
==== Front
J Gastrointest Oncol
J Gastrointest Oncol
JGO
Journal of Gastrointestinal Oncology
2078-6891
2219-679X
AME Publishing Company

jgo-15-04-1534
10.21037/jgo-23-940
Original Article
PD-1 blockade combined with chemotherapy and bevacizumab in DNA mismatch repair-proficient/microsatellite stable colorectal liver metastases
Men Qianqian 1 #
Duan Yinghua 2 #
Pei Fengyun 3 4 #
Yao Qijun 3 4 #
He Wan 5
Zhao Yandong 6
Shi Lishuo 7
Liu Guangjian 8 *
Huang Jun 3 4 9 10 *
1 Graceland Medical Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
2 Department of Traditional Chinese Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
3 Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
4 Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
5 Department of Oncology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China;
6 Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
7 Clinical Research Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
8 Department of Medical Ultrasonic, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
9 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
10 Guangdong Institute of Gastroenterology, Guangzhou, China
Contributions: (I) Conception and design: J Huang, G Liu; (II) Administrative support: J Huang; (III) Provision of study materials or patients: J Huang, Q Men; (IV) Collection and assembly of data: Y Duan, F Pei, Q Yao; (V) Data analysis and interpretation: W He, Y Zhao, L Shi; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

# These authors contributed equally to this work as co-first authors.

* These authors contributed equally to this work.

Correspondence to: Jun Huang, MD, PhD. Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancunerheng Road, Guangzhou 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancunerheng Road, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancunerheng Road, Guangzhou 510655, China; Guangdong Institute of Gastroenterology, Yuancunerheng Road, Guangzhou 510655, China. Email: huangj97@mail.sysu.edu.cn; Guangjian Liu, MD, PhD. Department of Medical Ultrasonic, The Sixth Affiliated Hospital, Sun Yat-sen University, Yuancunerheng Road, Guangzhou 510655, China. Email: liugj@mail.sysu.edu.cn.
12 8 2024
31 8 2024
15 4 15341544
27 11 2023
03 7 2024
2024 Journal of Gastrointestinal Oncology. All rights reserved.
2024
Journal of Gastrointestinal Oncology.
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.
Background

Single-agent immunotherapy is less effective in patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC). Whether pMMR/MSS mCRC patients benefit from combination immunotherapy remains unclear. This study aimed to evaluate the efficacy and safety of anti-programmed cell death protein 1 (PD-1) therapy combined with chemotherapy and bevacizumab in pMMR/MSS colorectal liver metastases (CRLM) patients.

Methods

A total of 12 patients with pMMR/MSS CRLM treated at The Sixth Affiliated Hospital of Sun Yat-sen University were enrolled. All patients were treated with at least 4 doses of PD-1 monoclonal antibody combined with chemotherapy and bevacizumab as neoadjuvant/adjuvant therapy.

Results

A total of 10 of the 12 patients received the combined therapies before primary tumor resection; the disease control rate (DCR) was 100% (10/10), and the objective response rate (ORR) was 70% (7/10). The ORR of liver metastases was 75% (9/12). Pathological complete response (pCR) was achieved in 1 primary tumor patient and 2 patients with hepatic lesions. A total of 5 patients underwent simultaneous resection of the primary tumor and liver metastases; 9 patients underwent microwave ablation for liver metastases. A total of 7 patients were assessed as having no evidence of disease (NED) with a median progression-free survival (PFS) interval of 9.2 (1.5–15.8) months after multimodality treatments for both primary and metastatic lesions. No severe immune-related adverse events (irAEs) and operational complications were observed.

Conclusions

PD-1 blockade combined with chemotherapy and bevacizumab might be safe and effective for patients with pMMR/MSS CRLM. This treatment strategy might lead to better tumor regression and a higher chance of achieving NED.

Keywords:

Colorectal cancer (CRC)
liver metastases
mismatch repair-proficient/microsatellite stable (pMMR/MSS)
programmed cell death protein 1 blockade (PD-1 blockade)
bevacizumab
the National Key Clinical Discipline, the National Natural Science Foundation of ChinaNo. 81972885 the 1010 Project of The Sixth Affiliated Hospital of Sun Yat-sen UniversityNo. 1010CG [2020]-20
==== Body
pmcHighlight box

Key findings

• This study found that programmed cell death protein 1 (PD-1) blockade combined with chemotherapy and bevacizumab might be safe and effective for patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal liver metastases (CRLM).

What is known and what is new?

