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Background Despite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM. Methods We searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS). Results Seven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan. Conclusions This systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758

Background Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). Methods/design INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator’s choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. Discussion INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. Trial registration INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

PURPOSE Cholangiocarcinomas (CCA) are a group of heterogeneous tumors arising from the biliary epithelia. Significant sequencing efforts have provided further insights into the molecular mechanisms of this disease including fibroblast growth factor receptor ( FGFR) alterations, which occurs in approximately 15%-20% of intrahepatic CCAs. Herein, we describe the FGFR inhibitor (FGFRi)-associated treatment toxicity and cancer-specific outcomes from a multicenter single-institution cohort. METHODS This is a retrospective study of patients with CCA and known FGFR alterations treated with FGFRi. We describe the toxicity and efficacy in patients treated at Mayo Clinic between January 2010 and December 2020. RESULTS Our group identified 61 patients with advanced or metastatic CCA, 19 males (31%) and 42 females (69%), harboring FGFR alterations who received FGFRi. The most common grade 1 or higher adverse events for all patients included fatigue (92%), AST elevations (78%), anemia (80%), decreased platelet count (63%), and hyperphosphatemia (74%). Median progression-free survival on FGFRi was 5.8 months for all patients (95% CI, 4.9 to 9.0). Females had significantly longer progression-free survival at 6.9 months (95% CI, 5.2 to 11.8) on FGFRi compared with males at 4.9 months (95% CI, 2.8 to not estimable; P = .038). CONCLUSION FGFRi are well tolerated with clinical efficacy. With the recent approval of FGFRi by the US Food and Drug Administration and ongoing clinical trials for new FGFRi, understanding outcomes and toxicity associated with these medications is important for precision oncology.

Metastatic colorectal cancer (mCRC) is the second most common cause of cancer-related death worldwide. In the mid-1980s, the median overall survival (OS) for patients with mCRC ranged from 10 to 12 months from the time of initial diagnosis. In more recent studies, this median has more than doubled and is commonly reported at more than 25 to 30 months. These improvements are due, in large part, to the introduction of multiple novel agents during the last 3 decades. Despite these improvements, however, nearly all patients treated with palliative chemotherapy will eventually develop resistance and ultimately succumb to progression of metastatic disease. Understanding the mechanisms by which malignant cells evade treatment could unlock novel therapeutic strategies that overcome resistance and improve survival. In this review, we will discuss some of the drivers of therapeutic resistance in patients with mCRC and present some novel strategies to overcome resistance.

PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.

Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

Recent studies of the human microbiome have offered new insights into how the microbiome can impact cancer development and treatment. Specifically, in pancreatic ductal adenocarcinoma (PDAC), the microbiota has been shown to modulate PDAC risk, contribute to tumorigenesis, impact the tumor microenvironment, and alter treatment response. These findings provide rationale for further investigations into leveraging the microbiome to develop new strategies to diagnose and treat PDAC patients. There is growing evidence that microbiome analyses have the potential to become easily performed, non-invasive diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. More excitingly, there is now emerging interest in developing interventions based on the modulation of microbiota. Fecal microbiota transplantation, probiotics, dietary changes, and antibiotics are all potential strategies to augment the efficacy of current therapeutics and reduce toxicities. While there are still challenges to overcome, this is a rapidly growing field that holds promise for translation into clinical practice and provides a new approach to improving patient outcomes.

Objectives This study sought to better characterize patient characteristics, treatment options, and outcomes for osteoclast-like giant cell carcinoma of the pancreas, a rare subtype of pancreatic adenocarcinoma. Methods This is a retrospective study of all patients with osteoclast-like giant cell carcinoma of pancreatic origin treated at Mayo Clinic from 2000 to present. Baseline patient characteristics, treatment modalities utilized, and outcomes were compiled. Overall survival (OS) and progression-free survival were assessed using Kaplan-Meier analysis with a significance level of P ≤ 0.05. Results Fifteen patients met criteria for inclusion. Four patients had distant metastases at diagnosis, the remaining 11 with locoregional disease. Median OS for the entire cohort was 11 months. Metastatic disease was associated with significantly shorter OS (3.5 vs 14.1 months; P = 0.005). Three patients had no evidence of disease at time of analysis; all 3 were treated with complete resection followed by adjuvant chemotherapy. Conclusions Osteoclast-like giant cell carcinoma of the pancreas is an aggressive malignancy with poor prognosis. For patients with locoregional disease, surgical resection followed by adjuvant chemoradiation may play a role in extended disease-free survival. Metastatic disease presents a challenging entity to treat with little data to support any effective chemotherapy regimens.

