it has a certain effect on MSS mCRC with RAS/BRAF mutation, but its immunotherapy road is long
.

With the further in-depth study of the mechanism of targeted therapy for colorectal cancer, targeted therapy for HER2, KRAS, VEGFR and other targets has made some new progress in 2022.
It brings new hope
to patients with more special types of colorectal cancer.

A number of studies such as HERACLES-A, MyPathway, and DESTINY-CRC01 have suggested that anti-HER2 therapy has a certain efficacy in HER2 amplification mCRC [52-54].

THE MOUNTAINEER STUDY, REPORTED AT THE 2022 ESMO ANNUAL MEETING, OFFERS A NEW COMBINATION THERAPY
.
The MOUNTAINEER study was a multicenter, open-label, randomized phase 2 clinical trial of the postline treatment of HER2-positive metastatic colorectal cancer [55] in patients treated with tucatinib alone or with trastuzumab
, respectively.

The results showed that the treatment group of tucatatinib combined with trastuzumab had a significant effect, with an ORR of 38.
1%, mDOR of 12.
4 months, mPFS of 8.
2 months, and mOS of 24.
1 months
.
However, in the face of numerous anti-HER2 regimens, such as trastuzumab-lapatinib, trastuzumab, DS8201, trastuzumab-tucardinib, further research is needed to explore the appropriate suitable population
.
Meanwhile, MOUNTAINEER-03, a phase 3 clinical trial MOUNTAINEER-03 in the treatment of HER2-positive RAS wild-type advanced bowel cancer with tucatanib and trastuzumab combined with chemotherapy is ongoing [56].

KRAS mutation is the most common type of mutation in mCRC, of which KRAS G12C mutation proportion is about 3%, and there has been a lack of effective treatment strategies and drugs
.
adagrasib is a highly selective and irreversible inhibitor of KRAS G12C
.
KRYSTAL-1 is a multi-cohort, Phase 1/2 clinical trial designed to evaluate the efficacy and safety of adagrasib in patients with advanced solid tumors with KRAS G12C mutation, in which the mCRC cohort was divided into late-line adagrasib monotherapy and adagrasib in combination with cetuximab
.

The latest data from the study presented at the 2022 ESMO Annual Meeting [57], with an ORR of 19% and 86% for DCR, mPFS of 5.
6 months, and mOS of 19.
8 months, and an ORR of 46% and 100% for ADAGHASIB plus cetuximab mPFS was 6.
9 months and mOS was 13.
4 months, and both treatment groups showed some clinical efficacy, but adagrasib combined with cetuximab did not translate into OS advantage
in this study.
A Phase 3 clinical trial of KRYSTAL-10 in the second-line treatment of KRAS G12C mutant colorectal cancer in combination with cetuxib is ongoing [58].

Sotorasib is another irreversible KRAS G12C inhibitor
.
CodeBreaK 100 was a phase 1/2 study of sotorasib for the treatment of multicohort solid tumors [59] in which the CRC cohort sotorasib monotherapy had an ORR of 9.
7%, a DCR of 82.
3%, an mPFS of 4.
0 months, and an mOS of 10.
6 months
。 The 2022 ESMO Annual Meeting published phase 1b expansion cohort data for sotorasib combined with panitumab for the treatment of refractory KRAS G12C mutant mCRC [60], and the results showed that the confirmed objective response rate of sotorasib combined with panitumab was 30%, DCR was 90%, and mPFS was 5.
7 months
.
Combination therapy was 3 times
higher than sotorasib monotherapy with ORR.
This result will drive further trial validation
of sotorasib in combination with panitumab.
This study provides further evidence
for the safety and tolerability of sotorasib in combination with panizumab in patients with mCRC with KRAS G12C mutation.

A phase 3 CodeBreaK 300 study of sotorasib in combination with panitumab versus chemotherapy [61] and the CodeBreaK 101 study of sotorasib + panizumab + FOLFIRI regimen for first-line therapy [62] are ongoing
.