• Single-agent immunotherapy is less effective in patients with pMMR/MSS CRLM.

• We found that PD-1 blockade combined with chemotherapy and bevacizumab in patients with pMMR/MSS CRLM might lead to better tumor regression and a higher chance of achieving no evidence of disease.

What is the implication, and what should change now?

• The therapy regimen of PD-1 blockade combined with chemotherapy and bevacizumab was associated with favorable disease control rate and objective response rate and an acceptable safety profile for patients with pMMR/MSS CRLM. The mechanism of action of the treatment combination deserves further analysis.

Introduction

Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related death worldwide (1-3). About 20% of CRC patients have liver metastasis at the time of diagnosis, and 40% of patients have liver metastasis during the early disease course after surgical resection. For 30% of CRC patients, the liver is the only site of metastasis (4). Surgical resection of liver metastases is the most effective treatment for patients with colorectal cancer liver metastases (CRLM), especially those with limited or few liver metastases (5). Among this subgroup of patients, the 5-year overall survival (OS) rate ranges from 20% to 58% (6-8), but the 90-day mortality rate is 4%, and the complication rate is 40% (9).

Ablation therapy is usually reserved for CRLM patients who are not suitable for surgery. Previous studies have shown that 5-year OS rates, 5-year recurrence-free survival (RFS), and local recurrence rate are 27–50%, 0–34%, and 11–37% in CRLM patients treated with ablative therapy (8,10). Chemotherapy, non-surgical local treatment, and local or liver-targeted therapy and treatment are effective methods for treating CRLM. The objective response rates (ORRs) of first-line treatment for metastatic colorectal cancer (mCRC) range from 34% to 66%; whereas the range for second-line treatment is 30% to 40% (11).

Bevacizumab targets vascular endothelial growth factor A (VEGF-A) and plays a role in anti-angiogenesis, as well as immune regulation (12). The interaction between angiogenesis and immune regulation makes bevacizumab an interesting combination of immunotherapy, and related clinical trials are currently underway. Programmed cell death protein 1 (PD-1) blockade has been recommended as the first-line treatment in DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) mCRC (13,14). It is worth investigating whether DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) CRLM patients benefit from PD-1 blockade combination therapy. This study aimed to evaluate the short-term efficacy and safety of anti-PD-1 therapy combined with chemotherapy and bevacizumab in pMMR/MSS CRLM patients. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-940/rc).

Methods

We retrospectively reviewed 12 pMMR/MSS CRLM patients who were treated with anti-PD-1 combined with chemotherapy and bevacizumab. All enrolled patients underwent imaging evaluations, including computed tomography (CT), magnetic resonance (MR), positron emission tomography (PET), or ultrasound colonoscopy, to determine the tumor stage before neoadjuvant/adjuvant therapy. The microsatellite instability (MSI) and mismatch repair (MMR) status of the tumors were all confirmed before the starting of anti-PD-1 therapy. The 4 MMR proteins (MLH1, MSH2, MSH6, and PMS2) were evaluated by staining, and the results were confirmed by a trained pathologist. MSI status was confirmed by immunohistochemistry (IHC) or next-generation sequencing (NGS). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of The Sixth Affiliated Hospital, Sun Yat-sen University (No. 2022ZSLYEC-39), and all the enrolled patients agreed to receive PD-1 blockade combined chemotherapy and bevacizumab as a neoadjuvant/adjuvant therapy before the treatment. The requirement for individual consent for this retrospective analysis was waived.

Treatment and evaluation

All enrolled patients received at least 4 courses of anti-PD-1 therapy combined with chemotherapy and bevacizumab. The response of the primary tumor was assessed according to the Immune Response Evaluation Criteria In Solid Tumors (iRECIST) (15). Surgical specimens were evaluated according to the American Joint Committee on Cancer criteria (7th edition) (16). The tumor regression grade (TRG) was determined according to National Comprehensive Cancer Network (NCCN) guidelines. Primary and metastatic tumors were assessed by routine hematoxylin and eosin (HE) and IHC staining. No residual viable tumor cells was defined as pathological complete response (pCR). No evidence of disease (NED) was defined as no residual tumor after resection or no blood supply to the ablated lesions assessed by ultrasound contrast and magnetic resonance imaging (MRI) and negative tumor marker analyses. Treatment-related adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (17). The last patient follow-up was conducted on 31 July 2022.

