Background Metastatic colorectal cancers (MCRCs) with microsatellite stability (MSS) are resistant to immunotherapy with programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 inhibitors. However, the addition of regorafenib to nivolumab was recently associated with a high response rate and a protracted progression‐free survival in a small cohort of MSS Japanese patients with metastatic colorectal cancer. Materials and Methods We evaluated the outcome of patients with MSS metastatic colorectal cancer who were treated on a compassionate basis with PD‐1 inhibitors in combination with regorafenib in a single U.S. center. Results A total of 18 patients were treated with a combination of regorafenib and PD‐1 inhibitors. No treatment‐related grade 3 or above toxicities were noted. Thirteen patients (69%) had progressive disease, and five patients (31%) experienced stable disease as best response. Four out of five stable diseases occurred in patients without liver metastases, whereas only 1 of 14 patients with history of liver metastases had a short disease stabilization. A rise in circulating tumor DNA (ctDNA) at the 4‐week time pointuniversally predicted tumor progression at 2 months, whereas a decline was associated with radiographic disease stabilization. Conclusions Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy‐resistant metastatic colorectal cancer. Selection for patients without history of liver metastases may identify a cohort of patients with MSS colorectal cancer with a higher likelihood of benefit from this combination. ctDNA may represent a powerful tool for predicting early therapeutic efficacy of immunotherapy in the MSS colorectal cancer population. Implications for Practice This study showed that the combination of regorafenib and nivolumab was associated with a modest clinical activity in patients with advanced microsatellite stability (MSS) metastatic colorectal cancer. This combination should be avoided in clinical practice, especially in patients with MSS colorectal cancer with liver metastases. Further investigation of regorafenib plus PD‐1 inhibitors should be considered in MSS colorectal cancer without liver metastases.

The authors followed up 41 consecutive patients (21 symptomatic) with internal carotid artery stenosis > or =70% and previous neck irradiation. After 28 months, 15 patients (36.6%) had died, five (12.2%) had had an ischemic stroke, and 15 (36.6%) had a new malignancy. Having a new malignancy was the only independent predictor of death. The major risk for patients with ICA stenosis > or =70% and previous neck irradiation is malignancy, not stroke.

200 Background: Signatera (S) assay is a CLIA certified minimal residual disease ctDNA assay that has become widely used for monitoring of disease relapse in patients (pts) with resected colorectal cancer. In a longitudinal study, S+ recurrence (SR) occurred at median > 10 months (mo) prior to radiographic disease recurrence (RDR) in a prospective clinical trial. However, the radiographic surveillance frequency in that study was inadequate by US standard practices. Methods: We retrospectively evaluated, in a single center, the sensitivity (ss), specificity (sp), positive predictive value (ppv) and negative predictive value (npv) of S, CT/MRI imaging (Im), and CEA in curatively resected stage II, III, IV pts against True Disease Recurrence (TDR). We considered TDR as any SR, RDR confirmed by pathology, RDR associated with CEA elevation, or RDR with sequential growth on imaging or regression with chemo. S and CEA were performed Q3 mo x 2 yrs and then Q6 mo x 3 yrs. Im was performed Q3 mo x 2 yrs and then Q6 mo x 3 yrs in resected stage IV, Q6 mo x 2 yrs and then Q yr x 3 in stage III/high-risk stage II, and Q yr x 5 yrs in low-risk stage II. Results: 48 pts underwent curative resection (31 stage II-III, 17 stage IV). 15 patients recurred during surveillance (6 stage II-III, 9 stage IV). The ss, sp, ppv, and npv of S, Im, CEA, and (Im and/or CEA) are tabulated below. S, Im, CEA, and Im or CEA were positive for recurrence at the diagnosis of TDR in 8, 9, 4, and 12, respectively. S sensitivity was poor for lung recurrence with 5/6 pts with lung-only mets (3 confirmed by path) being negative by S at the time of Im relapse. S was negative at the time of CNS recurrence and liver recurrence in 2 pts. 2 Pts with negative imaging at SR developed subsequent liver metastases. 2 Pts, counted as TDR, were SR and remain NED without any therapy, by CEA and Im > 1.5 years from S positivity. Conclusions: S does not appear to provide definitive advantages as a surveillance strategy over standard Im frequency- when performed as per NCCN guidelines. Sensitivity of S is particularly poor for low volume lung-only disease recurrence.[Table: see text]

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Introduction: Patients with microsatellite stable (MSS) metastatic colorectal cancer (MCRC) are considered resistant to immunotherapy with PD-1 and PD-L1 inhibitors. However, a recent study of regorafenib and nivolumab (REGONIVO) reported high response rates and a median progression free survival (PFS) of more than 6 months (mo) in a cohort of 24 Japanese patients (pts) with MSS chemo-resistant MCRC. Methods: We evaluated the outcome of advanced MSS MCRC pts who were treated on a compassionate basis with PD-1 inhibitors in combination with regorafenib 80 mg PO QD x 21 days every 28 days in a single US center. We report their response rate (RR), PFS, and overall survival (OS). Results: 16 pts (15 males) were treated with a combination of regorafenib + PD-1 inhibitors and were evaluable for response. 14 pts received regorafenib + nivolumab (5 with prior anti-PD-1 treatment) and 2 pts received regorafenib + pembrolizumab (both following pembrolizumab treatment). No treatment-related G3 or above toxicities were attributed to the combination therapy. No objective responses were noted on treatment. 11 pts had progressive disease (PD) and 5 pts experienced stable disease (SD) as best response at 2 mo. The duration of SD was 4 mo in 2 pts (1 pt with prior anti-PD1 exposure), 6 mo in 1 pt (prior anti-PD1 exposure), 5 mo+ in 2 pt (1 with prior anti-PD1 exposure). When limiting the analysis to the 9 regorafenib and checkpoint-inhibitor naïve patients, 2 pts were noted to have SD (4 months and 5 mo+). ctDNA assays were evaluated at baseline and at 4 weeks of treatment in 11 patients. All 9 patients with a rise in ctDNA at 4 weeks had PD at the 2-mo imaging point. 2 patients with declining ctDNA at 4 weeks experienced SD for 4 mo 5 mo+, each. OS analysis remains immature as the median follow-up is only 5 mo. Conclusions: Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy-resistant MCRC. This US-based small retrospective trial is at odds with the Japanese REGONIVO trial. ctDNA may represent a powerful tool for predicting progression prior to radiographic staging. Citation Format: Marwan Fakih, Dawnyel Chevalier, Janelle Saluja, Cecilia Lau, Chongkai Wang. Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4241.