Data analysis of the global multicenter Phase 3 clinical trial FRESCO-2 was presented at the 2022 ESMO Annual Meeting [63], which explored fruquintinib + optimal supportive care versus placebo + optimal supportive care for the third-line and above treatment of patients
with advanced refractory metastatic colorectal cancer.
The primary endpoint was OS
.
Unlike the FRESCO study, patients enrolled in FRESCO-2 received standard chemotherapy and TAS-102/regorafenib
.
In the global population, fruquintinib compared mOS (7.
4 vs.
4.
8 months; HR, 0.
66; P<0.
001) and mPFS (3.
7 vs.
1.
8 months; HR, 0.
32; P <0.
0010) both improved
significantly.
The FRESCO-2 study is a further evidence and supplement to the FRESCO study, which clarifies the survival benefit
of the original drug fruquintinib in China for patients with advanced CRC worldwide.

References

1.
Kato K, Ito Y, Daiko H, et al.
A randomized controlled phase III trial comparing two chemotherapy regimen and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced esophageal cancer, JCOG1109 NExT study.
J Clin Oncol 2022; 40:238.
2.
Jiang N, Jiang M, Zhu X, et al.
SCALE-1: Safety and efficacy of short course neoadjuvant chemo-radiotherapy plus toripalimab for locally advanced resectable squamous cell carcinoma of esophagus .
J Clin Oncol 2022; 40:4063.
3.
Xu X, Sun Z, Zhang Y, et al.
Neoadjuvant chemoradiotherapy combined with perioperative toripalimab in locally advanced esophageal cancer.
J Clin Oncol 2022; 40:e16065.
4.
Ko AH, Noel M, Chao J, et al.
1229P a multicenter phase II study of sotigalimab (CD40 agonist) in combination with neoadjuvant chemoradiation for resectable esophageal and gastroesophageal junction (GEJ) cancers.
Ann Oncol 2022; 33:S1111.
5.
Doki Y, Ajani JA, Kato K, et al.
Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.
N Engl J Med 2022; 386:49-462.
6.
Sun JM, Shen L, Shah MA, et al.
Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study.
Lancet 2021; 398:59-771.
7.
Wang ZX, Cui C, Yao J, et al.
Toripalimab plus chemotherapy in treatment-naive, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial.
Cancer Cell 2022; 40:277-288 e273.
8.
Xu R-h, Luo H, Lu J, et al.
ESCORT-1st: A randomized, double-blind, placebo-controlled, phase 3 trial of camrelizumab plus chemotherapy versus chemotherapy in patients with untreated advanced or metastatic esophageal squamous cell carcinoma (ESCC).
J Clin Oncol 2021; 39:4000.
9.
Lu Z, Wang J, Shu Y, et al.
Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): Multicentre, randomised, double blind, phase 3 trial.
BMJ 2022; 377:e068714.
10.
Chau I, Ajani JA, Doki Y, et al.
Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648.
J Clin Oncol 2022; 40:4035.
11.
Yoon H, Kato K, Raymond E, et al.
Lba-1 RATIONALE-306: Randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC).
Ann Oncol 2022; 33:S375.
12.
Kato K, Yoon H, Raymond E, et al.
70o randomized, global, phase III study of tislelizumab (TIS) + chemotherapy (chemo) vs chemo as first-line (1L) therapy for advanced or metastatic esophageal squamous cell carcinoma (ESCC) (RATIONALE-306): Asia subgroup.
Ann Oncol 2022; 33:S1458.
13.
Huang J, Song Y, Kou X, et al.
69O first-line serplulimab versus placebo in combination with chemotherapy in PD-L1-positive oesophageal squamous cell carcinoma (ASTRUM-007): A randomised, double-blind, multicentre phase III study.
Ann Oncol 2022; 33:S1457-S1458.
14.
Bai LY, Chiu CF, Kadowaki S, et al.
1209P A phase II study of regorafenib in combination with nivolumab in patients with recurrent or metastatic solid tumors: Results of the ESCC cohort.
Ann Oncol 2022; 33:S1101-S1102.
15.
Muro K, Kato K, Chin K, et al.
1241p phase Ib study of futibatinib plus pembrolizumab in patients with advanced or metastatic solid tumors: Tolerability results and antitumor activity in esophageal carcinoma.
Ann Oncol 2022; 33:S1116.
16.
He Y, Li C, Zhang F, et al.
Clinical study on the second-line treatment of advanced esophageal squamous cell carcinoma with camrelizumab combined with apatinib and irinotecan: A single-arm, multicenter, phase II study.
J Clin Oncol 2022; 40:319.
17.
Janjigian YY, Shitara K, Moehler M, et al.
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial.
The Lancet 2021; 398:27-40.
18.
Xu J, Jiang H, Pan Y, et al.
LBA53 sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16 ): First results of a randomized, double-blind, phase III study.
Ann Oncol 2021; 32:S1331.
19.
Janjigian YY, Kawazoe A, Yañez P, et al.
The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer.
Nature 2021; 600:727-30.
20.
