Immunotherapy and metastatic colorectal cancers

To cite this article: Cohen R, et al. Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency. Bull Cancer (2018), https://doi.org/10.1016/j.bulcan.2018.09.004 Bull Cancer 2018; //: ///

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Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency Romain Cohen 1, Anna Pellat 1, Hélène Boussion 2, Magali Svrcek 3, Daniel Lopez-Trabada 2, Isabelle Trouilloud 2, Pauline Afchain 2, Thierry André 1

Received 20 July 2018 Accepted 11 September 2018 Available online:

1. AP–HP, Sorbonne université, hôpital Saint-Antoine, department of medical oncology, 75012 Paris, France 2. AP–HP, hôpital Saint-Antoine, department of medical oncology, 75012 Paris, France 3. AP–HP, Sorbonne université, department of anatomopathology, hôpital SaintAntoine, 75012 Paris, France

Correspondence: Romain Cohen, Hôpital Saint-Antoine, service d'oncologie médicale, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France. [email protected]

Keywords Microsatellite instability Colorectal cancer Immune checkpoint Mismatch repair Lynch syndrome BRAF

Summary Microsatellite instability (MSI) is a molecular indicator of defective DNA mismatch repair (dMMR) and is observed in approximately 5% of metastatic colorectal cancers (mCRC). MSI is a major predictive biomarker for the efficacy of immune checkpoint inhibitors (ICKi) amongst mCRC patients. After summarizing the literature about the efficacy of conventional cytotoxic regimens, we will highlight studies that have demonstrated the clinical activity of ICKi for patients with chemoresistant MSI/dMMR mCRC. Then we will focus on ongoing clinical trials and emerging challenges for the treatment of patients with MSI/dMMR mCRC.

Introduction Microsatellite instability (MSI) is caused by the deficiency of the DNA mismatch repair (MMR) system, resulting from a germline mutation in MMR genes (MLH1, PMS2, MSH2, MSH6) predisposing to Lynch syndrome, or from an epigenetic inactivation of MLH1 (i.e. sporadic cancers). Approximately 5% of metastatic colorectal cancers (mCRC) exhibit MSI or dMMR [1]. Importantly, sporadic MSI/MMR-deficient (dMMR) CRCs are frequently associated with the BRAFV600E mutation, through its association with CpG island methylator phenotype (CIMP): one third of MSI/ dMMR mCRC are BRAFV600E-mutated and one fifth of all BRAFV600E-mutated mCRC are MSI/dMMR [2].

MSI is associated with favorable prognosis in localized CRC but poor outcomes in metastatic setting [3]. Indeed, Venderbosch et al. showed in a pooled analysis of four phase III studies that MSI was associated with reduced progression-free survival and overall survival, with an insignificant negative effect of BRAFV600E mutation amongst MSI/dMMR mCRC [2]. However, these results were not confirmed in a post-hoc analysis of the CALGB 80405 trial, with no impact of MSI on survival, whereas BRAFV600E mutation and CMS1 (Consensus Molecular Subtype) were associated with poor outcomes [4,5]. Our group also showed in a retrospective multicenter series that BRAFV600E had no significant prognostic impact on MSI/dMMR mCRC

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tome xx > n8x > xx 2018 https://doi.org/10.1016/j.bulcan.2018.09.004 © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

BULCAN-632

To cite this article: Cohen R, et al. Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency. Bull Cancer (2018), https://doi.org/10.1016/j.bulcan.2018.09.004

Review

R. Cohen, A. Pellat, H. Boussion, M. Svrcek, D. Lopez-Trabada, I. Trouilloud, et al.

patients, whereas the inherited or sporadic origin of the MMR deficiency did [6]. The paradoxical prognostic impact of MSI in stage II versus stage IV CRC might be explained by the overexpression of immune checkpoints (ICK) that counterbalances the positive effect of immune infiltrates on survival [7,8]. MSI/dMMR CRCs are characterized by a high tumor mutational burden (i.e. hypermutated phenotype), with highly immunogenic neoantigens arising from frameshift mutations. These tumors are associated with an upregulation of ICK (PD-1, PDL1, CTLA-4, LAG-3, IDO, etc.) that protects MSI cancer cells from their hostile immune microenvironment characterized by a high infiltration by activated cytotoxic T CD8+ lymphocytes [7,9]. MSI and dMMR have emerged as major predictive biomarkers for the efficacy of immune checkpoint inhibitors (ICKis), especially for mCRC patients. In this review, we will summarize data currently available on the efficacy of conventional chemotherapies amongst MSI/dMMR mCRC to go on ICKis and their promising clinical activity in this population. We will then focus to perspectives and issues that might become challenging for the treatment of MSI/dMMR mCRC patient in the next future.

