Clinical Relevance and Rationale of Using MSI-H/dMMR Biomarkers in Immunotherapy of Colorectal Cancer and Other Solid Tumors

Faculty Perspectives: Clinical Relevance and Rationale of Using MSI-H/dMMR Biomarkers in Immunotherapy of Colorectal Cancer and Other Solid Tumors | Part 3 of 4-Part

Cancers with deficiency in mismatch repair (dMMR) harbor high levels of microsatellite instability (MSI-H) and high mutational burden.1,2 Although the MSI-H/dMMR phenotype is a known hallmark of hereditary nonpolyposis colorectal cancer (CRC), or Lynch syndrome, it is also a distinctive feature in sporadic CRCs and to varying degrees in several other tumor types.1-3 There is renewed interest in MSI analysis because the MSI-H/dMMR phenotype has emerged as an actionable predictive biomarker for immune checkpoint blockade therapy in different cancer types. This review presents available evidence supporting the clinical relevance and predictive value of MSI/dMMR in cancers, including those treated with immune checkpoint inhibitors (ICIs), and outlines the diagnostic approaches developed to assess MSI/dMMR in clinical practice.

Clinical Utility of MSI-H/dMMR in CRC

MSI refers to differences in length of DNA attributed to spontaneous loss or gain of short repetitive tracts of nucleotides or microsatellites during DNA replication.1,2 It is estimated that cancers with MSI are associated with high mutational burden, with 100- to 1000-fold increased mutation rates of frameshift and missense mutations.1 The MSI phenotype impairs the MMR pathway, which is involved in the surveillance, recognition, and repair of genetic mismatches introduced in the microsatellites.1

Inactivation of the MMR system frequently occurs via mutational inactivation or epigenetic silencing of MMR genes (ie, germline mutations in the MMR genes MSH2, MSH6, MLH1, and PMS2, or somatic hypermethylation of MLH1).1,2 Tumors with MSI-H/dMMR exhibit a high mutation rate and neoantigen load that is positively associated with overall lymphocytic infiltration, tumor-infiltrating lymphocytes, T helper 1 cells, and memory T-cells, ultimately triggering an effective antitumor immune response.1,4,5 Moreover, the MSI-H/dMMR phenotype is associated with upregulated expression of several checkpoint proteins on immune cells, including programmed-cell death-1 (PD-1) and its ligand, PD-L1, indicating that checkpoint inhibition may be a rational therapeutic approach in these tumors.1,5

On the basis of available evidence in CRC, the clinical relevance of MSI-H/dMMR has been described in 3 areas: genetic assessment of Lynch syndrome, prognostication of disease, and prediction of response to conventional chemotherapy.2 The role of MSI as a genetic marker of Lynch syndrome is well established in the clinic and is routinely used for diagnosis. MSI resulting from germline mutations in one of the MMR genes leads to Lynch syndrome, which is characterized by an elevated risk for cancers, particularly for CRC (80% of patients) and endometrial cancer (60% of women).1 By contrast, sporadic tumors show MSI attributed to epigenetic silencing of the MLH1 promoter and are frequently associated with a somatic BRAF V600E mutation.1

In terms of prognostication, CRC exhibiting MSI is associated with a lower stage at diagnosis and improved prognosis (stage-dependent), and it is less prone to lymph node and distant metastatic spread.1,2,6 The prognostic advantage of MSI was demonstrated in a meta-analysis of 32 studies involving 1277 patients with MSI.7

The predictive value of MSI for response to 5-fluorouracil (5-FU), irinotecan, and other chemotherapeutic agents remains controversial. Although some data indicate that MSI-H tumors are less likely to benefit from conventional chemotherapy such as adjuvant 5-FU regimens, other findings show no significant clinical utility in using MSI status to guide treatment decisions on the use of 5-FU.2

Clinical Relevance of MSI-H/dMMR as a Biomarker

More recently, evidence indicates that MSI-H and dMMR are predictive biomarkers of treatment response to ICIs targeting PD-1, PD-L1, and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint receptor.8-16

Pembrolizumab

The anti–PD-1 monoclonal antibody pembrolizumab (Keytruda®; Merck & Co) was granted accelerated approval by the US Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.8,9 This tumor-agnostic, biomarker-guided indication represents a new phase in precision medicine and heralds a paradigm shift in cancer treatment, in which indications and treatment decisions are guided by the presence of a biomarker rather than where in the body the tumor originated.9