Shitara K, Ajani JA, Moehler M, et al.
Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer.
Nature 2022; 603:942-8.
21.
Shen L, Bai Y, Lin X, et al.
P-86 first-line nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis 2-year follow-up.
Ann Oncol 2022; 33:S279.
22.
Lorenzen S, Thuss-Patience PC, Knorrenschild JR, et al.
FOLFOX versus FOLFOX plus nivolumab and ipilimumab administered in parallel or sequentially versus FLOT plus nivolumab administered in parallel in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: A randomized phase 2 trial of the AIO.
J Clin Oncol 2022; 40:4043.
23.
Lorenzen S, Thuss-Patience PC, Folprecht G, et al.
FOLFOX plus nivolumab and ipilimumab versus FOLFOX induction followed by nivolumab and ipilimumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Results from the randomized phase II moonlight trial of the AIO.
1203O 2022 ESMO Congress 24.
Chung HC, Lwin Z, Gomez-Roca C, et al.
LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—results from the gastric cancer cohort.
J Clin Oncol 2021; 39: 230.
25.
Shitara K, Ben-Aharon I, Rojas C, et al.
1223P first-line lenvatinib (Len) + pembrolizumab (Pembro) + chemotherapy (Chemo) vs chemo in advanced/metastatic gastroesophageal adenocarcinoma: LEAP-015 safety run-in.
Ann Oncol 2022; 33:S1108.
26.
Bang YJ, Van Cutsem E, Feyereislova A, et al.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial.
Lancet 2010; 376:687-97.
27.
Catenacci DVT, Kang YK, Yoon HH, et al.
Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort a.
ESMO Open 2022; 7:100563.
28.
Ku G, Elimova E, Denlinger CS, et al.
1380p Phase (Ph) II study of zanidatamab + chemotherapy (chemo) in first-line (1L) HER2 expressing gastroesophageal adenocarcinoma (GEA).
Ann Oncol 2021; 32:S1044-S1045.
29.
Lee KW, Bai L-Y, Jung M, et al.
Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) and tislelizumab (TIS) as first-line (1L) therapy for patients (pts) with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma (G/GEJC): Preliminary results from a phase 1b/2 study.
J Clin Oncol 2022; 40:4032.
30.
Tabernero J, Shen L, Elimova E, et al.
HERIZON-GEA-01: Zanidatamab + chemo +/- tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma.
Future Oncol 2022; 18:3255-66.
31.
Shen L, Gong J, Niu Z, et al.
1210p the preliminary efficacy and safety of KN026 combined with KN046 treatment in HER2-positive locally advanced unresectable or metastatic gastric/ gastroesophageal junction cancer without prior systemic treatment in a phase II study.
Ann Oncol 2022; 33:S1102.
32.
Shitara K, Bang YJ, Iwasa S, et al.
Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer.
N Engl J Med 2020; 382:2419-30.
33.
Peng Z, Liu T, Wei J, et al.
Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: A single-arm phase II study.
Cancer Commun (Lond) 2021; 41:1173-82.
34.
Ku GY, Di Bartolomeo M, Smyth E, et al.
1205MO updated analysis of DESTINY-Gastric02: A phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive ( HER2+) unresectable/metastatic gastric/gastroesophageal junction (GEJ) cancer who progressed on or after trastuzumab-containing regimen.
Ann Oncol 2022; 33:S1100.
35.
Sahin U, Tureci O, Manikhas G, et al.
Fast: A randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.
2-positive gastric and gastro-oesophageal adenocarcinoma.
Ann Oncol 2021; 32:09-619.
36.
Qi C, Gong J, Li J, et al.
Claudin18.
2-specific CAR T cells in gastrointestinal cancers: Phase 1 trial interim results.
Nat Med 2022; 28:1189-98.
37.
Zhang Y, Wang ZX, Shen L, et al.
A phase Ib/II study of fruquintinib in combination with paclitaxel as the second-line therapy for advanced gastric cancer.
Cancer Commun (Lond) 2022 Nov 4 (Epub ahead of print).
38.
Cercek A, Lumish M, Sinopoli J, et al.
PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer.
N Engl J Med 2022; 386:2363-76.
39.
Verschoor YL, Berg Jvd, Beets G, et al.
Neoadjuvant nivolumab, ipilimumab, and celecoxib in MMR-proficient and MMR-deficient colon cancers: Final clinical analysis of the NICHE study.
J Clin Oncol 2022; 40:3511.
40.
Chalabi M, Verschoor YL, van den Berg J, et al.
LBA7 neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study.
Ann Oncol 2022; 33:S1389.
41.
Sobrero AF, Andre T, Meyerhardt JA, et al.
Overall survival (OS) and long-term disease-free survival (DFS) of three versus six months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): Final results from the IDEA (International Duration Evaluation Of Adj Chemotherapy) collaboration.
J Clin Oncol 2020; 38:4004.
42.
Kotaka M, Shirasu H, Watanabe J, et al.