Statistical analysis

All continuous data are expressed as the median with ranges. All discrete variables are presented as counts and percentages. The software program SPSS 26.0 (IBM Corp., Armonk, NY, USA) was used for statistical analyses.

Results

Patient characteristics

From August 2020 to July 2022, 12 patients with pMMR/MSS CRLM who were treated at The Sixth Affiliated Hospital of Sun Yat-sen University and received anti-PD-1 therapy (sintilimab injection) combined with systemic chemotherapy and targeted therapy were enrolled. The details of the enrolled patients are shown in Table 1. All 12 patients with pMMR/MSS had stage IV CRLM, and 2 had liver metastases 2 years after primary tumor surgery. Table 2 shows the location, size, and number of liver metastases, the surgical resection or ablative treatment administered, and the patients’ response to the treatment. As shown in Table 3, the median age of the enrolled patients was 53.5 years (range, 38–63 years); 8 of the patients were male. There were 6 patients diagnosed with rectal cancer, 2 with right colon cancer; and 4 with left colon cancer. The pathological tumor type was adenocarcinoma. A total of 10 patients received anti-PD-1 combined with chemotherapy and targeted neoadjuvant therapy.

Table 1 Cohort clinical characteristics and treatment details

No.	Age (years)	Gender	Clinical TNM	MMR or MSI status	BRAF	KRAS	Drug of ICB	Courses of ICB before surgery	Chemotherapy and targeted therapy	Clinical response	Surgery	Pathological tumor response	TRG	NED	
1	59	Male	cT3N0M1	pMMR/MSS	Wt	Wt	Sintilimab	6	mFOLFOX6 + bevacizumab	PR	Left hemicolectomy + hepatectomy + ablation	PR	1	–	
2	45	Male	M1	pMMR/MSS	Wt	Wt	Sintilimab	8	mFOLFOX6 + bevacizumab	SD	Ablation	–	–	Yes	
3	47	Male	cT3N1bM1c	pMMR/MSS	Wt	Wt	Sintilimab	4	mFOLFOX6/Xeloda + bevacizumab	PR	Lower anterior resection + ablation	PR	3	–	
4	54	Male	cT4aN2bM1	pMMR/MSS	Mt	Wt	Sintilimab	4	mFOLFXOX6 + bevacizumab	PR	Lower anterior resection + ablation	PR	1	Yes	
5	55	Male	cT4aN1bM1	pMMR/MSS	Wt	Wt	Sintilimab	5	mFOLFOX6 + bevacizumab	PR	Lower anterior resection + hepatectomy	PR	2	Yes	
6	55	Male	cT4aN2aM1	pMMR/MSS	Wt	Wt	Sintilimab	6	mFOLFOX6 + bevacizumab	PR	Left hemicolectomy + hepatectomy + ablation	PR	2	Yes	
7	52	Male	cT3N2bM1	pMMR/MSS	Wt	Wt	Sintilimab	7	mFOLFOX6 + bevacizumab	PR to PD	Ablation	–	–	–	
8	38	Female	cT3N1bM1	pMMR/MSS	Wt	Wt	Sintilimab	5	mFOLFOX6 + bevacizumab	PR	Right hemicolectomy + hepatectomy + ablation	PR	2	–	
9	63	Female	cT4aN2M1c	pMMR/MSS	Wt	Wt	Sintilimab	5	mFOLFOX6 + bevacizumab	PR	Left hemicolectomy + ablation	pCR	0	Yes	
10	52	Female	M1	pMMR/MSS	Wt	Wt	Sintilimab	4	mFOLFOX6 + bevacizumab	SD	Hepatectomy + ablation	PR	–	–	
11	69	Male	cT4aN1bM1	pMMR/MSS	–	–	Sintilimab	6	mFOLFOX6 + bevacizumab	PR	Right hemicolectomy + hepatectomy	PR	2	Yes	
12	53	Female	cT4aN2bM1	pMMR/MSS	–	–	Sintilimab	5	mFOLFOX6 + bevacizumab	PR	Lower anterior resection	pCR	2	Yes	
MSI, microsatellite instability; MMR, mismatch repair; ICB, immune checkpoint block; pCR, pathological complete response; PR, partial response; SD, stable disease; PD, progressive disease; pMMR, mismatch repair-proficient; MSS, microsatellite stable; NED, no evidence of disease; Mt, mutant; Wt, wild-type; TRG, tumor regression grade; TNM, tumor, node, metastasis.

