A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer.

BACKGROUND: Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. METHODS: Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. RESULTS: Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. CONCLUSIONS: The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT02393755.

Recurrence-free survival dynamics following adjuvant chemotherapy for resected colorectal cancer: A systematic review of randomized controlled trials.

BACKGROUND: Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. METHODS: The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests. RESULTS: The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010). CONCLUSIONS: In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.

Combination of Immunotherapy and Radiation Therapy in Gastrointestinal Cancers: An Appraisal of the Current Literature and Ongoing Research.

Oncological outcomes are improving in gastrointestinal cancer with advancements in systemic therapies, and there is notable potential in combining immunotherapy and radiation therapy (RT) to allow for further improvements. Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer. A few recent phase III studies have shown improved survival with the addition of immunotherapy to standard treatment for gastrointestinal cancer. The timing, duration, sequencing, and integration with other anti-cancer treatments are still areas of ongoing research. We have reviewed the published and ongoing studies of the combinations of immunotherapy and RT in gastrointestinal cancers.

Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164.

BACKGROUND: Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented. METHODS: Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%-46.0%) in cohort A and 34.9% (95% CI, 23.3%-48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1-8.1) in cohort A and 4.1 months (95% CI, 2.1-18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4-58.0) in cohort A and 47.0 months (95% CI, 19.2-NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response. CONCLUSIONS: Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC. CLINICAL TRIAL REGISTRY INFORMATION: ClinicalTrials.gov, NCT02460198.

Understanding Suboptimal Response to Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs), as a novel class of anticancer therapy, can be more efficacious and less toxic than chemotherapy, but their clinical success is confined to certain tumor types. Elucidating their targets, mechanisms and scope of action, and potential synergism with chemotherapy and/or targeted therapies are critical to widen their clinical indications. Treatment response to an ICI targeting programmed death-1 (anti-PD-1) is sought to be understood here by conducting a preplanned correlative analysis of a phase II clinical trial in patients with small bowel adenocarcinoma (SBA). The cytolytic capacity of circulating immune cells in cancer patients using a novel ex vivo cytotoxicity assay is evaluated, and the utility of circulating biomarkers is investigated to predict and monitor the treatment effect of anti-PD-1. Baseline expression of Bim and NKG7 and upregulation of CX3CR1 in circulating T cells are associated with the clinical benefit of anti-PD-1 in patients with SBA. Overall, these findings suggest that the frequency and cytolytic capacity of circulating, effector immune cells may differentiate clinical response to ICIs, providing a strong rationale to support immune monitoring using patient peripheral blood.

A dose regimen-finding study to evaluate the safety, tolerability, pharmacokinetics, and activity of oratecan in subjects with advanced malignancies.

PURPOSE: Irinotecan is a commonly used chemotherapeutic in solid tumor malignancies. Oratecan is an investigational product comprised of encequidar methanesulfonate, a novel minimally absorbed P-glycoprotein pump inhibitor, and irinotecan. This study sought to determine the maximum tolerated dose (MTD) of oratecan in patients with advanced malignancies. METHODS: Using a "3 + 3″ dose-escalation design, patients were treated with oratecan on day 1 every 21 days. The irinotecan dose was escalated from 20 to 320 mg/m2. The encequidar methanesulfonate dose was fixed at 15 mg (12.9 mg free base). PK sampling for irinotecan, encequidar and its major metabolites was performed following a single dose of oratecan during cycle 1. Patients were treated until disease progression or unacceptable toxicity. RESULTS: Thirty-five patients were treated. The MTD was determined to be 280 mg/m2 every 21 days. Irinotecan and SN-38 plasma concentration-time profile showed that irinotecan exposure increased with dose and followed biexponential decay. Nine of 17 patients at oratecan dose levels 200 mg/m2 and above had SN-38 exposures comparable to those with intravenous irinotecan at standard dosing. None of the 35 patients achieved a radiologic response, ten patients had SD for > 8 weeks; the median progression-free survival for all treated patients was 9 weeks (95% CI 8.6-13.9). CONCLUSIONS: The MTD of oratecan was encequidar methanesulfonate 15 mg plus irinotecan 280 mg/m2. Exposure for irinotecan and SN-38 increased with increased dose. Potential antitumor activity was observed at the 280 and 320 mg/m2 dose levels. The safety profile of oratecan was comparable to that of intravenous irinotecan.