Clinical activity of conventional chemotherapy The literature is very poor concerning the sensitivity of MSI/ dMMR mCRC to conventional cytotoxic agents and targeted therapies such as antiangiogenics and anti-EGFR monoclonal antibodies (mAbs). In a pooled analysis of CAIRO, CAIRO2, COIN and FOCUS trials, Venderbosch and colleagues showed that median progression-free survival (PFS) was significantly reduced in the MSI/dMMR population compared to microsatellite stable (MSS) mCRCs: 6.2 versus 7.6 months respectively, hazard ratio (HR) = 1.33 (1.12–1.57) [2]. In a large multicenter

French study with 284 MSI/dMMR mCRC patients, median PFS on palliative first-line chemotherapy was 3.9 months, with no observed difference according to the chemotherapy regimen (5fluorouracil-based, oxaliplatin-based or irinotecan-based). The addition of bevacizumab and anti-EGFR agents was associated with an unsignificant enhancement of median PFS [10]. Importantly, neither BRAF mutation neither the origin of the MMR deficiency (i.e. Lynch syndrome or sporadic) was found to impact first-line median PFS [2,6,10]. Interestingly, a post-hoc analysis of the CALGB 80405 study found that MSI mCRC patients might have improved survival when treated with bevacizumab compared to cetuximab; given the small number of patients, these results require confirmatory results [5].

Clinical activity of immune checkpoints inhibitors ICKis have demonstrated impressive clinical activity amongst MSI/dMMR mCRC patients. Three distinct regimens have been already evaluated in patients with chemoresistant MSI/dMMR mCRC: pembrolizumab, nivolumab alone (anti-PD-1 mAbs) and in association with ipilimumab (anti-CTLA4 mAb) [11–15]. Results of these non-randomized phase II studies are summarized in table I. One of the most clinically relevant endpoint is the duration of response (DOR) of MSI/dMMR tumors to ICKi, which was still not reached in none of the 4 reported cohorts (median duration of follow-up superior to 12 months in each cohort). This is a major indicator of the high durable activity of these compounds amongst MSI/dMMR tumors, which is also depicted by the high proportion of patients with long-term event-free survival (i.e. the survival curve tale with a highaltitude plateau).

TABLE I Immune checkpoint inhibitors in MSI/dMMR metastatic colorectal cancer n

CR (%)

PR (%)

SD (%)

PD (%)

NE (%)

1-year PFS rate (%)

Median PFS (months)

Median OS (months)

Median follow-up (months)

28

11

46

32

4

7

–

NR

NR

8.7

Pembrolizumab, cohort A 2 prior lines of therapy [28]

61

0

28

23

46

3

34

2.3

NR

13.2

Pembrolizumab, cohort B 1 prior line of therapy [14]

63

3

29

25

40

3

41

4,1

NR

12.6

Nivolumab [29]

74

9

24

31

31

5

44

6.6

NR

21

Nivolumab + ipilimumab [11]

119

3

51

31

12

3

71

NR

NR

13.4

Keynote-016 [15] Pembrolizumab Keynote-164

CheckMate-142

2

CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; PFS: progression-free survival; OS: overall survival; NE: not evaluable; NR: not reached.

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Toxicity of immune checkpoint inhibitors Toxicity of ICKis seems manageable. No treatment-related death has been reported in these studies. Grade 3 or 4 treatmentrelated adverse events were reported respectively in: 11% of patients treated with pembrolizumab (KEYNOTE-164 cohort B): diarrhea (2%), anemia (2%), pneumonitis (2%); 21% of patients treated with nivolumab alone: elevated lipase (8%), elevate AST and/or ALT (1%), maculopapular rash (1%); 32% of patients in the cohort combining nivolumab and ipilimumab: elevated AST and/or ALT (11%), elevated lipase (4%), anemia (3%), and colitis (3%). Interestingly, among patients of the nivolumab plus ipilimumab cohort who discontinued treatment because of adverse events (n = 16), the objective response rate and the disease control rate 12 weeks were respectively 63% and 81%, consistent with efficacy results in the overall population.