Table 2 Details about the liver metastases

No.	Timing of metastases	Location	Count	Resection	Ablation	Clinical response	Pathological response	
1	Synchronous	S3/S5/S8/S7	3	Yes	Yes	PR	PR	
2	Metachronous	S7	1	No	Yes	SD	–	
3	Synchronous	S6	>3	No	Yes	PR	–	
4	Synchronous	S8	1	No	Yes	PR	–	
5	Synchronous	S2	1	Yes	No	cCR	pCR	
6	Synchronous	S5/S6/S8	3	Yes	Yes	PR	PR	
7	Synchronous	S2/S5/S6/S7	>3	No	Yes	PR	–	
8	Synchronous	S2/S5/S8	>3	Yes	Yes	PR	PR	
9	Synchronous	S1/S4/S7	3	No	Yes	PR	–	
10	Metachronous	S3/S4/S8	>3	Yes	Yes	SD	PR	
11	Synchronous	S6	1	Yes	No	PR	PR	
12	Synchronous	S2/S3/S6/S7/S8	>3	No	No	PR	pCR	
cCR, clinical complete response; pCR, pathological complete response; PR, partial response; SD, stable disease.

Table 3 Characteristics of cohorts

Characteristic	Values	
Age, years, median [range]	53.5 [38–63]	
   ≥60, n (%)	2 (16.7)	
   <60, n (%)	10 (83.3)	
Sex, n (%)		
   Male	8 (66.7)	
   Female	4 (33.3)	
ECOG performance status score, n (%)		
   0	8 (66.7)	
   1	3 (25.0)	
   ≥2	1 (8.3)	
Primary tumor location, n (%)		
   Right-side	2 (16.7)	
   Left-side	4 (33.3)	
   Rectum	6 (50.0)	
Histological type, n (%)		
   Medium or well-differentiated	11 (91.7)	
   Poor differentiated	1 (8.3)	
Pathological type, n (%)		
   Adenocarcinoma	12 (100.0)	
Stage, n (%)		
   IV	12 (100.0)	
ECOG, Eastern Cooperative Oncology Group.

Tumor response after neoadjuvant anti-PD-1 therapy

All 12 patients were confirmed to have pMMR/MSS by IHC or NGS. A total of 10 of the 12 patients received combined therapy before primary tumor resection, with a median time from neoadjuvant therapy to surgery of 121.5 days (range, 62–161 days). The disease control rate (DCR) was 100% (10/10) and ORR was 70% (7/10) in primary tumors, and the ORR of liver metastases was 75% (9/12) after the combined therapy (Table 4). Comparison of the primary tumors before and after treatment is shown in Figure 1A (P<0.001); comparison of the rate of radiological and pathological residual cancer of the primary lesion is shown in Figure 1B (P=0.009). Meanwhile, Figure 1C shows the comparison of the liver metastases before and after treatment (P<0.001); Figure 1D displays comparison of the rate of radiological and pathological residual cancer of the liver metastases (P=0.09). There was 1 patient with a primary tumor and 2 with liver metastasis who achieved pCR. A total of 5 patients underwent simultaneous resection of the primary tumor and liver metastases, whereas 9 patients underwent microwave ablation for liver metastases. A total of 7 patients were assessed as having NED with a median progression-free survival (PFS) interval of 9.2 months after multimodality treatments for both primary and metastatic lesions.

Table 4 ORR in primary tumors and liver metastases (based on radiological changes in maximum tumor diameter)

Case	Primary tumor		Liver metastases	
Before treatment (mm)	Posttreatment (mm)	ORR, %	PTRR, %	Before treatment (mm)	Posttreatment (mm)	ORR, %	PTRR, %	
1	39.3	17.7	55	10		47.3	22.7	52	10	
2	–	–	–	40		31.5	30.8	2.2	–	
3	72.2	57.1	20.9	80		20.4	12.7	37.8	–	
4	55.1	42.8	22.3	1		14.6	14	4.1	–	
5	62.4	43.3	30.6	45		13.8	0	100	0	
6	36.4	13.7	62.4	–		35.2	15.6	54.8	–	
7	57	14	75.4	–		40.9	18.5	54.8	–	
8	30.2	16.8	44.4	50		39.7	14.3	64	50	
9	109.8	93.1	15.2	0		39.7	17.4	56.2	–	
10	–	–	–	–		68	65	4.4	70	
11	59.9	37.16	38	2		16.04	11.75	26.7	<1	
12	65.55	28.97	55.8	12		49.3	16.96	65.6	0	
ORR, objective response rate; PTRR, pathological tumor residue rate.