Based on hypothesis-generating data from small cohort studies, the premise that MSI-H and dMMR tumors contain a large number of somatic mutations that may render these tumors susceptible to immune checkpoint inhibition was tested in the investigator-initiated phase 2 KEYNOTE-016 study, in which 41 patients with progressive metastatic carcinoma with or without dMMR were treated with pembroliz­umab.8,10 Three cohorts were evaluated: (A) patients with dMMR CRC, (B) patients with MMR-proficient (pMMR) CRC, and (C) patients with dMMR non-CRC cancers. Among patients with dMMR CRC, the immune-related objective response rate (irORR) was 40% (4 of 10 patients) and the 20-week immune-related progression-free survival (irPFS) rate was 78% (7 of 9 patients).8,10

Similar activity was also noted among patients with dMMR non-CRC cancers, with an irORR of 71% (5 of 7 patients) and a 20-week irPFS rate of 67% (4 of 6 patients). By contrast, in patients with pMMR CRC, irORR was 0% and the 20-week irPFS rate was 11% (2 of 18 patients).10 Results of this proof-of-concept study were confirmed in larger, prospective, phase 2 studies (KEYNOTE-158 and KEYNOTE-164) as well as smaller retrospective analyses (KEYNOTE-028 and KEYNOTE-012).8

The approval of pembrolizumab was based on tumor response rate and durability of response from pooled data of 5 single-arm, open-label, biomarker-driven clinical trials (ie, KEYNOTE-016 [N = 58], KEYNOTE-164 [N = 61], KEYNOTE-012 [N = 6], KEYNOTE-028 [N = 5], and KEYNOTE-158 [N = 19]), which demonstrated the activity of pembrolizumab in patients with advanced dMMR cancers, including CRC.8,9 Across the trials, patients received either pembrolizumab 200 mg every 3 weeks or pembrolizumab 10 mg/kg every 2 weeks for a maximum of 24 months or until disease progression or unacceptable toxicity. Tumor status was assessed using local or central laboratory–developed, investigational polymerase chain reaction (PCR) tests for MSI-H status and immunohistochemistry (IHC) tests for dMMR status; these analyses identified dMMR in 47 patients, MSI-H in 60 patients, and both MSI-H/dMMR in 42 patients. In the total study population (N = 149), 39.6% (95% confidence interval [CI], 31.7-47.9) achieved an objective response rate (ORR), including (7.4%) complete responses (CRs) and (32.2%) partial responses (PRs). The median duration of response (DOR) had not yet been reached (range, 1.6+ to 22.7+ months), with 78% of responders maintaining their responses for at least 6 months (Table 1 click here to view).8 ORR was 36% in the 90 patients with CRC and 46% in 59 patients with other tumor types, including endometrial cancer, biliary cancer, gastric or gastroesophageal junction cancer, pancreatic cancer, small intestinal cancer, breast cancer, prostate cancer, esophageal cancer, retroperitoneal adenocarcinoma, and small-cell lung cancer.8

Recent reports attest to the activity of pembrolizumab in several solid tumors in addition to CRC. An expansion study of KEYNOTE-016 evaluated the efficacy of pembroliz­umab in patients with advanced dMMR cancers across 12 different tumor types and reported objective radiographic responses in 53% of 86 patients, including CRs in 21%; median progression-free survival (PFS) and overall survival (OS) were not reached.11 In the KEYNOTE-164 trial that enrolled 61 patients with MSI-H/dMMR CRC who had received ≥2 prior therapies, at data cutoff (February 10, 2017) ORR was 27.9% (n = 17) and median DOR and median OS had not been reached.12 In the phase 2 multicohort KEYNOTE-158 basket study that enrolled 77 patients with MSI-H/dMMR non-CRC across 20 tumor types, at data cutoff (January 27, 2017) ORR was 37.7% (n = 29) and median DOR and median OS had not been reached.12 Subsequent analyses reported durable antitumor activity in the advanced cervical cancer cohort of 98 patients (ORR, 13.3%; median DOR, not reached)13 and in the advanced small-cell lung cancer cohort of 107 patients (ORR, 18.7%; median DOR, not reached), with particular activity noted in PD-L1–positive tumors.13,14