Background This open-label, phase I/II study evaluated safety and efficacy for first-line liposomal irinotecan + oxaliplatin + 5-fluorouracil + leucovorin (NALIRIFOX). Methods Patients (aged ≥18 years) had locally advanced/metastatic pancreatic ductal adenocarcinoma (mPDAC), with an Eastern Cooperative Oncology Group performance status score of 0/1 and adequate organ function. Primary objectives were to determine the maximum tolerated dose (MTD) and to evaluate safety and tolerability. Treatment-emergent adverse events (TEAEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Efficacy end-points included progression-free survival (PFS) and overall survival (OS); disease assessments used Response Evaluation Criteria in Solid Tumors 1.1. Results The MTD (liposomal irinotecan 50 mg/m2 [free-base equivalent], oxaliplatin 60 mg/m2, 5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2 every 2 weeks) was based on dose-limiting toxicities and cumulative safety data in four dose-exploration cohorts. The MTD was received by 32 of 56 patients, seven during dose exploration and 25 during dose expansion (median age 58.0 years [range, 39–76], 28 [87.5%] with metastatic disease at diagnosis [29 at study entry], and one receiving study treatment at data cutoff [26 February 2020]). Of these patients, 22 of 32 had grade ≥3 treatment-related TEAEs, most commonly neutropenia (31.3%), febrile neutropenia (12.5%) and hypokalaemia (12.5%); ten had serious treatment-related TEAEs; and three died from TEAEs considered unrelated to treatment. Median PFS and OS were 9.2 (95% CI: 7.69–11.96) and 12.6 (8.74–18.69) months, respectively. Conclusion First-line NALIRIFOX for patients with locally advanced/mPDAC was generally manageable and tolerable. A randomised, controlled phase III study is underway.

Introduction Anorectal neuroendocrine carcinomas (NECs) are uncommon malignancies with poor prognosis. Consensus guidelines exist for treating extrapulmonary NEC. However, limited data is available to guide treatment for anorectal NEC. In this study, we sought to review the clinical characteristics and outcomes of patients with NEC of the rectum and/or anus at Mayo Clinic. Patients and Methods This is a retrospective study of all patients with the diagnosis of NEC of the anus and/or rectum treated across Mayo Clinic sites since 2000. Baseline patient characteristics, tumor pathology, imaging profiles, treatment strategies utilized, and survival outcomes were analyzed. Kaplan-Meier analysis was used with a significance level of P Results The study included a total of 38 patients with primary NEC of the anus and/or rectum. The median age at diagnosis was 55.5 years. The median follow-up was 18.8 months. Fifteen patients had locoregional disease (LRD) at diagnosis. The remaining 23 had metastatic disease. Overall survival was significantly shorter in patients with LRD compared with those with metastatic disease at diagnosis (18.1 vs. 13.8 months; P = .039). The majority (n = 11) of patients with LRD were treated with concurrent chemoradiation therapy, and 10 underwent surgical resection of the primary tumor. The majority (13/15) of patients with LRD progressed, with the majority (11/15) of progressions being distant. The median progression-free survival for patients with LRD was 5.7 months (1-year progression-free survival, 26.7%). Conclusion Anorectal NEC is an aggressive malignancy with poor prognosis requiring multidisciplinary discussion. In addition, the systemic nature of anorectal NEC with distant recurrences in LRD and poor outcomes in metastatic disease emphasizes the need to further develop better systemic treatment options that can potentially improve outcomes in NEC.

Introduction: Clonal hematopoiesis (CH) is defined by acquisition of somatic mutations in hematopoietic stem cells with potential for expansion over time. CH is influenced by exposures to chemotherapy/radiation & has been associated with therapy related myeloid neoplasms (tMN). Peptide receptor radionuclide therapy (PRRT) is a radionuclide therapy and is FDA approved for neuroendocrine tumors (NET). PRRT has been associated with a 2-10% risk of tMN, especially with prior exposure to alkylating agents. A prior study of 13 NET patients found CH prevalence of 64%. We carried out a prospective assessment of CH in NET patients prior to PRRT. Methods: We evaluated pre-PRRT blood samples in 37 NET patients. Genomic DNA from mononuclear cells was analyzed for CH using a custom panel targeting 229 genes to a targeted depth of >1000X. Results: After approval by Mayo Clinic IRB, 45 patients with Stage IV NET were enrolled & CH data was available for 37. Fifty-one percent of patients were female, with a median age of 68yrs (range, 34-84yrs). Types of NET included small bowel (51%), pancreatic (29%), carcinoid (8%), paraganglioma (5%), & other (5%). The median number of therapies prior to PRRT was 1 (range, 0-4) & included somatostatin analogues (SSA)-81%, alkylating agents-30%, & prior radiation-13%. Thirty-six of 37 patients had variants identified, 5 of which were presumed germline (DDX41, CDKN2B, CHEK2, POT1, ERBB2), & 17 (45.9%) had pathogenic variants meeting the operational definition of CH (DNMT3A, TET2, PPM1D, TP53, SF3B1, ASXL1). The median number of pathogenic variants per patient was 1 (range, 0-2), & 6 patients had >1. In patients >60yrs old, 46% had pathogenic variants & 3 patients with pathogenic variants (TET2, TP53, DNMT3A) were Conclusion: To our knowledge this is the largest prospective evaluation of CH in NET. We identified CH to be present in 46% of patients & DNMT3A mutations were most common. This establishes the clonal landscape with mutations involving epigenetic regulators, DNA damage repair, transcription & splicing factors. Prospective longitudinal evaluation will evaluate the association between CH, cytopenias and tMN. Citation Format: Yael Kusne, Terra Lasho, Zaid Elsabbagh, Abhishek Mangaonkar, Rachel Eiring, Timothy Hobday, Jason Starr, Tanios Bekaii-Saab, Thorvardur Halfdanarson, Mrinal Patnaik, Mohamad Sonbol. Prevalence of clonal hematopoiesis in neuroendocrine tumor patients prior to lutetium 177 dotatate therapy (Lu177): A prospective trial of 36 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5928.

Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Background Hand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation. Materials and Methods The Regorafenib Dose Optimization Study (ReDOS), a four-arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib. Results Sixty-one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p = .03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p = .35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p = .02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p = .12). Patient-reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol-induced adverse events were reported. Conclusion Preemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort. Implications for Practice Regorafenib causes hand-foot skin reactions. Preemptive clobetasol, a high-potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients.

Although the last two decades have seen a broad improvement in overall survival, colorectal cancer is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their colorectal cancer. Consequently, many patients present with metastatic colorectal cancer, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of colorectal cancer tumors and are associated with uninhibited cell proliferation, reduced apoptosis, and resistance to standard therapeutic options. In colorectal cancer, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared with tumors with wild-type BRAF. Success in treating other BRAFV600E-mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic colorectal cancer. Consequently, combination therapy with inhibitors of BRAF, MEK, and EGFR, which overcomes the innate treatment-resistant characteristics of BRAFV600E-mutant colorectal cancer, is now recommended by treatment guidelines.

Background Necuparanib, a rationally engineered low-molecular-weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomised multicentre phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreatic ductal adenocarcinoma (PDAC). Patients and methods Eligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and Eastern Co-Operative Oncology Group performance status of 0–1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8 and 15 of 28-day cycles. The primary end-point was median overall survival (OS), and secondary end-points included median progression-free survival, response rates and safety. Results One-hundred ten patients were randomised, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis, and the study was terminated by the Data Safety Monitoring Board. The median OS was 10.71 months (95% confidence interval [CI]: 7.95–11.96) for necuparanib arm and 9.99 months (95% CI: 7.85–12.85) for placebo arm (hazard ratio: 1.12, 95% CI: 0.66–1.89, P-value: 0.671). The necuparanib arm had a higher incidence of haematologic toxicity relative to placebo patients (83% and 70%). Conclusion The addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243

Background The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC. Methods Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm. Results The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%–19%) in arm 1 versus 10% (95% CI 0%–23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2. Conclusions This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.

OBJECTIVES Survival benefit of combination over single-agent chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) was demonstrated in younger patients in clinical trials. The authors aimed to evaluate whether this survival benefit of combination chemotherapy is present in elderly patients with metastatic PDAC. MATERIALS AND METHODS The authors identified elderly patients (age 65 y or older) with stage IV PDAC and extracted available clinical information from a prospectively maintained institutional pancreatic cancer registry from 2007 to 2016. The primary endpoint was overall survival. Cox proportional hazards regression was used for multivariable survival analyses. Survival outcomes for the entire cohort and by age group I (elderly, 65 to 75 y) and age group II (very elderly, older than 75 y) were assessed. RESULTS A total of 606 patients were included with a median age of 73.8 years. Among them, 239 patients (39%) received combination chemotherapy and 152 patients (25.1%) received single-agent chemotherapy as first-line treatment. Combination chemotherapy was associated with significantly longer median overall survival compared with single-agent chemotherapy (10.9 vs. 7.5 mo, P

Background/Objectives Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. Methods Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. Results Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2–7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. Conclusions Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.

Amplification of ERBB2 (formerly referred to as HER2) is present in nearly 3% of patients with metastatic colorectal cancer overall and 5% of patients with KRAS and NRAS wild-type tumors. Despite the availability of several ERBB2-targeted therapeutic options for patients with ERBB2-positive breast and gastric/gastroesophageal tumors, to date, there are currently no approved therapies for patients with ERBB2-positive metastatic colorectal cancer, although ERBB2-targeted therapies are recommended in National Comprehensive Cancer Network guidelines. Recent evidence indicates that anti-ERBB2 therapeutic strategies are active in patients with ERBB2-positive metastatic colorectal cancer and could potentially represent a new standard-of-care.The protein ERBB2 is a member of a family of epidermal growth factor receptors that also includes epidermal growth factor receptor (ERBB1), ERBB3, and ERBB4. Amplification of ERBB2 leads to overexpression of the ERBB2 tyrosine kinase receptor, resulting in aberrant signaling and cell migration, growth, adhesion, and differentiation. Colorectal tumors that harbor ERBB2 amplification are more likely to originate on the left side of the colon, are associated with primary and acquired resistance to anti-epidermal growth factor receptor therapies, and have increased incidence of central nervous system metastases. Using immunohistochemistry, fluorescence in situ hybridization, next-generation sequencing, and liquid biopsy techniques, several randomized clinical trials have evaluated the efficacy of ERBB2-targeted therapies in patients with ERBB2-positive metastatic colorectal cancer. These therapies include monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors, many of which were associated with favorable efficacy and safety profiles when treating patients with ERBB2-positive metastatic colorectal cancer.The results of this review suggest the ERBB2 receptor is a promising target for patients with metastatic colorectal cancer; however, to date, no therapies are approved for use in this patient population. Therefore, it is imperative to continue to work to address this unmet need so that patients with ERBB2-positive metastatic colorectal cancer have therapeutic options should they become refractory to treatment with standard therapies.

