437P Designing clinical profiles that influence the discordance of RAS mutations in blood and tissue: Sidedness and anatomical metastasis as factors of disagreement

Abstract

Background: Second-line treatment of KRAS-mutated metastatic colorectal cancer (mCRC) confers a dismal patient (pt) outcome with response rates of 4% to FOLFIRI (5-fluorouracil (5FU), leucovorin, irinotecan) + bevacizumab (bev) and median progression-free survival (PFS) of 5.5 months. PLK1 is a serine/threonine kinase, master regulator of mitosis. PLK1 inhibition has synthetic lethality with KRAS-mutated CRC tumor cells. Onvansertib is an oral and highly-selective PLK1 inhibitor with demonstrated efficacy as a single agent and synergistically with irinotecan in CRC preclinical models.Methods: This single-arm phase Ib/II study (NCT03829410) assesses the safety and preliminary efficacy of onvansertib in combination with FOLFIRI + bev in second line KRAS-mutated mCRC. Pts are treated with onvansertib (days 1-5) + FOLFIRI-bev (day 1) in a 14-day cycle. In the phase Ib, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase II dose. Secondary objectives are preliminary efficacy determined by radiographic scans every 8 weeks and reduction in KRAS mutant allelic burden evaluated by liquid biopsy.

Reply to F. Dayyani et al

“…3,4 Even within colorectal cancers, sidedness and location of the primary tumor has an apparent impact on ctDNA shedding. 5,6 Location of metastases or micrometastases has also been reported to affect shedding. [5][6][7] As illustrated in Figure 1 (showing relative levels of ctDNA at different metastatic sites), prior studies have shown that certain organ locations yield lower levels of ctDNA compared with other locations, which may result in so-called fluctuating levels of ctDNA above or below the limits of detection.…”

“…5,6 Location of metastases or micrometastases has also been reported to affect shedding. [5][6][7] As illustrated in Figure 1 (showing relative levels of ctDNA at different metastatic sites), prior studies have shown that certain organ locations yield lower levels of ctDNA compared with other locations, which may result in so-called fluctuating levels of ctDNA above or below the limits of detection. [5][6][7] We have observed that with longer follow-up, many patients with low-shedding tumors end up declaring metastatic/recurrent disease.…”

“…[5][6][7] As illustrated in Figure 1 (showing relative levels of ctDNA at different metastatic sites), prior studies have shown that certain organ locations yield lower levels of ctDNA compared with other locations, which may result in so-called fluctuating levels of ctDNA above or below the limits of detection. [5][6][7] We have observed that with longer follow-up, many patients with low-shedding tumors end up declaring metastatic/recurrent disease. In some cases, a diagnostic laparoscopy revealed extensive peritoneal disease that was not detected with cross-sectional computed tomography, magnetic resonance imaging, and/or positron emission tomography scans.…”