Nivolumab

Based on preliminary antitumor activity observed in early trials of pembrolizumab in patients with MSI-H/dMMR metastatic CRC (mCRC), the multicenter, open-label, phase 2 CheckMate-142 trial evaluated the efficacy and safety of the anti–PD-L1 antibody nivolumab (Opdivo®; Bristol-Myers Squibb) alone or in combination with ipilimumab in pretreated patients with MSI-H and/or dMMR mCRC. Eligible patients were adults aged ≥18 years with histologically confirmed recurrent or metastatic CRC assessed as MSI-H/dMMR positive and who had progressed on or after, or been intolerant of, ≥1 prior treatments, including a fluoropyrimidine plus oxaliplatin or irinotecan.15

Separate analyses of the nivolumab and nivolumab plus ipilimumab cohorts were reported.15,16 In both cohorts, the primary end point was investigator-assessed ORR as per Response Evaluation Criteria in Solid Tumors, version 1.1. Both cohorts were heavily pretreated, with 54% of patients in the nivolumab monotherapy cohort and 40% in the nivolumab plus ipilimumab cohort having received ≥3 prior systemic therapies, including 5-FU, oxaliplatin, irinotecan, VEGF inhibitors (bevacizumab, aflibercept, and ramucirumab), and EGFR inhibitors (cetuximab and panitumumab).15,16

Nivolumab monotherapy

In the nivolumab monotherapy cohort of CheckMate-142, 74 patients with MSI-H/dMMR mCRC received nivolumab 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxic effects, withdrawal of consent, or end of study.15 Notably, of these, 29 tumors (39%) were both BRAF and KRAS wild-type and 12 (16%) harbored a BRAF mutation. At a median follow-up of 12 months, investigator-assessed ORR was 31.1%, and 69% of patients had disease control for 12 weeks or longer; median DOR had not been reached (Table 2 click here to view).15 These responses were observed across all subgroups tested, regardless of tumor or immune cell PD-L1 expression, BRAF or KRAS mutation status, or clinical history of Lynch syndrome. The 12-month PFS was 50% (95% CI, 38%-61%) and the 12-month OS rate was 73% (95% CI, 62%-82%).15

The safety profile of nivolumab was consistent with that previously reported, with no new safety signals reported. Grade 3/4 drug-related adverse events (AEs) were reported in 15 patients (20%), including 6 (8%) with increased lipase and 2 (3%) with increased amylase. Five patients (7%) discontinued treatment due to drug-related AEs; no treatment-related deaths occurred. Analyses of patient-reported outcomes showed clinically meaningful improvements in functioning, symptoms, and quality of life. As assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) instrument, ≥50% of patients reported no clinically meaningful (≥10-point change) deterioration in functioning or worsening of symptoms and global health status or quality of life.15 Based on these results, the FDA granted accelerated approval of nivolumab for the treatment of patients with MSI-H/dMMR mCRC who have progressed on conventional chemotherapy.17

Nivolumab plus ipilimumab combination therapy

In the nivolumab plus ipilimumab combination cohort of CheckMate-142, 119 patients with MSI-H/dMMR mCRC were enrolled. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (4 doses), followed by nivolumab 3 mg/kg once every 2 weeks.16 At baseline, 22% of patients had a PD-L1 expression level ≥1%, 55% had a level <1%, 29% had Lynch syndrome, 26% had BRAF/KRAS wild-type, 24% were BRAF mutation–positive, and 37% were KRAS mutation–positive. At a median follow-up of 13.4 months, the investigator-assessed ORR was 55%, including 4 (3%) CRs and 61 (51%) PRs; the disease control rate for ≥12 weeks was 80% (Table 3 click here to view).16 Durable responses were achieved with combination treatment; at data cutoff, median DOR had not been reached and responses were ongoing in 94% of responders. Those responding achieved a response irrespective of tumor BRAF or KRAS mutation status (ORR: BRAF-positive, 55%; KRAS-positive, 57%; and BRAF/KRAS wild-type, 55%) or tumor PD-L1 expression (≥1, 54%; <1, 52%). Patients with a clinical history of Lynch syndrome had an ORR of 71% compared with 48% among patients with no such history. The 12-month rates of PFS and OS were 71% and 85%, respectively, both of which were higher than those achieved with nivolumab monotherapy.15,16