Figure 1 Affective outcomes after treatment by the maximum diameter of the tumor, RTRR and PTRR. (A) Comparison of the primary tumors before and after treatment; (B) comparison of the rate of radiological and pathological residual cancer of the primary lesion; (C) comparison of the liver metastases before and after treatment; (D) comparison of the rate of radiological and pathological residual cancer of the liver metastases. RTRR, radiological tumor residue rate; PTRR, pathological tumor residue rate.

Safety and feasibility

AEs are shown in Table 5. All AEs had been previously reported in other immunotherapy studies (18-21). A total of 10 patients experienced at least 1 AE. Events of clinical interest included hand-foot syndrome (41.7%), nausea (33.3%), elevated alanine aminotransferase (16.7%), rash or pruritus (16.7%), diarrhea (8.3%), thyroiditis or hypothyroidism (8.3%), and chylous ascites (8.3%). All AEs were level 1–2; no level 3 AEs occurred. All AEs were secondary to chemotherapy or surgery, which were controlled or reduced, and the patients returned to normal; no surgeries were delayed. No perioperative mortality was observed among the patients who received surgery. Postoperative complications such as infection, anastomotic leakage, obstruction, urinary retention, and other complications occurred.

Table 5 Adverse events observed in the cohort

Adverse events	Grade 1–2, n (%)	Grade ≥3, n (%)	Any grade, n (%)	Immune-related adverse reactions	Adverse reactions secondary to chemotherapy or surgery	
Hand-foot syndrome	5 (41.7)	0	5 (41.7)	No	Yes	
Itch	1 (8.3)	0	1 (8.3)	No	Yes	
Rash or pruritus	2 (16.7)	0	2 (16.7)	No	Yes	
Elevated alanine aminotransferase	2 (16.7)	0	2 (16.7)	No	Yes	
Nausea	4 (33.3)	0	4 (33.3)	No	Yes	
Vomit	2 (16.7)	0	2 (16.7)	No	Yes	
Diarrhea	1 (8.3)	0	1 (8.3)	No	Yes	
Thyroiditis or hypothyroidism	1 (8.3)	0	1 (8.3)	No	Yes	
Myocarditis	1 (8.3)	0	1 (8.3)	No	Yes	
Upper respiratory infection	1 (8.3)	0	1 (8.3)	No	Yes	
Cough	1 (8.3)	0	1 (8.3)	No	Yes	
Fever	2 (16.7)	0	2 (16.7)	No	Yes	
Cold intolerance	1 (8.3)	0	1 (8.3)	No	Yes	
Fatigue	3 (25.0)	0	3 (25.0)	No	Yes	
Headache	1 (8.3)	0	1 (8.3)	No	Yes	
Surgery-related adverse events						
   Surgical site infection	0	0	0			
   Anastomotic leak	0	0	0			
   Obstruction/ileus	0	0	0			
   Chylous ascites	1 (8.3)	0	1 (8.3)	No	Yes	
   Urinary retention	0	0	0			
All	10 (83.3)	0	10 (83.3)	No	Yes	

Discussion

Targeting immune checkpoint molecules, such as PD-1, has achieved lasting clinical benefits in patients with dMMR/MSI-H mCRC, which contributes only 5% of mCRC (22,23). The liver is one of the most common sites of CRC metastasis. Hepatectomy is the mainstay treatment with a 5-year survival rate of 40–60% (24). Conversion therapy has been used for patients with unresectable liver metastases. Preoperative chemotherapy and new therapeutic strategies were used to shrink the tumor and promote resection (25). Ye et al. showed that patients who received targeted therapy or chemotherapy in combination with hepatectomy had significantly longer median survival compared to those who did not undergo hepatectomy (46.4 vs. 25.7 months in the targeted treatment group and 36.0 vs. 19.6 months in the chemotherapy alone group) (26). The final analysis of the TRICC0808 trial showed that patients who underwent hepatectomy after treatment with mFOLFOX6 and bevacizumab had better long-term survival outcomes, although most of the patients eventually relapsed. Therefore, hepatectomy after chemotherapy may improve the survival of CRLM patients, although achieving a cure remains challenging (27).

