An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

Figures & data

Figure 1 Flowchart showing the systematic literature search and screening procedure following the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Data extraction was performed using modified criteria based on the guidelines given by the Cochrane Collaboration for the 31 studies included.

Table 1 Study Characteristics and Response Data from Included Cohort Studies

Study	Country	Cancer Center	Study Design	LS Cases	Total Cohort	Cancer Type	Treatment	ORR (LS)	PFS (LS)	ORR (Spor. MSI)	MMR Germline Mutation	Details/Comments
Le et al, 2015^Citation19	USA	Johns Hopkins University	Prospective, multicenter study (3 centers included)	N=13	N=41 (MSS and MSI tumors)	Colorectal cancer and noncolorectal cancer	Pembrolizumab	CRC: 25% NonCRC: 33% Total: 27%	PFS: none	CRC: 100% NonCRC: 100%	CRC: MLH1 (N=3), MSH2 (N=3), unknown (N=2), non-RC: MSH2 (N=3)	Phase II trial incl. 13 LS pts. Response evaluable for 11 LS pts and 4 sporadic MSI cases. LS CRC: 2 PR, 5 SD, 1 PD; LS nonCRC: 1 PR, 2 PD; sporadic CRC: 2 PR; sporadic nonCRC: 2 PR
Le et al, 2017^Citation25	USA	Johns Hopkins University	Prospective, multicenter study (6 centers included)	N=39	N=86 (only MSI tumors)	Colorectal cancer and noncolorectal cancer	Pembrolizumab	CRC: 46% NonCRC: 59%	Not specified for LS	Not specified	3 unknowns, CRC: MLH1 (N=6), PMS2 (N=2), MSH2 (N=9), MSH6 (N=1), VUS (N=2); nonCRC: MLH1 (N=3), MSH2 (N=7), MSH6 (N=3), VUS (N=3)	Phase II trials incl. 39 LS pts. ORR are calculated for all 39 LS, though germline mutation was only reported for 36 cases including 5 VUS cases. Average time to response for the entire study cohort was 21 weeks. No data available for sporadic MSI alone and no specific PFS or responses for LS alone. ORR for the total cohorts: CRC: 52%; nonCRC: 54%
Overman et al, 2018^Citation8	USA	MD Andersen Cancer Center	Prospective, multicenter study (28 centers)	N=35	N=119 (MSI or dMMR tumors)	Metastatic colorectal cancer	Nivolumab + ipilimumab	71%	Not specified for LS	48%	35 LS cases (clinical history, germline testing not mandatory)	Phase II trial incl. 35 LS pts (25 responders), 31 pts with sporadic MSI tumors (15 responders), and 53 pts with unknown LS status (25 responders).
Hu et al, 2018^Citation33	USA	Memorial Sloan Kettering Cancer Center	Retrospective cohort study	N=7	N=833 (MSS and MSI tumors)	Pancreatic ductal adenocarcinoma	Anti-PD-1/anti-PD-L1	60%	PFS: mean 12,5 months (of 4 pts)	NA	MLH1 (N=1), PMS2 (N=1), MSH2 (N=2), MSH6 (N=1)	833 consecutively collected pancreatic cancers investigated for dMMR/MSI—7 cases with MSI (all LS), of which 5 were treated with evaluable response: 1 CR, 2 PR, 1 SD and 1 PD
Raj et al, 2019^Citation32	USA	Memorial Sloan Kettering Cancer Center	Prospective, single center study	N=2	N=39 (MSS and MSI tumors)	Adrenocortical carcinoma	Pembrolizumab	100%	PFS: mean 27.5 months	0%	MSH2 (N=1) MSH6 (N=1)	Phase II trial with 39 pts not selected for MSI/dMMR. 6 tumors showed MSI/dMMR, incl. 2 LS pts with PR response. 4 pts with sporadic MSI tumors: 2 SD, 2 PD
Abida et al, 2019^Citation31	USA	Memorial Sloan Kettering Cancer Center	Prospective, single center study	N=2	N=1033 (MSS and MSI tumors)	Prostate cancer	Anti-PD1/PDL1 therapy	50%	Mean PFS: 5.6 months	50%	MSH2 (N=1) MSH6 (N=1)	1033 consecutively collected prostate cancer patients of which 11 pts were treated, 8 pts completed/evaluated. Sporadic MSI: 3 PR + 1 SD + 2 PD; LS: 1 PR + 1 PD. Only MSI/dMMR tumors were evaluated for response to therapy. One MSS tumor in a patient with an MSH6 germline variant was not treated.
Bari et al, 2020^Citation21	USA	H. Lee Moffitt Cancer Center	Retrospective, single center study	N=22	N=194 (only LS tumors—MSS and MSI)	Different cancer types	Immune checkpoint inhibitors (80% pembrolizumab)	14%	NA	NA	262 LS cases (mutated genes not reported)	Retrospectively collected cohort focused on LS cases identified 22 pts treated, 1 PD after 1 month, 21 pts evaluated: 2 CR, 1 PR, 13 SD and 5 PD

Abbreviations: ORR, objective response rate; PFS, progression-free survival; CRC, colorectal cancer; MSI, microsatellite instable; MSS, microsatellite stable; LS, Lynch syndrome; NA, not available; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; pts, patients.

