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Takayuki Yoshino, MD, PhD provides perspective on key issues surrounding therapy selection in gastrointestinal cancers.
Remarkable advances in precision oncology over the last 2 decades have highlighted the necessity for genotyping in patients with advanced cancers to ensure appropriate therapy selection. Practice guidelines outlined by the National Comprehensive Cancer Network, the European Society for Medical Oncology, and the Japanese Society of Medical Oncology now include recommendations for genotyping to guide therapy selection in different cancer types.1-3 Although impressive progress has been achieved through the development of biomarker-targeted clinical trials, the pace of precision oncology innovations remains limited due to the daunting logistical realities of patient identification. Furthermore, because many actionable targets are present in only a small fraction of patients, hundreds or even thousands of patients need to be screened for enrollment in a single study. Compounding this patient identification
barrier are the additional substantial challenges associated with traditional trial designs—such as the high cost of genotyping, lengthy screening periods, and limited access to screening populations—which collectively lead to increasingly low enrollment rates of otherwise eligible patients.
Patients with metastatic colorectal cancer (mCRC) are no exception. To date, several established and actionable genomic alterations have been identified in mCRC, including KRAS/NRAS mutations, BRAF V600E mutations, HER2 amplification, microsatellite instability–high or mismatch repair–deficient tumors, and NTRK fusions.4 Additional targetable genomic alterations are emerging in mCRC, such as FGFR alterations, PIK3CA mutations, homologous recombination deficiency, MET amplification, and EGFR mutations.4
The COlorectal Cancer and Liquid BiOpsy Screening Protocol for Molecularly Assigned ThErapy (COLOMATE; NCT03765736) trial discussed by Kristen K. Ciombor, MD, MSCI, and colleagues herein is a screening platform for mCRC developed by the Academic and Community Cancer Research United consortium. COLOMATE utilizes Guardant360 (Guardant Health) molecular profiling, a comprehensive 74-gene circulating tumor DNA (ctDNA) sequencing assay, to identify potential patients for COLOMATE-associated studies.5 Complementary to this trial is the SCRUM-Japan screening project that was launched in January 2018; it initiated the GOZILA platform, a nationwide plasma genomic profiling platform study involving 31 core institutions using the same Guardant360 assay. The clinical utility of such rapid screening methods based on ctDNA genotyping has been leveraged in umbrella- and basket-type clinical trials
utilizing the GOZILA platform.6
The GOZILA investigators compared data derived from the ctDNA of 1687 patients with advanced gastrointestinal cancers in GOZILA with data derived from tumor samples of 5621 patients in SCRUM-Japan GI-SCREEN to assess the clinical utility of ctDNA genotyping vs tissue analysis for the identification of patients as candidates for targeted clinical trials.6 Although the composition of the screening populations was similar, the tumor testing characteristics were significantly better in GOZILA compared with those in GI-SCREEN. Specifically, for GOZILA vs GI-SCREEN, the sample unavailability rate was 0.3% vs 1.5%, respectively; the failure rate was 0.1% vs 10.6%; the median sample acquisition duration was 4 vs 14 days; and the median turnaround time (TAT) was 7 vs 19 days. Furthermore, the median time from testing to trial enrollment was only 1.0 months for cell-free DNA testing vs 5.9 months for tumor testing, representing an 83% decrease. Overall, ctDNA genotyping led to a statistically significant increase in enrollment in genotype-matched clinical trials relative to enrollment conducted via tumor-based screening
(9.5% vs 4.1%, respectively; P < .0001) without compromising treatment efficacy (response rate, 20.0% vs 16.7%; median progression-free survival, 2.4 months vs 2.8 months). Given our GOZILA experience, we believe that the COLOMATE approach will maximize both efficient trial enrollment and opportunities for patients while accounting for a dynamic tumor environment, thus serving as a model for clinical cancer research in the years ahead.
Notably, key elements necessary to maintain such a genomic screening platform include (1) an overall high “hit rate,” (2) a quick TAT between informed consent and enrollment in a molecularly matched trial, (3) actionable targets treated with best-in-class therapies, (4) a dynamic trial structure allowing the opening and closing of treatment cohorts based on the best available science, (5) flexibility to maximize academia and biopharma partnerships (investigator-initiated vs biopharma-sponsored trials) depending on the target, and (6) financial sustainability.
Although some investigators and pharmaceutical companies remain skeptical of this platform, we anticipate that in the near future, most will accept this without any reservation; their attitude will shift from “maybe” to “must be” regarding an indispensable genomic screening
platform. The GOZILA group advocates that the COLOMATE platform receive more support from related pharmaceutical companies and public funds. Such support is also crucial to perform attractive translational studies and longitudinal liquid biopsy tests; these have the advantage in potentially evaluating early therapeutic effects as well as elucidating mechanisms of resistance.
Both the COLOMATE and GOZILA platforms have identified patients with mCRC for studies examining HER2 amplification, BRAF V600E mutation, BRAF non-V600E mutations, MET amplification, FGFR alterations, and anti-EGFR antibody rechallenge. Both are well-qualified ctDNA-based screening platforms for matched target therapies, particularly in patients with mCRC. The existence of various associated trials for common target alterations using these platforms can lead to future international collaboration.
Financial disclosures: TY reports research grants from Amgen Inc; Chugai Pharmaceutical Co, Ltd; Daiichi Sankyo Co, Ltd; Ono Pharmaceutical Co, Ltd; Parexel International; MSD; Sanofi; Sumitomo Dainippon Pharma; and Taiho Pharmaceutical Co, Ltd.