FL118, acting as a 'molecular glue degrader', binds to dephosphorylates and degrades the oncoprotein DDX5 (p68) to control c-Myc, survivin and mutant Kras against colorectal and pancreatic cancer with high efficacy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), a difficult-to-treat cancer, is expected to become the second-largest cause of cancer-related deaths by 2030, while colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer deaths. Currently, there is no effective treatment for PDAC patients. The development of novel agents to effectively treat these cancers remains an unmet clinical need. FL118, a novel anticancer small molecule, exhibits high efficacy against cancers; however, the direct biochemical target of FL118 is unknown. METHODS: FL118 affinity purification, mass spectrometry, Nanosep centrifugal device and isothermal titration calorimetry were used for identifying and confirming FL118 binding to DDX5/p68 and its binding affinity. Immunoprecipitation (IP), western blots, real-time reverse transcription PCR, gene silencing, overexpression (OE) and knockout (KO) were used for analysing gene/protein function and expression. Chromatin IP was used for analysing protein-DNA interactions. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromid assay and human PDAC/CRC cell/tumour models were used for determining PDAC/CRC cell/tumour in vitro and in vivo growth. RESULTS: We discovered that FL118 strongly binds to dephosphorylates and degrades the DDX5 oncoprotein via the proteasome degradation pathway without decreasing DDX5 mRNA. Silencing and OE of DDX5 indicated that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins, including survivin, Mcl-1, XIAP, cIAP2, c-Myc and mutant Kras. Genetic manipulation of DDX5 in PDAC cells affects tumour growth. PDAC cells with DDX5 KO are resistant to FL118 treatment. Our human tumour animal model studies further indicated that FL118 exhibits high efficacy to eliminate human PDAC and CRC tumours that have a high expression of DDX5, while FL118 exhibits less effectiveness in PDAC and CRC tumours with low DDX5 expression. CONCLUSION: DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumour sensitivity to FL118. This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic. FL118 may act as a 'molecular glue degrader' to directly glue DDX5 and ubiquitination regulators together to degrade DDX5.

Underdiagnosis of iron deficiency anemia among patients with colorectal cancer: an examination of electronic medical records.

BACKGROUND: Timely diagnosis and management of iron deficiency anemia (IDA) in colorectal cancer (CRC) patients improves overall quality of life and survival. This study assessed the proportion of CRC patients who were formally diagnosed with IDA and factors that predict a formal diagnosis of IDA and receiving iron therapy. METHODS: We retrieved electronic medical records (EMRs) of CRC patients from a large comprehensive cancer center in the Northeastern part of the United States (n = 499). We abstracted sociodemographic characteristics, relevant laboratory results, IDA diagnosis, and iron supplementation from the EMRs. We assessed relationships between participant characteristics, a diagnosis of IDA and receiving iron therapy through adjusted logistic regressions. RESULTS: IDA was formally diagnosed in 26 (5.2%) individuals judged by EMR documentation. Only 153 (30.7%) participants had iron laboratory results available. Among the 153 patients with iron panel data available, 113 (73.9%) had iron deficiency. Seventy-six had absolute iron deficiency as shown by ferritin levels below 100 ng/mL and iron saturation less than 20% and 37 had functional iron deficiency as shown by ferritin levels between 100 and 500 ng/mL and iron saturation less than 20%. 12% of all patients had documentation of iron therapy receipt. A formal diagnosis of IDA was not associated with any of the covariates. CONCLUSIONS: Iron deficiency anemia is under-diagnosed among CRC patients and most likely under-documented in clinical notes. Rates of iron repletion are low, suggesting that many patients with IDA are untreated. Future research should explore provider-level and other strategies for improving assessment and diagnosis of IDA among CRC patients.