Table 2 Study Characteristics and Response Data from Included Case Reports

Study	Country	Cancer Center	Study Design	Cancer Type	Treatment	Line of Therapy	Response	Criteria	Progression-free survival	MMR Germline Mutation	Details/Comments
Chan et al. 2020^Citation37	USA	Saint Michael’s Medical Center	Case report (N=1)	Colon cancer	Pembrolizumab	3. line	PD (N=1)	RECIST	PFS: 1 month	MSH6 mutation carrier	1 pt treated with PD after 1 month (1 cycle)
Salman et al, 2018^Citation36	Chile	Arturo Lopez Pérez	Case report (N=1)	Colorectal cancer	Pembrolizumab	2. line	SD (N=1)	RECIST	PFS: 7 months	MSH2/EPCAM mutation carrier	1 pt treated with SD at 2.8 months (mean of 2 metastases) and PD at 7 months (mean of 2 metastases)
Keating et al, 2019^Citation35	USA	Roger Williams Medical Center	Case report (N=1)	Metastatic colorectal cancer	Pembrolizumab	4. line	SD (N=1)	Clinical benefit	PFS: 42 months	MSH2 mutation carrier	1 pt treated with SD at 42 months
Demisse et al, 2020^Citation28	USA	UC Davis Comprehensive Cancer Center	Case report (N=1)	Advanced rectal cancer	Pembrolizumab	1. line	PR (N=1)	RECIST	PFS: 10 months	Unspecified clinical history, no MMR gene test available	1 pt treated with pathologic CR after surgery at 10 months
Zhang et al, 2019^Citation29	China	The Sixth Affiliated Hospital, Sun Yat-sen University	Case report (N=2)	Locally advanced rectal cancer	Nivolumab	1. line (pt #1) and 2. line (pts #2)	CR (N=2)	Pathologic complete response	PFS: Mean 12 months	Amsterdam I, no MMR gene test available	2 pts treated with pathological and clinical CR at 1 year
Patel et al, 2018^Citation26	USA	Stanford Cancer University	Case report (N=1)	Rectal cancer	Pembrolizumab	2. line	PD (N=1)	Tumor increase	PFS: 1.4 months	Carrier of two MSH6 VUS	1 pt treated tumor progression after 1.4 month
Feng et al, 2019^Citation38	China	Bejing National Cancer Center	Case report (N=1)	Ureter + colorectal cancer	Pembrolizumab	4. line	PR (N=1) PD (N=1)	RECIST	PFS: 7 months	MSH2 mutation carrier	1 pt treated: PR in ureter at 7 months and PD in CRC
Ghatalia et al, 2017^Citation18 and Winer et al, 2019^Citation24	USA	Brown University	Case report (N=1)	Metastatic colorectal cancer + bilateral ureter cancer + bladder cancer	Pembrolizumab Atezolizumab Pembrolizumab Nivolumab + Ipilimumab Nivolumab	3. line for CRC and 1 line for urothelial cancers	SD (CRC) SD (N=3 urothelial cancers)	Tumor decrease	PFS: 26 months	MSH2 mutation carrier	1 pt with 4 cancers (3 urothelial tumors and liver metastases from a previous CRC) treated with different regimens due to progression three times—tumor decrease of urothelial tumors and disease control for CRC metastasis at 26 months
Musher and Rahal, 2019^Citation34	USA	Baylor College of Medicine	Case report (N=1)	Colorectal cancer (N=1) and intrahepatic cholangiocarcinoma (N=1)	Pembrolizumab	1. line	PR (N=2)	RECIST	PFS: 18 months	MLH1 mutation carrier	1 pt with 2 primary tumors—both responsive at 16 months
Yang et al, 2019^Citation48	USA	Virginia Commonwealth University	Case report (N=1)	Glioblastoma multiforme	Pembrolizumab	2. line	SD (N=1)	RECIST	PFS: 12 months	MSH6 mutation carrier	1 patient treated with SD at 12 months
Bouffet et al, 2016^Citation23 and Larouche et al, 2018^Citation22	Canada	The hospital for sick children and Montreal Children’s hospital	Case report (N=2)	Glioblastoma multiforme	Nivolumab Nivolumab Nivolumab + ipilimumab Nivolumab	2. line(pt #1) and 1. line (pt #2)	PR (N=1) (pt #1) CR (N=1) (pt #2)	RECIST	PFS: 11 months (pt #1) and 30 months (pt #2)	Homozygous biallelic PMS2 mutations	Siblings with biallelic MMR mutations—one had PR at 1,4 months and PD at 11 months and the other had PR at 9 months and CR at 30 months