Previous research has evaluated the efficacy of atezolizumab in combination with bevacizumab and/or FOLFOX in patients with mCRC. Patients who received atezolizumab, bevacizumab, and FOLFOX as the first-line treatment had an ORR of 52% and a median PFS of 14.1 months, with no significant benefit (28). In this study, 10 of the 12 patients received the combined therapies before primary tumor resection. The DCR of the primary tumors was 100%, and the ORR was 70%. The ORR of the liver metastases was 75% (9/12) after treatment. The therapeutic effect on both the primary tumors and liver metastases was statistically significant (P<0.001), and there was also a statistically significant reduction in radiological and pathological residual cancer in the primary lesion (P=0.009). These preliminary results suggest that neoadjuvant immunotherapy combined with chemotherapy plus targeted therapy might be a promising strategy for pMMR/MSS CRLM patients.

A previous study on anti-PD-1 in dMMR mCRC reported a response rate of 32–53% (22). In the NICHE phase I/II trial, 4 of 15 pMMR tumors achieved pathological remission (3 cases of major remission and 1 partial remission). The difference in response between dMMR and pMMR patients is mainly attributed to variations in tumor load/neoantigens and T cell tumor mutation burden. Higher numbers of tumor-infiltrating PD-1+CD8+ T cells and Th1 T cells have been shown to predict the response of dMMR/MSI-H population to checkpoint blockade (29,30). Additionally, a study on the adjuvant ipilimumab combined with nivolumab in early-stage MSS CRC demonstrated a 27% pathological response rate, further supporting the notion that CRC can be targeted by immunotherapy and is not an immune desert (31). Recently, the combination of vascular endothelial growth factor receptor (VEGFR) inhibitors and anti-PD-1 antibodies has shown encouraging clinical activity in patients with MSS mCRC (32,33). Increasing evidence indicates that vascular endothelial growth factor (VEGF) can inhibit the maturation of dendritic cells, reduce the expression of MHC I, increase the expression of checkpoint molecules, and inhibit the activation of CD8+ T cells by recruiting bone marrow-derived inhibitory cells (34). The R0 hepatectomy rate of mFOLFOX6 combined with bevacizumab was 44.4%, with a favorable outcome rate of 23.1% and a low rate of surgical complications (27). Chemotherapy drugs may lead to liver injury, such as steatohepatitis and sinusoidal obstruction, as well as surgical complications (35). In contrast, the combination of bevacizumab and oxaliplatin can reduce hyperemia (36). The radiologic response rate was high (55.6%), and the pathological response rate was significant (the main response with necrosis of >1/3 of the tumor =42.5%). Based on these findings, the combination of bevacizumab and oxaliplatin is acceptable for patients who are not suitable for liver metastasis resection, and is not limited to the Kras wild-type population (27).

It is well known that bevacizumab targets VEGF-A and has both anti-angiogenesis and immune-modulating effects (12). There is a lack of biomarkers to guide bevacizumab treatment strategies. The interaction between angiogenesis and immunotherapy makes bevacizumab an interesting combination of immunotherapy, and ongoing clinical trials are investigating its potential. These reports suggest that immune checkpoint inhibition combined with bevacizumab may play a role in neoadjuvant therapy for patients with localized liver disease (37). Previous research has shown that chemotherapy can improve the immune score and promote CD8+ T cell infiltration in CRC (38). After tumor cell necrosis or apoptosis, neoantigens can be released and activate cytotoxic T lymphocytes (CTLs) (39). In this study, 5 patients underwent simultaneous resection of the primary tumor and liver metastases, whereas other patients underwent microwave ablation for liver metastases. pCR was achieved in 1 patient with a primary tumor and 2 patients with hepatic lesions. A total of 7 patients were assessed as NED, with a median PFS interval of 9.2 months after multimodality treatments for both primary and metastatic lesions. Therefore, it was concluded that the combination of chemotherapy and targeted therapy with immunotherapy might improve the efficiency of PD-1 blockade for pMMR/MSS CRLM. In this study, neoadjuvant/adjuvant therapy with anti-PD-1 was associated with acceptable AEs. Even when used in combination with chemotherapy and targeted therapy, the toxicity profile was consistent with that observed in other studies using pembrolizumab or nivolumab alone (22). Moreover, there were no AEs leading to surgical delays, and only 1 adverse reaction was recorded secondary to surgery. These results suggest that PD-1 blockade combined with chemotherapy and targeted therapy might be a safe option for CRLM patients planning to undergo surgery.