Treatment-related AEs (TRAEs) of any grade were experienced by 73% of patients, with 13% discontinuing treatment due to TRAEs. Grade 3/4 TRAEs that occurred in 32% of patients included increased aspartate aminotransferase (8%), increased alanine aminotransferase (7%), diarrhea (2%), fatigue (2%), pruritus (2%), rash (2%), hypothyroidism (1%), and nausea (1%). With combination therapy, no new safety signals or treatment-related deaths were observed. Patient-reported outcomes, as assessed by the EORTC QLQ-C30 and the EuroQol 5 dimensions visual analog scale, demonstrated statistically significant and clinically meaningful improvements in key symptoms, functioning, and global health status/quality-of-life measures, which were maintained with continued treatment.16

The FDA has approved the combination of nivolumab and low-dose ipilimumab for the treatment of adult and pediatric patients aged 12 years and older with MSI-H/dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This accelerated approval was based on ORR and DOR rates from the ongoing phase 2 CheckMate-142 study.18

Ongoing Trials

Several ongoing trials in different phases of clinical testing are evaluating checkpoint inhibitors in MSI-H or dMMR solid tumors. Prominent among these is the ongoing phase 3 KEYNOTE-177 trial (NCT02563002)19 that is evaluating whether frontline treatment with pembrolizumab can improve PFS compared with standard-of-care chemotherapy in patients with stage IV CRC. In the KEYNOTE-177 trial, patients with locally confirmed MSI-H/dMMR advanced CRC will be randomly assigned to either pembrolizumab 200 mg every 3 weeks or investigator’s choice of 1 of 6 chemotherapy regimens (chosen before randomization) until disease progression, unmanageable toxicity, or the completion of 35 cycles (pembrolizumab only). A crossover is allowed for patients who progress on the standard chemotherapy arm who would prefer anti–PD-1 therapy. The primary end points are PFS and OS; the secondary end point is ORR.19

In addition, a phase 2 clinical trial is evaluating nivolu­mab or nivolumab combinations in recurrent and metastatic MSI-H and non–MSI-H colon cancer (NCT02060188).20 An estimated 340 participants will receive either nivolumab monotherapy, nivolumab plus ipilimumab with or without cobimetinib, nivolumab plus BMS-986016, or nivolu­mab plus daratumumab. The primary outcome measure is investigator-assessed ORR in all MSI-H and non–MSI-H subjects. Another phase 2 trial is studying a combination of nivolumab plus ipilimumab with radiation therapy in microsatellite-stable CRC, pancreatic cancer, or MSI-H CRC (NCT03104439).21 Other checkpoint inhibitors such as durvalumab are undergoing clinical testing in dMMR CRC patients (NCT02227667).22

Testing Landscape of MSI-H/dMMR

MSI testing is routinely performed in diagnostic laboratories and is currently optimized for the detection of MSI in CRC. Molecular detection of MSI is commonly done by 2 reliable methods: (1) examining informative microsatellite markers using PCR-based methods or (2) IHC detection of MMR proteins.2,23

Although the human genome contains several microsatellites, MSI testing for diagnostic purposes typically involves amplifying predefined microsatellite loci using PCR. The 1997 “Bethesda guidelines” recommend a reference panel of 5 microsatellite loci (BAT25, BAT26, D5S346, D2S123, and D17S250), which are initially amplified in both the tumor and normal tissue, with the sizes assessed by gel or capillary electrophoresis using autoradiography, silver staining, or fluorescent methods.1,24,25 Comparison of sample microsatellite sizes to normal DNA from the same individual allows determination of MSI status. There are 3 categories of MSI, depending on the MSI score obtained: (1) high, defined as instability in ≥2 of the microsatellite loci or ≥30% of the larger panel loci; (2) low, described as instability in only 1 of the microsatellite loci or 10% to 30% of the larger panel loci; and (3) stable, defined as absence of any evidence of microsatellite loci instability or <10% of the larger panel loci.2,24

Alternatively, MSI testing may be performed with real-time quantitative PCR melting point analysis with sequence-specific fluorescent-labeled hybridization probes.25 More recently, the advent of next-generation sequencing (NGS) with targeted gene sequencing or whole exome/genome sequencing is allowing examination of several microsatellites simultaneously using computational tools such as mSINGS, MSIsensor, MANTIS, and MOSAIC, which may pave the way for easier integration of MSI testing into routine clinical practice.26