Immunotherapy or chemotherapy? Pembrolizumab is currently under evaluation in first-line setting in a phase 3 randomized controlled trial. The Keynote-177 study (NCT02563002) evaluates the efficacy and safety of this anti-PD1 mAb versus standard-of-care chemotherapy as first-line therapy for MSI/dMMR mCRC. Patients are randomized to receive pembrolizumab 200 mg every 3 weeks or investigator's choice of chemotherapy (FOLFOX6 m or FOLFIRI alone or in combination with bevacizumab or cetuximab). Treatment will continue until disease progression, unacceptable toxicity or completion of 35 cycles (pembrolizumab, i.e. 2 years). Crossover to pembrolizumab for patients randomized in the control arm is allowed. Primary end point is PFS per RECIST v1.1 by central review. This phase 3 study, which recruitment is completed (number of patients to include: 270), might lead to the approval of pembrolizumab in first-line for MSI/dMMR mCRC patients if this trial met its primary endpoint. Enrollment is completed and results are awaited soon. In first-line setting, the COMMIT phase III trial studies atezolizumab (anti-PD-L1 mAb; NCT02997228) alone or in combination


with FOLFOX and bevacizumab, as compared to FOLFOX bevacizumab (control arm) for chemo-naïve MSI/dMMR mCRC patients. The primary objective is progression-free survival. This study, as well as the SAMCO trial (see below), will provide the first data concerning the clinical activity of PD-L1 blockade for MSI/dMMR mCRCs. The PRODIGE 54 - SAMCO study is a phase II randomized trial (NCT03188326) comparing avelumab, an anti-PD-L1 mAb, to standard chemotherapy in second-line setting for patients with MSI/dMMR mCRC. There is no planned crossover to avelumab in case of disease progression with conventional chemotherapy. The NIPICOL single-arm phase II study (55 patients planned; NCT03350126), which is sponsored by the Groupe coopérateur multidisciplinaire en oncologie (GERCOR) and enrolled patients with chemoresistant MSI/dMMR mCRC, is now closed to inclusion. Patients are treated with a combination of nivolumab and ipilimumab. The primary objective is to evaluate the interest of iRECIST radiological assessment for disease control rate (DCR at 12 weeks by RECIST 1.1 and iRECIST). To note, another anti-PD-1 mAb (TSR-042) is currently evaluated in a expansion cohort from a phase I trial for patients with MSI [or DNA polymerase epsilon (POLE)-mutated] colorectal cancer have progressed after or been intolerant to fluoropyrimidine, oxaliplatin, and irinotecan (NCT02715284). Another important trial will evaluate the role of PD-L1 inhibition in stage III MSI-H colon cancer. Also developed through the cooperative group system, Alliance A021502 plans to evaluate FOLFOX atezolizumab in 720 patients with stage III colon cancer (NCT02912559). In the experimental arm, patients will receive 6 months of adjuvant FOLFOX concurrently with atezolizumab, which will then be followed by 6 additional months of atezolizumab monotherapy. The primary endpoint is diseasefree survival. Overall survival and adverse events will be the secondary endpoints. ICKi clinical trials currently opened for recruitment in France are summarized in table II.

Reinforcing the efficacy of immunotherapy Despite these promising results, several issues remain unresolved. As mentioned above, primary resistance to ICKi is observed in 12% to 40% of patients. Acquired resistance might also emerged amongst tumors that were initially sensitive to ICKi [16,17]. Importantly, no predictive biomarker for response to ICKi has yet been found amongst MSI cancer patients, including KRAS, NRAS or BRAF mutational status, Lynch syndrome, tumor PD-L1 expression, or tumor mutational burden [11,12,18]. However it is worthy to note that the methodology to assess the sporadic or inherited origin of the MMR deficiency was unclear in these studies and more accurate analysis are required [6]. Interestingly several mechanisms might be responsible for resistance of MSI tumors to ICKis, notably JAK loss-offunction mutations (10–20% of MSI CRCs), beta-2-microglobulin

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Importantly, the amount of patients experiencing immediate progressive disease varies in cross trial comparison from 12% with the combination of nivolumab and ipilimumab, to 40% with pembrolizumab in the Keynote-164 trial. This fluctuating proportion of primary resistant MSI/dMMR mCRC patients to ICKi requires further analysis. Importantly, one positive result with PCR (microsatellite status) or immunohistochemistry (MMR status) by local assessment was sufficient to include patients in these trials. One might hypothesize that some patients included in these trials were wrongly diagnosed as MSI/dMMR by local assessment, being truly MSS/ pMMR tumors and hampering, de facto, results of these clinical trials.

