Immune Checkpoint Inhibition in Colorectal Cancer: Microsatellite Instability and Beyond

117 Background: The benefit of immune checkpoint inhibition is limited to the small percentage of advanced colorectal cancer (CRC) patients whose tumors present mismatch repair (MMR) gene abnormalities; immunotherapy has not shown benefit in patients with MMR proficient CRC. Oncolytic immunotherapy represents a unique therapeutic platform. This phase I trial tests the safety of the combination of pexastimogene devacirepvec (Pexa-Vec) plus durvalumab (durva) in patients with locally advanced or metastatic CRC. Methods: Eligible patients with advanced proficient mixed match repair (pMMR) CRC received intravenous infusion of Pexa-Vec at dose level 3 x 108 plaque forming units (pfu) (DL1) or at 109 pfu (DL2) every 2 weeks for 4 doses and durva 1500 mg every 28 days. Response was assessed with CT every 8 weeks. Adverse events were recorded and managed. The primary endpoint included safety, tolerability and feasibility of this combination therapy. Samples of tumor and peripheral blood were collected for assessment of immune parameters. Results: Sixteen patients (6 males and 10 females) enrolled with a median age of 52.1 years (range 39-69) from Dec, 2017 to Oct, 2018. Four patients were treated with Pexa-Vec at DL1 and durva;twelve patients were treated with Pexa-Vec at DL2 and durva.The most common treatment related adverse events (TRAE) included fever 15/16 (94 %), hypotension 12/16 (75 %), chills 12/16 (75%), fatigue 8/16 (50%), sinus tachycardia 7/16 (44%) and rash 6/16 (38%). Grade 3/4 TRAEs were reported in 8/16 (50%)patients; the most common were fever 7/16 (44 %), lymphopenia 2/16 (13%), neutropenia 1/16 (6%) and anemia 1/16 (6%). 14 patients were evaluable for response analysis; one patient 1/14 (7 %) achieved a confirmed partial response (lasting 7.1 months) and continues to receive treatment, while 13 patients had progressive disease. The median progression free survival (PFS) was 2.2 months (95% CI: 2.2-2.3 months) and the median overall survival (OS) was 7.5 months (CI: 4.9-10.1 months). Conclusions: Combination therapy of Pexa-Vec with durva ICI issafe, well tolerated and demonstrates possible activity in patients with advanced pMMR CRC. Clinical trial information: NCT03206073.

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Immune Checkpoint Modulation in Colorectal Cancer: What’s New and What to Expect

Journal of Immunology Research ◽

10.1155/2015/158038 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 23

Author(s):

Julie Jacobs ◽

Evelien Smits ◽

Filip Lardon ◽

Patrick Pauwels ◽

Vanessa Deschoolmeester

Keyword(s):

Colorectal Cancer ◽

Immune System ◽

Immune Responses ◽

Metastatic Disease ◽

Immune Checkpoint ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

The Many ◽

Related Mortality

Colorectal cancer (CRC), as one of the most prevalent types of cancer worldwide, is still a leading cause of cancer related mortality. There is an urgent need for more efficient therapies in metastatic disease. Immunotherapy, a rapidly expanding field of oncology, is designed to boost the body’s natural defenses to fight cancer. Of the many approaches currently under study to improve antitumor immune responses, immune checkpoint inhibition has thus far been proven to be the most effective. This review will outline the treatments that take advantage of our growing understanding of the role of the immune system in cancer, with a particular emphasis on immune checkpoint molecules, involved in CRC pathogenesis.

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MEK Inhibitors in Combination with Immune Checkpoint Inhibition: Should we be Chasing Colorectal Cancer or the KRAS Mutant Cancer

Global Journal of Cancer Therapy ◽

10.17352/gjct.000019 ◽

2017 ◽

Vol 3 (1) ◽

pp. 030-031

Author(s):

J Strauss

Keyword(s):

Colorectal Cancer ◽

Immune Checkpoint ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Mek Inhibitors

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Prevalence of microsatellite instability and monitoring response to immune checkpoint inhibition utilizing liquid biopsy among African American men with advanced prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.16 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 16-16

Author(s):

Tamer Khashab ◽

Alexander D Le ◽

Samantha Cohen ◽

Salma Kaochar ◽

Heidi Dowst ◽

...

Keyword(s):