Certainly, there were some limitations in this study. This study was a retrospectively pilot small cohort with a short postoperative follow-up period. Notably, the response to immunotherapy combined with chemotherapy and targeted therapy was relatively poor in the 2 metachronous CRLM patients. One patient with potentially resectable synchronous CRLM achieved a significant response while presenting with extrahepatic metastases and progression of intrahepatic metastases after the sixth course of the combined therapy, but the primary tumor remained in clinical complete response (cCR). Furthermore, current clinical trials of immunotherapy and targetable therapy mainly focus on patients with primary liver cancer, with limited reports on resectable or potentially resectable CRLM. To determine the role of neoadjuvant immune checkpoint blocking therapy in patients with pMMR/MSS CRLM, more cases and long-term follow-up studies are needed. The abstract of this study has been selected for online publication in 2022 ASCO Annual Meeting (submission ID: 362684, abstract number for publication: e15547).

Conclusions

Although this study has limitations such as its small sample size and retrospective design, we believe that PD-1 blockade combined with chemotherapy and bevacizumab might be safe and effective for patients with pMMR/MSS CRLM. This treatment strategy might lead to better tumor regression and a higher chance of achieving NED. Further phase II clinical studies are required to evaluate the long-term effectiveness of this combined therapeutic approach.

Supplementary

The article’s supplementary files as

10.21037/jgo-23-940 10.21037/jgo-23-940

Acknowledgments

Funding: This work was supported by the National Key Clinical Discipline, the National Natural Science Foundation of China (No. 81972885 ) and the 1010 Project of The Sixth Affiliated Hospital of Sun Yat-sen University (No. 1010CG [2020]-20 ).

Data Sharing Statement

Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-940/dss 10.21037/jgo-23-940

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of The Sixth Affiliated Hospital, Sun Yat-sen University (No. 2022ZSLYEC-39), and all the enrolled patients agreed to receive PD-1 blockade combined chemotherapy and bevacizumab as a neoadjuvant/adjuvant therapy before the treatment. The requirement for individual consent for this retrospective analysis was waived.

Peer Review File
Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-940/prf

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-940/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-940/coif). The authors have no conflicts of interest to declare.
==== Refs
References