PURPOSE Recent advances in molecular diagnostic technologies have allowed for the evaluation of solid tumor malignancies via noninvasive blood sampling, including circulating tumor DNA (ctDNA) profiling. We sought to characterize the ctDNA genomic alteration landscape in patients with biliary tract cancers (BTCs). PATIENTS AND METHODS From January 2015 to February 2018, 124 patients with BTC at the Mayo Clinic Comprehensive Cancer Center underwent ctDNA testing using a clinically available assay. The majority of samples (n = 122) were tested using the 73-gene panel that includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. RESULTS A total of 138 samples were included, with approximately 70% of patients having intrahepatic BTC. All patients had locally advanced or metastatic BTC. Samples with one or more alterations, when variants of unknown significance were excluded, numbered 105 (76%). Each sample contained, on average, three alterations with a median allelic fraction of 0.52%. The overall landscape of alterations is summarized in Figures 1 and 2. After excluding variants of unknown significance, therapeutically relevant alterations were observed in 76 patients (55%), including BRAF mutations, ERBB2 amplifications, FGFR2 fusions, FGFR2 mutations, and IDH1 mutations seen in 21% of patients. A different spectrum of alterations was observed in patients with early-onset BTC (younger than age 50 years) compared with older patients (older than age 50 years). CONCLUSION Data on ctDNA in BTC is currently limited. Our study, the largest cohort reported to date to our knowledge, demonstrates the feasibility of ctDNA testing in this disease. We provide a foundation upon which the field can continue to grow.

BackgroundPancreatic cancer (PC) is a challenging target for immunotherapy due to its immune-suppressive microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of tumor-infiltrating lymphocytes (TILs). We hypothesized that the combination of CRT and pembrolizumab can further expand and activate TILs.MethodsPatients with resectable or borderline resectable PC were randomized 2:1 to the investigational treatment (Arm A) of pembrolizumab 200mg IV every 3 weeks concurrently with CRT (capecitabine 825 mg/m2 orally twice daily and radiation 50.4 Gy in 28 fractions over 28 days) or CRT only (Arm B) prior to surgical resection. The primary endpoints were safety and difference in TILs density between Arm A and B assessed using multiplexed immunofluorescence on resected tumor specimens. As a correlate analysis, single cell RNA-sequencing (scRNA-seq) was performed to quantify gene expression in T cells from tumors and peripheral blood, and to track expanded T cell clonotypes in these compartments (n=4 patients Arm A; n=3 patients Arm B). The study was amended after enrollment of 37 patients to allow FOLFIRINOX prior to CRT, given changes in standard of care.Results37 patients were enrolled (24 Arm A, 13 Arm B). After neoadjuvant therapy, 13 patients had unresectable disease (9 on A, 4 on B), and 24 patients underwent surgery and were evaluable for the TILs primary endpoint (17 arm A, 7 arm B). The mean difference (A-B) in CD8+ T cell density was 36 cells/mm2 (95% CI -85 to 157, stdev 130) (p 0.48). Additional analysis did not show significant differences in activated cytotoxic T cells, regulatory T cells, M1- or M2-like polarized macrophages, or granulocytes. The median recurrence free survival (RFS) was 18.2 months on Arm A and 14.1 on Arm B (p 0.41). Overall survival was 27.8 months on Arm A and 24.3 on Arm B (p 0.68) with a median follow up of 2.2 years. The most common grade 3 treatment-related toxicities were lymphopenia reported in 29% on Arm A and 31% on Arm B, respectively followed by diarrhea in 8% on Arm A attributed to CRT. scRNA-seq revealed clonal expansion and expression of co-inhibitory markers among TIL subsets.ConclusionsThe combination of CRT and pembrolizumab is safe. Preliminary analysis shows that the addition of pembrolizumab to CRT has minimal effects on intratumoral densities of TILs and other immune cell populations. Single cell transcriptome analyses enable in-depth characterization of the functional responses of T cells to pembrolizumab in the setting of CRT.AcknowledgementsThis study was funded by MerckTrial RegistrationNCT02305186Ethics ApprovalThe study was conducted at 6 sites: University of Virginia, Dana Farber Cancer Institute, MD Anderson Cancer Center (MDACC), Mayo Clinic, Hartford Healthcare Cancer Center, and University of Miami. Written informed consent was provided by the study participants and the protocol was approved by the relevant local IRBs in each site.