Prostate Cancer ◽

African American ◽

Microsatellite Instability ◽

Immune Checkpoint ◽

Liquid Biopsy ◽

Patient Population ◽

Safety Net ◽

Inactive Disease ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

16 Background: African American (AA) men have higher prostate cancer (PC) incidence and PC-specific mortality than non-AA men. Socioeconomic/healthcare access and environmental factors contribute to the disparity in clinical outcomes. Moreover, AA PC exhibits increased inflammatory and immune response signaling, which may contribute to its aggressive behavior, but also allow for therapeutic intervention. Microsatellite instability (MSI) is a tissue-agnostic biomarker predictive of response to immune-checkpoint inhibition (pembrolizumab) that can be assessed by NGS testing of tumor tissue or circulating tumor DNA (ctDNA, liquid biopsy). The latter is particularly relevant for patients with PC, a disease which frequently metastasizes to bone and other deep sites, making conventional tissue biopsies invasive, painful and potentially risky. Methods: We retrospectively analyzed NGS results obtained via Tempus|xT tissue assay and/or Tempus|xF liquid biopsy assay for MSI, as well as clinical data (response to pembrolizumab), from 100 PC patients (53 AA) receiving androgen deprivation therapy for locally advanced, biochemically recurrent or metastatic disease at Ben Taub Hospital (BTH, a safety net hospital in Houston serving a patient population of which 91% are racial/ethnic minorities). We also analyzed de-identified NGS data from a nationwide cohort of 2090 metastatic PC patients (225 AA) previously sequenced with xT and/or xF by Tempus Labs (Chicago, IL). Results: MSI-High status (MSI-H) was detected using xT and/or xF assays in 4/100 (4%) of patients in the BTH cohort and in 62/2090 (3%) of metastatic PC patients in the nationwide Tempus Labs cohort. Specifically, within the AA PC patient population, MSI-H was detected in 2/53 (3.7%) in the BTH cohort and in 8/225 (3.6%) in the nationwide Tempus Labs cohort. For those patients who had both tissue and liquid biopsy testing, there was 100% concordance in MSI-H detection between the two assays. Genomically-driven treatment of two MSI-H AA CRPC patients with pembrolizumab resulted in prompt and durable clinical, biochemical and molecular responses, with precipitous decline in PSA levels to below detection limit, complete radiographic response of metastatic lymphadenopathy, radiographic non-progression of visceral disease (per iRECIST and PC Working Group 3 criteria) and disappearance of PC-derived ctDNA mutations in the liquid biopsy. Conclusions: MSI-H status is present in advanced AA PC at a frequency comparable to non-AA PC. Liquid biopsy (xF assay) is a minimally invasive tool that allows detection of MSI-H in PC patients, as well as longitudinal monitoring of response to treatment with pembrolizumab. Liquid biopsy conversion from positive to negative may provide reassurance that any residual lesions seen on imaging represent treated/inactive disease.

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Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer

JAMA Oncology ◽

10.1001/jamaoncol.2020.0910 ◽

2020 ◽

Vol 6 (6) ◽

pp. 831 ◽

Cited By ~ 10

Author(s):

Eric X. Chen ◽

Derek J. Jonker ◽

Jonathan M. Loree ◽

Hagen F. Kennecke ◽

Scott R. Berry ◽

...

Keyword(s):

Colorectal Cancer ◽

Supportive Care ◽

Immune Checkpoint ◽

Advanced Colorectal Cancer ◽

Best Supportive Care ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

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Abstract 522: Immunogenic chemotherapy and immune checkpoint inhibition (ICI) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): Biomarkers indicative of durable treatment response

10.1158/1538-7445.am2021-522 ◽

2021 ◽

Author(s):

Anne Hansen Ree ◽

Sebastian Meltzer ◽

Kine M. Bakke ◽

Hanne M. Hamre ◽

Christian Kersten ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Treatment Response ◽

Immune Checkpoint ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

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A phase I/II study of pexa-vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer: Safety report.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.646 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 646-646 ◽

Cited By ~ 4

Author(s):

Maria Pia Morelli ◽

Changqing Xie ◽

Gagan Brar ◽

Charalampos S. Floudas ◽

Suzanne Fioravanti ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Checkpoint ◽

Oncolytic Virus ◽

Safety Data ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Therapeutic Platform ◽

Favorable Safety ◽

Dose Levels

646 Background: The efficacy of immune checkpoint inhibitor has been limited to small portion of colorectal cancer (CRC) patients whose tumors with mismatch repair (MMR) gene abnormalities. There is an urgent need for patients with MMR proficient (pMMR) tumors. Oncolytic immunotherapy represents a novel therapeutic platform for the treatment of cancer with unique activity compared to conventional chemotherapy. The trial is to evaluate if the combination of Pexa-Vec oncolytic virus (PV) with immune checkpoint inhibition enhance antitumor immunity. Methods: Patients with microsatellite-stable and MSI-H mCRC refractory to PD-1 monotherapy were enrolled. Patients received either Arm A treated with PV + Durvalumab or Arm B with PV + Durvalumab and Tremelimumab. Each arm had two dose levels (DL) of PV, 3 x 108 pfu in DL1 and at 109 pfu in DL2, every 2 weeks for total 4 doses. The first dose of PV was administered on Day -12, followed by three more dose administration on Days 2, 16 and 30 in combination with the immune checkpoint inhibition. The primary endpoint is response rate, safety, tolerability and feasibility of these combination therapy in refractory metastatic CRC. Results: Here we report the safety data of Arm A.A total of 9 patients was enrolled so far. The longest follow-up time is 8 months. Four patients received DL1 PV and subsequent five patients received DL2 PV. No DLT was observed at the time of this abstract. No grade 4-5 adverse event (AE) were observed. All patients experienced lymphopenia. All patients with DL2 developed fever, hypotension and papulopastular rashes and were successfully managed with antipyretics, fluid support and skin protection, respectively. The most frequent treatment-related AEs were lymphopenia (8 [100%], fever (7 [87.5%]), chills (6 [75.0%]), hypotension (5 [62.5%]), papulopastular rashes (5 [62.5%], flu-like symptoms (2 [12.5%]), Nausea/vomiting (2 [12.5%]). Conclusions: Pexa-Vec in combination with Durvalumab showed a favorable safety profile. Clinical trial information: NCT03206073.

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