1 Keum N Giovannucci E . Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol 2019;16 :713-32. 10.1038/s41575-019-0189-8 31455888
2 Rawla P Sunkara T Barsouk A . Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol 2019;14 :89-103. 10.5114/pg.2018.81072 31616522
3 Sung H Ferlay J Siegel RL Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71 :209-49. 10.3322/caac.21660 33538338
4 Kow AWC . Hepatic metastasis from colorectal cancer. J Gastrointest Oncol 2019;10 :1274-98. 10.21037/jgo.2019.08.06 31949948
5 Van Cutsem E Cervantes A Adam R ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27 :1386-422. 10.1093/annonc/mdw235 27380959
6 Weiser MR Jarnagin WR Saltz LB . Colorectal cancer patients with oligometastatic liver disease: what is the optimal approach? Oncology (Williston Park) 2013;27 :1074-8.24575534
7 Belinson S, Chopra R, Yang Y, et al. Local Hepatic Therapies for Metastases to the Liver From Unresectable Colorectal Cancer. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Dec. Report No.: 13-EHC014-EF.
8 Cirocchi R Trastulli S Boselli C Radiofrequency ablation in the treatment of liver metastases from colorectal cancer. Cochrane Database Syst Rev 2012;(6 ):CD006317. 10.1002/14651858.CD006317.pub3 22696357
9 Puijk RS Ruarus AH Vroomen LGPH Colorectal liver metastases: surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial. BMC Cancer 2018;18 :821. 10.1186/s12885-018-4716-8 30111304
10 Stoltz A Gagnière J Dupré A Radiofrequency ablation for colorectal liver metastases. J Visc Surg 2014;151 Suppl 1 :S33-44. 10.1016/j.jviscsurg.2013.12.005 24582728
11 Modest DP Pant S Sartore-Bianchi A . Treatment sequencing in metastatic colorectal cancer. Eur J Cancer 2019;109 :70-83. 10.1016/j.ejca.2018.12.019 30690295
12 Ntellas P Mavroeidis L Gkoura S Old Player-New Tricks: Non Angiogenic Effects of the VEGF/VEGFR Pathway in Cancer. Cancers (Basel) 2020;12 :3145. 10.3390/cancers12113145 33121034
13 Le DT Durham JN Smith KN Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357 :409-13. 10.1126/science.aan6733 28596308
14 Le DT Uram JN Wang H PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372 :2509-20. 10.1056/NEJMoa1500596 26028255
15 Seymour L Bogaerts J Perrone A iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18 :e143-52. 10.1016/S1470-2045(17)30074-8 28271869
16 Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-4.
17 National Cancer Institute Common terminology criteria for adverse events v4.0 (CTCAE). 2009. Available online: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed December 5, 2017.
18 Hu H Kang L Zhang J Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022;7 :38-48. 10.1016/S2468-1253(21)00348-4 34688374
19 Fukuoka S Hara H Takahashi N Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J Clin Oncol 2020;38 :2053-61. 10.1200/JCO.19.03296 32343640
20 Damato A Iachetta F Antonuzzo L Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated - NIVACOR trial (GOIRC-03-2018). BMC Cancer 2020;20 :822. 10.1186/s12885-020-07268-4 32867715
21 Lenz HJ Parikh A Spigel DR Modified FOLFOX6 plus bevacizumab with and without nivolumab for first-line treatment of metastatic colorectal cancer: phase 2 results from the CheckMate 9X8 randomized clinical trial. J Immunother Cancer 2024;12 :e008409. 10.1136/jitc-2023-008409 38485190
22 Overman MJ McDermott R Leach JL Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18 :1182-91. 10.1016/S1470-2045(17)30422-9 28734759
23 Overman MJ Lonardi S Wong KYM Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol 2018;36 :773-9. 10.1200/JCO.2017.76.9901 29355075
24 Kato T Yasui K Hirai T Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions. Dis Colon Rectum 2003;46 :S22-31.14530655
25 Folprecht G Gruenberger T Bechstein WO Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010;11 :38-47. 10.1016/S1470-2045(09)70330-4 19942479
26 Ye LC Liu TS Ren L Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol 2013;31 :1931-8. 10.1200/JCO.2012.44.8308 23569301
27 Yasuno M Uetake H Ishiguro M mFOLFOX6 plus bevacizumab to treat liver-only metastases of colorectal cancer that are unsuitable for upfront resection (TRICC0808): a multicenter phase II trial comprising the final analysis for survival. Int J Clin Oncol 2019;24 :516-25. 10.1007/s10147-018-01393-8 30612267
28 Wallin J Pishvaian MJ Hernandez G Abstract 2651: clinical activity and immune correlates from a phase Ib study evaluating atezolizumab (anti-PDL1) in combination with FOLFOX and bevacizumab (anti-VEGF) in metastatic colorectal carcinoma. Cancer Res 2016;76 :2651. 10.1158/1538-7445.AM2016-2651
29 Schrock AB Ouyang C Sandhu J Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol 2019;30 :1096-103. 10.1093/annonc/mdz134 31038663
30 Wang C Gong J Tu TY Immune profiling of microsatellite instability-high and polymerase ε (POLE)-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy. J Gastrointest Oncol 2018;9 :404-15. 10.21037/jgo.2018.01.09 29998005
31 Chalabi M Fanchi LF Dijkstra KK Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26 :566-76. 10.1038/s41591-020-0805-8 32251400
32 Fukuoka S Hara H Takahashi N Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J Clin Oncol 2020;38 :2053-61. 10.1200/JCO.19.03296 32343640
33 Wang C Chevalier D Saluja J Regorafenib and Nivolumab or Pembrolizumab Combination and Circulating Tumor DNA Response Assessment in Refractory Microsatellite Stable Colorectal Cancer. Oncologist 2020;25 :e1188-94. 10.1634/theoncologist.2020-0161 32406541
34 Chen DS Hurwitz H . Combinations of Bevacizumab With Cancer Immunotherapy. Cancer J 2018;24 :193-204. 10.1097/PPO.0000000000000327 30119083
35 Kishi Y Zorzi D Contreras CM Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol 2010;17 :2870-6. 10.1245/s10434-010-1166-1 20567921
36 Klinger M Eipeldauer S Hacker S Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol 2009;35 :515-20. 10.1016/j.ejso.2008.12.013 19200687
37 Stift J Graf A Neudert B Immune checkpoints and liver resection after neoadjuvant chemotherapy including bevacizumab in patients with microsatellite-stable colorectal liver metastases. HPB (Oxford) 2022;24 :40-6. 10.1016/j.hpb.2021.05.015 34158230
38 Galluzzi L Buqué A Kepp O Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell 2015;28 :690-714. 10.1016/j.ccell.2015.10.012 26678337
39 Liu DX Li DD He W PD-1 blockade in neoadjuvant setting of DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer. Oncoimmunology 2020;9 :1711650. 10.1080/2162402X.2020.1711650 32042474