BackgroundATRC-101 is an engineered version of an immunoglobulin G1 antibody that was discovered in a patient with non-small cell lung cancer (NSCLC) experiencing stable disease while being treated with anti–programmed death-1 therapy. ATRC-101 targets a tumor-specific ribonucleoprotein complex containing polyadenylate binding protein-1, which has been found to be present in the majority of NSCLC, acral melanoma, breast, colorectal, and ovarian cancer samples tested. Target immunoreactivity and single-agent activity have been observed in mouse models. Preclinical data suggest that ATRC-101 stimulates both innate and adaptive immune activity against tumors.MethodsATRC-101-A01 is a phase 1b trial (3+3 dose escalation with expansion cohorts) in patients with solid tumors treated with ATRC-101 monotherapy every 2 or 3 weeks (Q2W or Q3W), or ATRC-101 in combination with pembrolizumab, until unacceptable toxicity or disease progression at doses of 0.3–30 mg/kg, pending dose-limiting toxicities. The primary objective is safety and secondary objectives are to characterize the pharmacokinetic profile, immunogenicity, and anti-tumor activity of ATRC-101, and to determine the recommended dose for expansion. Pharmacodynamic studies will also be performed to evaluate changes from baseline in specific immune cell populations and cytokine levels in blood and tumors. Results from the ATRC-101 0.3–30 mg/kg monotherapy Q3W cohorts are presented in this abstract (data cutoff: July 16, 2021).ResultsTwenty-four participants with solid tumors (13 colorectal, 5 ovarian, 3 breast, 2 NSCLC, 1 acral melanoma) aged 27–75 years with a median 5 lines of prior therapy were treated Q3W in five dose cohorts. No dose-limiting toxicities were observed. Eight participants (33%) experienced grade ≥3 treatment-emergent adverse events. The maximum serum concentration of ATRC-101 and treatment exposure appeared to be dose proportional. Stable disease was observed in eight patients and best response per RECIST v1.1 was associated with expression of the ATRC-101 target. Multiple biomarkers, such as treatment-associated changes in the composition of CD3+, CD4+, and CD8+ T cells in the blood, and serum cytokines/chemokines, including those predicted to activate antigen-presentation pathways, support the proposed mechanism of action of ATRC-101 and will be presented.ConclusionsThese first-in-human data suggest a manageable safety profile for ATRC-101 Q3W, with no dose-limiting toxicities observed. Pharmacokinetics appear to be dose proportional. Enrollment in the Q2W monotherapy dose-escalation cohort and at the 30 mg/kg dose level Q3W is continuing. Trial sites have been activated to test ATRC-101 in combination with pembrolizumab, and combination with chemotherapy is also planned.Trial RegistrationTrial Registration: NCT04244552Ethics ApprovalThis study was approved by the institutional review board or ethics committee as required for each participating site.

Background: PDAC is a highly morbid disease with no validated biomarkers for first-line (1L) treatment selection. The PurIST single-sample molecular subtyping gene signature, initially described by Rashid et al. (Clin. Cancer Res., 2020), classifies PDAC tumors as basal or classical. Prior work showed that these subtypes are associated with prognosis and that basal subtype patients have significantly lower objective response rate to FOLFIRINOX (FFX) compared to classical subtype patients. This suggests potential implications for treatment with FFX versus gemcitabine and nab-paclitaxel (GnP). Here, we retrospectively demonstrate the clinical validity of PurIST implemented as a laboratory developed test (LDT) on the Tempus Labs sequencing platform using a real-world dataset of advanced PDAC patients. Methods: De-identified PDAC patients were selected from the Tempus Oncology Data Ecosystem under an IRB-approved protocol according to the following inclusion criteria: no systemic treatment, surgically unresectable/metastatic, available RNA-sequencing data from primary or metastatic tissue, and FFX or GnP as 1L systemic therapy with available outcomes. Sequencing was performed by the CAP/CLIA validated Tempus xT assay. The PurIST model was applied to normalized RNA-sequence abundance files to compute a basal or classical subtype label. Predefined statistical analysis parameters included 12-month survival rate and median overall survival (OS) in FFX treated patients. OS was compared using Kaplan-Meier estimates, hazard ratios, and log-rank statistical tests. Results: 258 PDAC patients (64.9 +/- 9.9 yrs, 42% female), were identified for analysis with median OS of 11.7 months (95% CI: 10.6-13.7) and 12-month censorship rate of 12.8%. 151 patients were treated with FFX and 107 with GnP. 42 patients (28%) receiving FFX and 31 patients (29%) receiving GnP were classified as basal. Among FFX treated patients, median OS was 14.4 months (95% CI: 12.5-16.9) in classical patients vs. 9.4 months (95% CI: 8.3-14.5) in basal patients (HR = 1.72, 95% CI = 1.2-2.6, p=0.006). The 12-month survival rate was significantly lower in basal patients receiving FFX vs. classical patients (33.3% vs. 59.4%, p=0.011). In basal patients, no difference in OS was observed between FFX and GnP groups (p=0.6). Classical patients receiving FFX had a 14.4 months median OS vs. 10.8 months for patients receiving GnP (p=0.046). Conclusions: In this real-world cohort, we validate the association between PurIST subtypes and PDAC patient survival when administered FFX or GnP. Among FFX-treated patients, classical patients had significantly better outcomes compared to basal patients. Moreover, classical patients appeared to have improved outcomes with FFX vs. GnP. These findings represent underlying biological PDAC differences and demonstrate the clinical validity of PurIST as a prognostic marker in PDAC patients when performed as an LDT on the Tempus xT platform. Ongoing evaluation of PurIST performance will be continuously monitored through the Tempus Oncology Data ecosystem. Citation Format: Stephane Wenric, James M. Davison, Yun E. Wang, Gregory M. Mayhew, Kirk Beebe, Hyunseok P. Kang, Michael V. Milburn, Vincent Chung, Tanios Bekaii-Saab, Charles M. Perou. Purity Independent Subtyping of Tumor (PurIST): Real-world data validation of a pancreatic ductal adenocarcinoma (PDAC) gene expression classifier and its prognostic implications [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A002.