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Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency


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TABLE II Clinical trials with immune checkpoint inhibitors opened for recruitment of MSI colorectal cancer patients in France Registration number

Trial

Condition

Intervention

Type

Target

NCT02671435

–

MSI or MSS

Duvalumab plus monalizumab

Phase I

PD-L1 and NKG2A

NCT03202758

MEDI TREME COLON

MSI or MSS; chemotherapy-naïve

Durvalumab plus tremelimumab and FOLFOX

Phase I–II

PD-L1 and CTLA-4

NCT02791334

PACT

MSI

LY3300054

Phase I

PD-L1

NCT02332668

KEYNOTE-051

MSI; chemoresistant; under 18 years

Pembrolizumab

Phase II

PD-1

NCT03186326

SAMCO

MSI; second-line treatment

Avelumab plus chemotherapy

Randomized phase II

PD-L1

NCT02528357

ENGAGE-1

MSI; chemoresistant

GSK3174998 alone or with pembrolizumab

Phase I

OX-40 and PD-1

I9L-MC-JZCA

MSI; resistant to PD-1 or PD-L1 inhibitors

LY3300054

Phase I

PD-L1 and IDO

Trials dedicated to MSI cancers

Dedicated to cancers resistant to anti-PD1 or -PD-L1 agents NCT03343613

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truncating mutation [19–22] or loss of major histocompatibility complex (MHC) molecules. To note, the tumor mutational burden varies across MSI neoplasms, and MSH2/MSH6-negative cancers seem associated with a significantly higher mutational load than MLH1/PMS2-negative tumors [23]. Combining immunotherapy with conventional cytotoxic regimen (as evaluated in the COMMIT phase III trial) might also be a promising strategy, since it has already proved its efficacy in advanced non-squamous non-small cell lung carcinoma (NSCLC) with the association of atezolizumab, carboplatin and paclitaxel (IMpower150 trial [24]). More, combining ICKis in order to enhance their efficacy is a therapeutic strategy that has already demonstrated its potential. The association of nivolumab and ipilimumab showed an enhanced activity, with a 54% objective response rate, compared to 31% with nivolumab alone [11]. Moreover, translational researches have showed that MSI tumors exhibit an enhanced expression of multiple immune checkpoints [7]. Several studies are currently evaluating new compounds that are targeting immune checkpoints (i.e. LAG-3, TIM-3, IDO, etc.), with cohorts dedicated to patients resistant to ant-PD-1 or antiPD-L1 inhibitors. Notably, the I9L-MC-JZCA trial (NCT03343613) is evaluating the efficacy of LY3381916, an agent targeting IDO1, alone or in combination with an anti-PD-L1 inhibitor (LY3300054), for solid tumors resistant to anti-PD-1 and -PDL1 agents.

Surgery for MSI/dMMR stage IV colorectal cancer treated with ICKi Future researches will have to study the role of surgery for ICKitreated MSI/dMMR mCRC patients. Several scenarios need to be analyzed: surgery of metastasis for patients with MSI/dMMR resectable metastatic disease (i.e. what is the best therapeutic strategy between metastasectomy and immunotherapy?); surgery of residual mass amongst patients responding to ICKi; surgery of metastasis for patients experiencing disease progression confined to a single metastatic site. These issues are currently emerging, since the number of ICKitreated MSI/dMMR mCRCs is growing exponentially. One might take advantage of the experience in melanoma patients, with publications showing some benefit from surgery amongst melanoma responding to ICKi [25].

Duration of treatment Another emerging issue is the optimal duration of treatment for patients who respond to immunotherapy. The strategy varies across trials, with a fixed duration of ICKi (1 or 2 years of treatment, then stop) or the continuation of treatment until progression or unacceptable toxicity. Open-ended treatment with ICKis is a burden for patients and the healthcare systems. However, the question remains unanswered and clinical trials



are needed to explore not the possibility of an early stop as well as possible predictors of success with such a strategy [26,27].

Conclusion Immunotherapy is about to revolutionize the treatment and the prognosis of patients with MSI/dMMR tumors. The Food and Drug Administration granted accelerated approval to pembrolizumab or nivolumab monotherapy and nivolumab in combination with ipilumumab for the treatment of patients with MSI/dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Although these compounds do not have such marketing approval in Europe as of this writing, several ICKi trials dedicated to MSI/dMMR tumors are open for

recruitment in France. Awaiting results of the MK-3475-177 and COMMIT phase III studies might lead to approvals of ICKi in first-line metastatic setting if they meet their primary endpoints. Nevertheless, several emerging issues, such as the surgery of metastasis, the duration of treatment and the therapeutic strategies for primary and acquired resistance of MSI/dMMR tumors to ICKi, required further translational research with tumor tissue, blood samples and fecal microbiota analysis.

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Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency

Disclosure of interest: Thierry André has served in a consulting/advisory role for Roche, Amgen, Bristol-Myers Squibb, MSD Oncology, Servier and has received travel, accommodations, and expenses from Roche/ Genentech, MSD Oncology, and Bristol-Myers Squibb. The remaining authors declare that they have no competing interest.

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