Kawashima et al, 2019^Citation39	Japan	Japanese Foundation for Cancer research	Case report (N=1)	Lung cancer	Nivolumab	2. line	SD (N=1)	Tumor decrease	PFS: 2 months	MSH2 mutation carrier	1 pt treated with tumor decrease at 2 months
Masuzawa et al, 2020^Citation40	Japan	Keio University School of Medicine	Case report (N=1)	metastatic non-small-cell lung cancer	Nivolumab	3. line	PR (N=1)	RECIST	PFS: 27 months	MLH1 mutation carrier	1 pt treated with response at 7 months
Nevgi et al, 2020^Citation41	Australia	University of Melbourne	Case report (N=1)	Adrenocortical carcinoma	Nivolumab + ipilimumab	2. line	PR (N=1)	Tumor decrease	PFS: 23 months	MSH2 mutation carrier	1 pt treated with PR of liver metastases at 23 months
Casey et al, 2018^Citation42	UK	Cambridge University	Case report (N=1)	Adrenocortical carcinoma	Pembrolizumab	2. line	PD (N=1)	RECIST	PFS: 2.8 months	MSH2 mutation carrier	1 pt with recurrence and liver metastases treated with progression at 2.8 months
Mancuso et al, 2020^Citation43	Canada	Cancer Prevention Centre	Case report (N=1)	Muscle invasive bladder cancer	Pembrolizumab	2. line	CR (N=1)	RECIST	PFS: 22 months	MSH2 mutation carrier	1 pt treated with CR at 22 months
Graham et al, 2020^Citation46	USA	University of Washington and University of Michigan	Case report (N=2)	Metastatic prostate cancer	Pembrolizumab	2. line	SD (N=2)	PSA decrease	PFS: Mean 12,5 months	MSH2 mutation carriers	2 pts treated with decreasing PSA and clinical response at 10 and 15 months
Patil and Khan, 2020^Citation47	USA	Henry Ford Health System	Case report (N=1)	Pancreatic cancer	Pembrolizumab	3. line	PR (N=1)	Tumor decrease	PFS: 11 months	MLH1 mutation carrier	1 pt treated with PR in liver metastases at 11 months
Hu et al, 2018^Citation49	USA	Memorial Sloan Kettering Cancer Center	Case report (N=1)	Pancreatic cancer	Anti-PD-L1-therapy	2. line	PD (N=1)	Clinical benefit	PFS: 22 months	MLH1 mutation carrier	1 pt treated with PD at 22 months. Immunotherapy continued despite gynecological metastases
Ngo et al, 2020^Citation44	USA	University of Louisville School of Medicine	Case report (N=1)	Pancreatic cancer	Pembrolizumab	3. line	PR (N=1)	Tumor decrease	PFS: 35 months	MSH2 mutation carrier	1 pt treated with two liver metastases—1 responded all 35 months and the other progressed after 8 months but remained decreased after radiation
Patel et al, 2018^Citation26	USA	Stanford Cancer Institute	Case report (N=1)	Pancreatic cancer	Pembrolizumab	2. line	SD (N=1)	Tumor decrease	PFS: 11.9 months	MLH1 VUS carrier	1 pt treated with pancreatic cancer and 3 vetebral metastases—tumor decrease after 11.9 months
Tlemsani et al, 2020^Citation45	France	Hôpital Cochin	Case report (N=1)	Rhabdomyosarcoma	Nivolumab	2. line	CR (N=1)	RECIST	PFS: 12 months	MLH1 mutation carrier	1 pt treated with lung metastases completely removed at 12 months
Carvalho et al, 2020^Citation27	Brazil	University of Sao Paulo	Case report (N=1)	Endometrial cancer	Pembrolizumab	1. line	PR (N=1)	RECIST	PFS: 24 months	MLH1 VUS carrier	1 pt treated after hysterectomy with lymph node metastases—PR at 2.1 month and sustained for 24 months

Abbreviations: ORR, objective response rate; PFS, progression-free survival; CRC, colorectal cancer; MSI, microsatellite instable; MSS, microsatellite stable; LS, Lynch syndrome; VUS, variant of unknown significance; NA, not available; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; PSA, prostate specific antigen; pt/pts, patient/patients.

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