This letter to the editor reports subsequent rechallenge with peptide receptor radionuclide therapy (PRRT) in a patient with pancreatic neuroendocrine tumor bearing BRCA1 mutation previously treated with PRRT.

BackgroundFluoropyrimidine with platinum-based chemotherapy has become the standard of care for advanced gastric and gastroesophageal (GEJ) cancer. Trials in colon cancer show that induction chemotherapy followed by maintenance chemotherapy is an efficacious strategy to maximize clinical response while minimizing toxicity. The current retrospective study aims to evaluate the efficacy and tolerability of maintenance versus continuous treatment in advanced GEJ malignancy.MethodsA retrospective analysis of patients with metastatic gastric/GEJ adenocarcinoma treated with fluoropyrimidine and platinum chemotherapy between 2007-2017 was performed. Patients who achieved at least stable disease after initial induction treatment were included. After 16 weeks of induction chemotherapy, patients were categorized into the continuous group if induction chemotherapy was continued and the maintenance group if chemotherapy was switched to maintenance fluoropyrimidine monotherapy or observed off treatment. Endpoints were progression-free survival (PFS), overall survival (OS), and toxicities.ResultsIn total, 90 patients met the criteria, 48 received continuous therapy, and 42 received maintenance. Baseline characteristics were comparable. No difference in PFS (9.9 vs 8.4 months p = .28) or in OS (16.1 vs 21.3 months p = .75) was observed, including after controlling for the best response on induction therapy and other variables. In patients on continuous induction therapy, there was a higher prevalence of grade three neuropathy (42.6% vs 9.8% p = .001) and neutropenic fever (13% vs 0% p =.03).ConclusionsMaintenance therapy following induction fluoropyrimidine and platinum-based therapy is associated with an improved toxicity profile and appears to have comparable efficacy to continuous treatment in metastatic gastric/GEJ cancer.

Background:Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations.Methods:This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results:Twelve patients were enrolled prior to early termination of the trial. Clinical benefit (defined as complete/partial response + stable disease) of 45.5% was observed. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed.Conclusions:Ponatinib as a single agent in FGFR altered BTC is tolerable with very modest clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

Summary Background Regorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules. Methods In this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0–1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov , number NCT02368886 . This study is fully accrued but remains active. Findings Between June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98–1·57). The primary endpoint was met: 23 (43%, 95% CI 29–56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15–37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3–4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction). Interpretation The dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data. Funding Bayer HealthCare Pharmaceuticals.

Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

PURPOSE To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with resected biliary tract cancer. METHODS ASCO convened an Expert Panel to conduct a systematic review of the literature on adjuvant therapy for resected biliary tract cancer and provide recommended care options for this patient population. RESULTS Three phase III randomized controlled trials, one phase II trial, and 16 retrospective studies met the inclusion criteria. RECOMMENDATIONS Based on evidence from a phase III randomized controlled trial, patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a duration of 6 months. The dosing used in this trial is described in the qualifying statements, while it should be noted that the dose of capecitabine may also be determined by institutional and regional practices. Patients with extrahepatic cholangiocarcinoma or gallbladder cancer and a microscopically positive surgical resection margin (R1 resection) may be offered chemoradiation therapy. A shared decision-making approach is recommended, considering the risk of harm and potential for benefit associated with radiation therapy for patients with extrahepatic cholangiocarcinoma or gallbladder cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Purpose: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors. Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3+3+3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. Results: The safety analysis set included 111 patients who received ≥1 dose of AMG 337. Thirteen patients had ≥1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade ≥3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n = 6) and fatigue (n = 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%–17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%–50.2%) in MET-amplified patients; median (range) duration of response was 202 (51–1,430+) days in all patients and 197 (64–1,430+) days in MET-amplified patients. Conclusions: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation. See related commentary by Ma, p. 2375

Napabucasin (also known as BBI-608 or BBI608) is an investigational, oral agent hypothesized to inhibit multiple oncogenic pathways. In this article, we describe the design and rationale for the CanStem111P clinical trial, a multicenter, randomized, open-label, Phase III study designed to determine the efficacy and safety of combining napabucasin with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma (NCT02993731). Patients were randomized in a 1:1 fashion to receive weekly gemcitabine and nab-paclitaxel with or without napabucasin. The results of this study will help define the role of this novel agent in the management of advanced pancreatic cancer.

