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CRC Targeted Agents
Reflections on Optimizing Biomarker Testing for Colorectal Cancer in the Era of Immunotherapy

Released: April 25, 2017

Expiration: April 24, 2018

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Authors: Robert A. Anders, MD, PhD and Feriyl Bhaijee, MD

The application of targeted molecular therapy for patients with colorectal carcinoma (CRC) is revolutionizing both diagnostic approaches and therapeutic paradigms. Consider, for example, a patient who presents with metastatic adenocarcinoma of unknown origin: Even in stage IV or inoperable cases, if the tumor bulk is amenable to needle biopsy, the pathologist typically receives a modest amount of tissue for evaluation. So, if the standard approach with H&E-stained tissue sections and subsequent IHC reveals an adenocarcinoma with expression of CK20 and CDX2, it would be reasonable to suggest a colorectal primary tumor. In addition, if enough tissue remains, we would perform ancillary mismatch repair (MMR) protein testing and/or molecular studies for microsatellite instability (MSI). Moreover, BRAF mutational analysis offers prognostic stratification, and if the oncologist is considering EGFR-targeted therapy, KRAS and NRAS mutational testing should be used to identify those patients most likely to benefit. There may not always be enough tissue remaining for ancillary testing, unfortunately, which presents a conundrum, given the clinical impracticality of additional needle biopsies in each case.

MMR and MSI Testing
Regardless, the value of MMR and MSI testing for CRC has been firmly established. In addition to identifying patients with Lynch syndrome (hereditary nonpolyposis CRC), emerging data now suggest that MMR status plays both prognostic and predictive roles, as MMR-deficient tumors may be amenable to immune checkpoint inhibitor therapy, such as antibodies against PD-1 and its ligand, PD-L1. In early-phase trials, few patients with CRC responded to immune checkpoint inhibitors; however, it was later determined that those patients who did respond had MSI-H tumors. Subsequent trials evaluated these agents in patients with MMR-deficient/MSI-H CRC tumors.

Immunotherapy in CRC
Due to success in clinical trials across multiple solid tumors, several immune checkpoint inhibitors have gained FDA approval and PD-1/PD-L1 testing is gaining clinical momentum. Established guidelines are also recommending the use of nivolumab and pembrolizumab in previously treated MMR-deficient/MSI-H metastatic CRC. Notably, a supplemental Biologics License Application for pembrolizumab, an anti–PD-1 therapy, has been submitted to the FDA for use in patients with advanced MSI-H CRC who failed standard therapy. In a phase I study of pembrolizumab in patients with CRC and MMR deficiency (n = 28), the ORR was 57% (including CRs in 11%) vs 0% in patients with MMR-proficient disease (n = 25). Another PD-1–targeted antibody, nivolumab, has demonstrated promising clinical activity and survival (with and without ipilimumab) in patients with MSI-H metastatic CRC enrolled in the CheckMate-142 phase II trial (n = 74). In this study, the ORR to nivolumab monotherapy was approximately 30%, including 2 CRs by blinded central review, and an additional 40% of patients achieved stable disease. Furthermore, a 74% 12-month OS rate was noted among patients with MMR-deficient/MSI-H CRC who received single-agent nivolumab.

Implications for Obtaining and Processing Specimens
Of importance, targeting PD-1 improves outcomes regardless of tumor type—although this bodes well for patients with CRC, it also suggests a fundamental paradigm shift in how we process patient specimens. If molecular phenotype trumps tissue of origin for guiding treatment choices, should pathologists consider prioritizing limited tissue samples for predictive IHC studies to establish molecular phenotype (eg, MMR and PD-1/PD-L1 tests) rather than the standard approach of identifying molecules such as CK7, CK20, and CDX2 to determine tissue of origin? Should clinicians obtain additional needle biopsies, dedicated to molecular studies, for each case? Do laboratories across the country have the capacity to handle this increased level of testing, considering the rigorous validation steps required for biomarker testing and the various algorithms and “reflex” testing at different locations? And, which members of the multidisciplinary care team are going to drive these decisions? The implications for pathologists, clinicians, oncologists, surgeons, and molecular diagnostics laboratories require careful deliberation if we are going to harness the full potential of targeted molecular therapy.

We will not know the outcome of the FDA application for pembrolizumab to treat CRC until summer 2017, but in the interim, it is certainly worth reflecting on current best practices and how we can optimize tumor sampling, specimen processing, and biomarker testing in order to deliver the highest quality of patient care in every possible case.

For more detailed information on biomarkers of response to immunotherapy, please click here to review additional educational materials and resources in this program.

Have you implemented testing for MMR and MSI in your patients with CRC? Share your experiences in the comment box below!

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