Association of circulating tumor DNA dynamics with clinical outcomes in the adjuvant setting for patients with colorectal cancer from an observational GALAXY study in CIRCULATE-japan.
J Clin Oncol 2022; 40:9.
43.
Tie J, Cohen JD, Lahouel K, et al.
, for the DYNAMIC Investigators.
Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer.
N Engl J Med 2022; 386:2261-72.
44.
Heinemann V, von Weikersthal LF, Decker T, et al.
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial.
Lancet Oncol 2014; 15:1065-75.
45.
Venook AP, Niedzwiecki D, Lenz H-J, et al.
CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).
J Clin Oncol 2014; 32:LBA3.
46.
Yoshino T, Watanabe J, Shitara K, et al.
Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Results from the phase 3 PARADIGM trial.
J Clin Oncol 2022; 40:LBA1.
47.
Diaz LA, Jr.
, Shiu K-K, Kim T-W, et al.
Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer ( KEYNOTE-177): Final analysis of a randomised, open-label, phase 3 study.
Lancet Oncol 2022; 23:659-70.
48.
Lenz H-J, Parikh AR, Spigel DR, et al.
Nivolumab (NIVO) + 5-fluorouracil/leucovorin/oxaliplatin (mFOLFOX6)/bevacizumab (BEV) versus mFOLFOX6/BEV for first-line (1L) treatment of metastatic colorectal cancer (mCRC): Phase 2 results from CheckMate 9x8.
J Clin Oncol 2022; 40:8.
49.
Antoniotti C, Rossini D, Pietrantonio F, et al.
Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): A multicentre, open-label, randomised, controlled, phase 2 trial.
Lancet Oncol 2022; 23:876-887.
50.
Damato A, Bergamo F, Antonuzzo L, et al.
Phase II study of nivolumab in combination with FOLFOXIRI/bevacizumab as first-line treatment in patients with advanced colorectal cancer RAS/BRAF mutated (mut): NIVACOR trial ( GOIRC-03-2018).
J Clin Oncol 2022; 40: 3509.
51.
Fang X, Zhong C, Zhu N, et al.
A phase 2 trial of sintilimab (IBI 308) in combination with CAPEOX and bevacizumab (BBCAPX) as first-line treatment in patients with RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer.
J Clin Oncol 2022; 40:3563.
52.
Sartore-Bianchi A, Trusolino L, Martino C, et al.
Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): A proof-of-concept, multicentre, open-label, phase 2 trial.
Lancet Oncol 2016; 17:738-746.
53.
Meric-Bernstam F, Hurwitz H, Raghav KPS, et al.
Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): An updated report from a multicentre, open-label, phase 2a, multiple basket study.
Lancet Oncol 2019; 20:518-30.
54.
Siena S, Di Bartolomeo M, Raghav K, et al.
Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): A multicentre, open-label, phase 2 trial.
Lancet Oncol 2021; 22:779-89.
55.
Strickler J, Cercek A, Siena S, et al.
Lba-2 primary analysis of MOUNTAINEER: A phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC.
Ann Oncol 2022; 33:S375-S376.
56.
André T, Bekaii-Saab T, Tabernero J, et al.
438tip MOUNTAINEER-03: Phase III study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer (trial in progress).
Ann Oncol 2022; 33:S734-S735.
57.
Klempner SJ, Weiss J, Pelster M, et al.
Lba24 KRYSTAL-1: Updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation.
Ann Oncol 2022; 33:S1391.
58.
Tabernero J, Bendell J, Corcoran R, et al.
P-71 KRYSTAL-10: A randomized phase 3 study of adagrasib (MRTX849) in combination with cetuximab vs chemotherapy in patients with previously treated advanced colorectal cancer with KRASG12C mutation.
Ann Oncol 2021; 32:S121.
59.
Fakih MG, Kopetz S, Kuboki Y, et al.
sotorasib for previously treated colorectal cancers with KRAS(G12C) mutation (CodeBreak100): A prespecified analysis of a single-arm, phase 2 trial.
Lancet Oncol 2022; 23:115-24.
60.
Kuboki Y, Yaeger R, Fakih M, et al.
45MO sotorasib in combination with panitumumab in refractory KRAS G12C-mutated colorectal cancer: Safety and efficacy for phase Ib full expansion cohort.
Ann Oncol 2022; 33:S1445-S1446.
61.
Paez D, Meriggi F, Cremolini C, et al.
437TiP trial in progress: A phase III global study of sotorasib, a specific KRAS G12C inhibitor, in combination with panitumumab versus investigator's choice in chemorefractory metastatic colorectal cancer (CodeBreaK 300).
Ann Oncol 2022; 33:S734.
62.
Masuishi T, Kuboki Y, Fakih MG, et al.
444TiP trial in progress: A phase Ib study of sotorasib, a selective KRAS G12C inhibitor, in combination with panitumumab and FOLFIRI in treatment naive and previously treated metastatic colorectal cancer (CodeBreaK 101).
Ann Oncol 2022; 33:S737-S738.
63.
Dasari NA, Lonardi S, Garcia-Carbonero R, et al.
LBA25 FRESCO-2: A global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer.
Ann Oncol 2022; 33:S1391-S1392.