An increasing number of patients with metastatic colorectal cancer (mCRC) are able to receive 3 or more lines of therapy. Treatments in this setting can include regorafenib (an oral multikinase inhibitor), trifluridine/tipiracil hydrochloride (TAS-102), antibodies that target epidermal growth factor receptor for patients with RAS wild-type tumors (if no prior exposure), and, where approved, anti-programmed cell death protein 1 inhibitors for patients with microsatellite instability-high mCRC. Although guidelines describe the available treatment options, few insights are provided to guide selection and sequencing. In this article, we share expert opinion from diverse geographic regions, to offer guidance for best practice when selecting and managing third-line treatment for mCRC. Various factors, including performance status, age, and tumor sidedness, can be used to guide treatment selection. Biomarkers, such as RAS, BRAF, and microsatellite instability, can be useful for treatment stratification. Management of adverse events, to maintain quality of life, is a key consideration and is crucial to best practice in this setting. Common toxicities associated with third-line treatments are hand-foot skin reaction, fatigue, diarrhea, and cytopenias. Patients who receive third-line and later-line treatments should be monitored for these events, especially during the first 2 cycles. Dose modifications can also be used to manage toxicities and to minimize the effect on quality of life, while maximizing treatment benefit. Clinical trials of emerging agents, new treatment combinations, and novel therapies continue the efforts to improve outcomes for patients with mCRC. Sharing expert opinions on best practice for treatment selection and management can ultimately improve outcomes for patients with mCRC.

Background FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated. Methods We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III–IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method. Results We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III–IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX. Conclusions This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

Introduction Because of the improved colorectal cancer (CRC) survival in the U.S., patients may live long enough after CRC diagnosis to the point where non–cancer-related comorbidities may considerably impact their overall survival. In this study, we perform a long-term analysis of causes of death (CODs) following nonmetastatic CRC with respect to different demographic and tumor-related criteria. Materials and Methods We gained access to the Surveillance, Epidemiology, and End Results data to review patients diagnosed with nonmetastatic CRC during 2000–2015. We calculated standardized mortality ratios (SMRs) for each COD following CRC. SMRs represented the change of risk of a specific COD following CRC diagnoses when compared with the risk in the general U.S. population. Results We reviewed 302,345 patients, of whom 112,008 died during the study period. More deaths (68.3%) occurred within 5 years following nonmetastatic CRC diagnosis, with 76,486 deaths. CRC was the most common COD (51.4%) within 5 years of diagnosis followed by heart disease (15.2%) and other cancers (8.4%). As time passed after diagnosis, the number of CRC deaths decreased, and other noncancer causes increased to the point that after 10 years only 10.4% of deaths were attributed to CRC, 15.3% were attributed to other cancers, and 34.2% were secondary to heart disease. Conclusion Following nonmetastatic CRC diagnosis, most deaths remain secondary to CRC. Other causes, including other cancers and cardiovascular disease, represent a significant number of deaths, especially in the 5 years following initial CRC diagnosis. Our findings help guide counseling patients with CRC regarding future health risks. Implications for Practice Most common causes of death following nonmetastatic colorectal cancer (CRC) are heart diseases, other cancers, chronic obstructive pulmonary disease, and cerebrovascular diseases. Physicians should counsel patients regarding survivorship with cancer screening and focus on prevention of noncancer deaths. These findings should be considered by physicians who give care for survivors of nonmetastatic CRC.

Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in patients with hepatobiliary cancer, we undertook a prospective multi-site study of germline sequencing using a >80-gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected on the basis of stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were White, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer, and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n = 32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. A total of 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer, and 33% in carcinoma of ampulla of Vater. On the basis of these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers. Prevention Relevance: Universal multi-gene testing in hepatobiliary cancers was associated with heritable mutations in over 15% of patients, most of whom would not have been tested using current guidelines. 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Germline testing should be considered in all patients with hepatobiliary cancers.

