COLOMATE Challenge to Overcome Resistance in Metastatic Colorectal Cancer

Yoshino is director of the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwanoha, Kashiwa, Japan

Most patients with metastatic colorectal cancer (mCRC) who receive palliative systemic therapy eventually develop resistance to treatment. Understanding the mechanisms by which malignant cells evade treatment could open novel therapeutic strategies that can overcome resistance and ultimately improve survival. In other words, a new challenge for drug development in mCRC is the development of treatment resistance.

For the vast majority of colorectal cancers, targeting a single gene alteration (mostly a mutation) is either ineffective (primary resistance) or leads to disease progression after a certain period of response (secondary resistance). Until recently, understanding the mechanisms of secondary resistance relied almost exclusively on post-progression tissue biopsies. However, it is not practical to conduct serial tissue biopsies because of both their invasive nature and poor cost-effectiveness. Furthermore, a single-site tumor biopsy is a relatively poor representation of the spectrum of intra- and intertumoral heterogeneity.¹ As tumors progress, metastasize, or are exposed to stressors (such as targeted inhibitors or chemotherapy), they develop acquired gene alterations that are not uniformly distributed throughout single tumors or within multiple tumors in the same patient.² If we are to reach the ultimate goal of successfully implementing precision oncology, we must understand the dynamic interplay between preexisting mutational profiles and those which are induced or unmasked by treatment.

Fortunately, analysis of circulating tumor DNA (ctDNA) is a noninvasive technology that can be harnessed to overcome most of these shortcomings and provide a diagnostic tool for longitudinal and dynamic disease monitoring. Indeed, this approach has allowed for the design of multiple novel clinical trial platforms that are tailored not only to a specific disease state or line of therapy but also to underpinnings of molecular resistance.³

The COlorectal Cancer and Liquid BiOpsy Screening Protocol for Molecularly Assigned ThErapy trial (COLOMATE; NCT03765736), discussed by Jeremy C. Jones, MD, and John Strickler, MD, is a screening platform developed by the Academic and Community Cancer Research United Consortium for mCRC. COLOMATE utilizes Guardant360 (Guardant Health) molecular profiling, a comprehensive 74-gene ctDNA sequencing assay, to identify potential patients for COLOMATE-associated studies. Three clinical studies are being conducted as part of the COLOMATE trial: (1) panitumumab (Vectibix) rechallenge (PULSE; NCT03992456) for secondary resistance to EGFR inhibitors; (2) tucatinib (Tukysa), trastuzumab (Herceptin), and TAS-102 (3T study) for secondary resistance to ERBB2 inhibition; and (3) rechallenge with encorafenib (Braftovi), cetuximab (Erbitux), and binimetinib (Mektovi) for secondary resistance to BRAFV600E inhibitors. Notably, across these studies, patients can participate in one trial and seamlessly switch to another at the first sign of resistance.

The authors also emphasized that this clinical trial approach will require rethinking clinical trials and statistical designs, in order to offer a novel approach to overcome resistance. However, if we can predict the gene alterations that will occur due to secondary resistance before treatment, clinical trial and statistical design of clinical development will change further—that is, it will allow the development of combination therapies that block the identical resistance gene alteration from the beginning. For this purpose, it is necessary to catalogue the gene alterations before and after treatment and develop an artificial intelligence–based predictor for the preemptive treatment strategy (Figure 1). It is my belief that the results of COLOMATE will be crucial to building a database and preparing for such next-generation clinical development.

FIGURE 1. Present and Next-Generation Clinical Trial Designs

Conflict of Interest Statement: TY reports research grants from Taiho Pharmaceutical Co, Ltd; Sumitomo Dainippon Pharma; Ono Pharmaceutical Co, Ltd; Chugai Pharmaceutical Co, Ltd; Amgen Inc; Parexel International; MSD; Daiichi Sankyo Co, Ltd; and Sanofi.

References

1. Parikh AR, Leshchiner I, Elagina L, et al. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nat Med. 2019;25(9):1415-1421. doi:10.1038/s41591-019-0561-9

2. Siravegna G, Mussolin B, Buscarino M, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21(7):795-801. doi:10.1038/nm.3870

3. Nakamura Y, Taniguchi H, Ikeda M, et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med. 2020;26(12):1859-1864. doi:10.1038/s41591-020-1063-5