About the author

Xu Ruihua, chief physician, professor, doctoral supervisor, director, dean and director of the Institute of Cancer Prevention and Treatment of Sun Yat-sen University, director of the State Key Laboratory of Oncology in South China, director of the Collaborative Innovation Center of the Ministry of Oncology, director of the National New Drug (Anti-tumor Drug) Clinical Trial Center, was selected as the Nanyue Baijie Talent Training Project, the National Millions of Talents Project, and the State Council Government Special Allowance Expert
.
He is currently the chairman of the Chinese Society of Clinical Oncology (CSCO), the chairman of the Chinese Anti-Cancer Association, and the editor-in-chief
of Cancer Communications 。 He has been engaged in gastrointestinal tumor diagnosis, individualized treatment and translational research for a long time, and has achieved internationally advanced and innovative results in early diagnosis and immunotherapy, with a total of more than 300 papers published, and more than 200 papers published in top international journals as a corresponding / first author, such as JAMA, Nature Materials, Nature Medicine, Lancet Oncology, Journal of Clinical Oncology, JAMA Oncology, Annals of Oncology, etc.
, won 2 second prizes of National Science and Technology Progress Award (first completer) and 6 provincial and ministerial first prizes such as the Chinese Medical Science and Technology Award
.
Luo Huiyan, chief physician, graduate tutor, vice chairman of the Youth Committee of the Gastric Cancer Professional Committee of the Chinese Anti-Cancer Association, member of the Standing Committee and Secretary-General
of the Tumor Targeted Therapy Professional Committee of the Guangdong Anti-Cancer Association.
Mainly engaged in the diagnosis, individualization treatment and translational research
of digestive tract tumors.
As the main researcher, he has presided over or participated in many scientific research projects
such as national key research and development projects and National Natural Science Foundation of China.
He has published more than 100 articles in domestic and foreign journals, and has published more than 30 papers in JAMA, Nature Materials, Lancet Oncology, Science Translational Medicine, Annals of Oncology, PNAS
, etc.
as the first author.
The two findings were adopted by the NCCN guidelines in the United States, rewriting the global care model
.
He has won 1 second prize of National Science and Technology Progress Award and 4 first prizes of provincial and ministerial awards
.
Ye He, physician, MD, assistant researcher, visiting scholar at the University of Michigan, winner of The Abraham H.
Grant Award at the University of Michigan
.
Mainly engaged in the diagnosis, individualization treatment and translational research
of digestive tract tumors.
He presided over 1 National Natural Science Youth Foundation of China and 1 postdoctoral project in China
.

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