Simple Summary Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play instrumental roles in carcinogenesis. However, the genetic alterations of the STAT3/CDK2/4/6 signaling axis and its role in predicting immune infiltration and immunotherapeutic response remain unclear. Here, we used in silico analyses of multi-Omics data to map out the role of epigenetic and genetic alterations of STAT3/CDK2/4/6 in tumor immune infiltrations, immunotherapy response, and prognosis of cancer patients. Our study collectively suggested that STAT3/CDK2/4/6 are important onco-immune signatures that contribute to tumor immune invasion, poor prognoses, and immune therapy failure. Our finding may be clinically useful in designing therapeutic strategies, prognosis assessment, and follow-up management in patients receiving immunotherapy in multiple cancers. Abstract Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play an important implicative role in cancer initiations, progression, drug resistance, and metastasis, and has been extensively explored in cancer therapy. However, the genetic alterations of STAT3/CDK2/4/6 and its role in predicting immune infiltration and immunotherapeutic response are yet to be well exploited. In this study, we use in silico methods to analyze differential expression, prognostic value, genetic and epigenetic alterations, association with tumor-infiltrating immune cells, and cancer-associated fibroblast (CAF) infiltrations of STAT3/CDK2/4/6 in multiple cancer types. Our results revealed that the expression of STAT3/CDK2/4/6 was altered in various cancers and is associated with poor overall and disease-free survival of the cohorts. Moreover, genetic alterations in STAT3/CDK2/4/6 co-occurred with a number of other genetic alterations and are associated with poorer prognoses of the cohorts. The protein-protein interaction (PPI) network analysis suggests CDK2/4/6/STAT3 may directly interact with factors that promote tumorigenesis and immune response. We found that STAT3/CDK2/4/6 expressions were associated with infiltrations of CAF and the various immune cells in multiple cancers and it’s associated with poor response to immunotherapy. Collectively, our study suggested that STAT3/CDK2/4/6 are important onco-immune signatures that play central roles in tumor immune invasion, poor prognoses and, immune therapy response. Findings from the present study may therefore be clinically useful in prognosis assessment and follow-up management of immunotherapy.

Purpose: Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Patients and Methods: Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Results: Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. Conclusions: In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Background: Sarcopenia is one of the early pathological features of cancer cachexia, yet the effect of sarcopenia on clinical outcomes in patients with advanced HCC is unclear. Our objective was to determine the effect of Sarcopenia on response to systemic therapy with advanced HCC. Methods: Patients with unresectable and advanced liver cancer were retrospectively evaluated between 2010 to 2019. Skeletal muscle area (SMA) was computed with a previously validated computed tomography (CT) body composition AI algorithm. The skeletal muscle index (SMI) was derived from the skeletal muscle area (SMA) (cm2) divided by patient height (m2) calculated from images at the level of L3 on pretreatment CT. Sarcopenia cutoffs for females was less than 39 cm2/m2 SMI or less than 50 cm2/m2 SMI for males. Patients’ demographics, systemic treatment response, toxicity, progression-free survival (PFS) and overall survival (OS) were compared between first-line therapy groups. Kaplan-Meier and Cox proportional hazards regression were used for survival analysis comparisons. Results: A total of 146 patients with advanced HCC were assessed from Mayo Clinic Arizona and Emory University. Seventy-six patients received immunotherapy as first-line treatment and seventy patients received TKI as first-line therapy. Sarcopenia at baseline was assessed in a total of 91 patients at first-line systemic treatment: n=48 with immunotherapy (IO) and n=43 with tyrosine kinase inhibitor (TKI). Sarcopenia was more prevalent in male patients (p=0.009), and in patients with low BMI (p=0.02). When comparing those with sarcopenia at baseline, higher response rate was observed in patients treated with IO without sarcopenia (47% versus 15%, p=0.019), this was not observed in TKI group. Interestingly, median PFS and OS was not significantly changed in patients with or without sarcopenia treated with IO or TKI on first-line therapy. Conclusions: Sarcopenia was associated with reduced response rate (RR) in patients treated with IO, but not in TKI groups. Both didn’t translate into deleterious effect in PFS and or OS. Further research with sufficient adjustments for confounding factors is warranted to better elucidate the prognostic value of sarcopenia in these patients. Citation Format: Gehan Botrus, Pedro Luiz Serrano Uson Junior, Heidi Kosiorek, Mehmet Akce, Isabela Chang, Zhubene Mesbah, Eric Yancey, Daniel Blezek, Jason Klug, Lana Khalil, Puneet Raman, Mohamad Sonbol, Mitesh Borad, Daniel Ahn, Tanios Bekaii-Saab. Prognostic impact of Sarcopenia on clinical outcomes in advanced hepatocellular carcinoma (HCC) treated with systemic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6274.

Modified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression free survival (mPFS), with secondary objectives including median overall survival (mOS), safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically-defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classified patients into 3 groups based on TMB level: low (P = 0.0005 and 0.0001, respectively). Tumor PD-L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB.

Importance The treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials. Objective To evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy. Data Sources We searched various databases for abstracts and full-text articles published from database inception through March 2020. Study Selection We included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting. Data Extraction and Synthesis The reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model. Main Outcomes and Measures Outcomes of interest included overall (OS) and progression-free survival (PFS). Findings Fourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others. Conclusions and Relevance This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.

Esdeveniments adversos; Càncer colorectal metastàtic; Regorafenib Eventos adversos; Cáncer colorrectal metastásico; Regorafenib Adverse events; Metastatic colorectal cancer; Regorafenib Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Bayer.