As a complement to genetic MSI testing in Lynch syndrome, assessment of the expression profile of MMR proteins (such as MSH2, MLH1, and PMS2) by IHC using mutation-specific monoclonal antibodies provides a snapshot of the functionality of the MMR system.2 A diagnosis of dMMR is made based on the lack of expression of ≥1 MMR proteins, and interpretation of the IHC protein expression patterns directs which gene should undergo further germline evaluation.1,2,23 For example, expression of MSH2 and MSH6 but not of MLH1 and PMS2 is indicative of deficient MLH1 expression. In addition, the MSI phenotype is strongly associated with mutations in specific oncogenes and tumor suppressor genes, particularly BRAF (BRAF V600E mutation).2 Therefore, typical MMR testing involves assessment of not only MMR protein expression but also somatic mutations in BRAF.

In sporadic unstable tumors, the molecular basis for instability predominantly stems from hypermethylation of the MLH1 promoter, leading to epigenetic silencing of the MLH1 promoter and loss of both mRNA and protein expression; lack of expression of MSH2, MSH6, or PMS2 proteins is usually not seen.2,23 Another distinguishing feature of sporadic tumors from Lynch syndrome is the presence of the BRAF V600E mutation, which is documented in 50% to 68% of tumors.23

Future Perspectives on MSI-H/dMMR

In MMR-proficient tumors that harbor no mutations in the MMR genes, other causes of hypermutations have been described in different cancers, including somatic or germline mutations in DNA polymerase epsilon (POLE) and DNA polymerase D1 (POLD1) genes in CRC.27,28 DNA polymerase delta (encoded by the POLD1 gene) and polymerase epsilon (encoded by the POLE gene) are enzymes involved in both synthesis and repair of DNA and carry an exonuclease (proofreading) domain that corrects errors during replication, thus ensuring a high-fidelity replication process.28 CRC with mutations in the exonuclease domain of POLE is associated with a high number of mutations, multiple tumor neo-epitopes, and extensive T-lymphocyte infiltration; this predisposes patients to multiple colorectal adenomas and carcinomas, suggesting that a hypermutated phenotype in POLE may be a useful predictive biomarker in this disease.28 Furthermore, POLE-mutated tumors are associated with an upregulation of genes that encode immune checkpoints, such as PD-1, PD-L1, and CTLA4.28 Taken together, polymerase mutations may be new molecular markers beyond dMMR that can be used to identify hypermutated CRC tumors that may respond to ICIs.

As recently demonstrated, anti–PD-1 or anti–PD-L1 checkpoint antibodies may represent viable and effective treatment options for patients with MSI-H/dMMR status, biomarkers that have been shown to predict response to immune checkpoint blockade in solid tumors. These data and the findings of the MSI/dMMR molecular signature across a wide range of tumor types has thrust MSI testing onto center stage, underscoring the need to assess MSI and dMMR status in a broad group of patients with cancer. However, although MSI testing has been accessible to molecular pathology laboratories and is increasingly becoming an integral part of molecular biomarker evaluations in CRC, its prognostic and predictive role for other tumor types has thus far not been fully appreciated, and MSI testing has not been incorporated into daily clinical routine testing outside of CRC. Broader adoption of MSI and MMR assays across tumor types is needed, which will likely require the application of novel technologies and methods allowing comprehensive examination of genomic and immune microenvironment profiles. Use of multipanel NGS platforms may facilitate easier adoption of MSI/dMMR assays in clinical practice and eliminate the need for separate testing by IHC or PCR.

There is uncertainty about the optimal timing to conduct MSI, dMMR, and PD-L1 testing. Previous cancer therapy has been shown to influence changes in MSI status, as evidenced in a study of 239 patients with surgically resected CRC after administration of neoadjuvant therapy.29 MMR expression analysis of 37 patients with matched, paired pre- and post-treatment specimens found expression changes in MMR genes following therapy, underscoring the importance of timing of the test in the interpretation of results.29

The approval of immunotherapy based on MSI biomarker status rather than tumor histology gives credence to the role of MSI as a predictive biomarker, not only in CRC but also for other tumor types, and represents an important milestone in oncology. Data from well-designed clinical trials will provide further support for the clinical utility and implementation of MSI in daily clinical practice.

References

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Last modified: November 12, 2018