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC. Objectives: To assess whether the addition of atezolizumab to capecitabine and bevacizumab therapy improves progression-free survival (PFS) among patients with refractory mCRC and to perform exploratory analyses among patients with microsatellite-stable (MSS) disease and liver metastasis. Design, Setting, and Participants: This double-blind phase 2 randomized clinical trial enrolled 133 patients between September 25, 2017, and June 28, 2018 (median duration of follow-up for PFS, 20.9 months), with data cutoff on May 4, 2020. The study was conducted at multiple centers through the Academic and Community Cancer Research United network. Adult patients with mCRC who experienced disease progression while receiving fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-epidermal growth factor receptor antibody therapy (if the patient had a RAS wild-type tumor) were included. Interventions: Patients were randomized (2:1) to receive capecitabine (850 or 1000 mg/m2) twice daily on days 1 to 14 and bevacizumab (7.5 mg/kg) on day 1 plus either atezolizumab (1200 mg; investigational group) or placebo (placebo group) on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary end point was PFS; 110 events were required to detect a hazard ratio (HR) of 0.65 with 80% power (1-sided α = .10). Secondary end points were objective response rate, overall survival (OS), and toxic effects. Results: Of 133 randomized patients, 128 individuals (median age, 58.0 years [IQR, 51.0-65.0 years]; 77 men [60.2%]) were assessed for efficacy (82 in the investigational group and 46 in the placebo group). Overall, 15 patients (11.7%) self-identified as African American or Black, 8 (6.3%) as Asian, 1 (0.8%) as Pacific Islander, 101 (78.9%) as White, 1 (0.8%) as multiple races (Asian, Native Hawaiian/Pacific Islander, and White), and 2 (1.6%) as unknown race or unsure of race. Microsatellite-stable disease was present in 110 patients (69 in the investigational group and 41 in the placebo group). Median PFS was 4.4 months (95% CI, 4.1-6.4 months) in the investigational group and 3.6 months (95% CI, 2.2-6.2 months) in the placebo group (1-sided log-rank P = .07, a statistically significant result; HR, 0.75; 95% CI, 0.52-1.09). Among patients with MSS and proficient mismatch repair, the HR for PFS was 0.66 (95% CI, 0.44-0.99). The most common grade 3 or higher treatment-related adverse events in the investigational vs placebo groups were hypertension (6 patients [7.0%] vs 2 patients [4.3%]), diarrhea (6 patients [7.0%] vs 2 patients [4.3%]), and hand-foot syndrome (6 patients [7.0%] vs 2 patients [4.3%]). One treatment-related death occurred in the investigational group. In the investigational group, the response rate was higher among patients without liver metastasis (3 of 13 individuals [23.1%]) vs with liver metastasis (4 of 69 individuals [5.8%]). The benefit of atezolizumab for PFS and OS was greater among patients without vs with liver metastasis (primary analysis of PFS: HR, 0.63 [95% CI, 0.27-1.47] vs 0.77 [95% CI, 0.51-1.17]; OS: HR, 0.33 [95% CI, 0.11-1.02] vs 1.14 [95% CI, 0.72-1.81]). Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to capecitabine and bevacizumab therapy provided limited (ie, not clinically meaningful) clinical benefit. Patients with MSS and proficient mismatch repair tumors and those without liver metastasis benefited more from dual inhibition of the vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 pathways. Trial Registration: ClinicalTrials.gov Identifier: NCT02873195.

Population pharmacokinetics of liposomal irinotecan in patients with cancer and exposure-safety analyses in patients with metastatic pancreatic cancer.

Liposomal irinotecan is a liposomal formulation of irinotecan, which prolongs circulation of irinotecan and its active metabolite SN-38. A population pharmacokinetic (PK) model was developed based on data from seven studies (N = 440). Adequacy of the model was assessed using multiple methods, including visual predictive check. Associations between PK exposure and the incidence of diarrhea (grade ≥3) and neutropenia adverse events (AEs) (grade ≥3) at first event in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) were investigated using logistic regression based on data from two studies (the phase III NAPOLI-1 [N = 260] and phase I/II NCT02551991 [N = 56] trials). The PKs of total irinotecan was described by a two-compartment model with first-order elimination, with SN-38 formed directly by a first-order constant from the central compartment of irinotecan or after using a transit compartment. Clearance was 17.9 L/week (0.107 L/h) and 19,800 L/week (118 L/h) for total irinotecan and SN-38, respectively. The UGT1A1*28 7/7 homozygous genotype had no significant impact on SN-38 clearance. Model evaluation was satisfactory for both irinotecan and SN-38. The incidence of diarrhea (grade ≥3) at first event was significantly higher with increasing average concentrations of total irinotecan and SN-38; there was no significant association between an increased risk of neutropenia AEs (grade ≥3) at first event and average SN-38 concentrations. In summary, the PKs of total irinotecan and SN-38 after administration of liposomal irinotecan were well-described by the model. The UGT1A1*28 status had no significant impact on the PKs of liposomal irinotecan.

Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer.

PURPOSE: We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with RAS wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC). PATIENTS AND METHODS: In this phase Ib/II study, cetuximab was combined with pembrolizumab in patients with RASwt mCRC with ≥ one prior line of therapy for advanced disease. We analyzed baseline on-treatment tumor tissues for changes in the tumor microenvironment (TME), using flow cytometry and multispectral immunofluorescence. RESULTS: Forty-four patients were evaluable for efficacy. The study was negative for the primary efficacy endpoint [overall response rate: 2.6%, 6-month progression-free survival (PFS): 31%; P = 0.52]. Median PFS was 4.1 months [95% confidence interval (CI): 3.9-5.5 months]. No increase in adverse effects was identified. We observed favorable immunomodulation with 47% increase in the number of intratumoral CTLs posttreatment (P = 0.035). These changes were more pronounced in patients with tumor shrinkage (P = 0.05). The TME was characterized by high numbers of TIM3+ and CTLA4+ cells; there were few activated OX40+ cells. PD-L1 expression was higher in pretreatment tumor cells from metastatic sites versus primary tumor samples (P < 0.05). Higher numbers of PD-L1+ tumor cells at baseline were associated with tumor shrinkage (P = 0.04). Analysis of immune populations in the blood demonstrated decreases in PD-1+ memory effector cells (P = 0.04) and granulocytic myeloid-derived suppressor cells (P = 0.03), with simultaneous increases in CD4+/CTLA4+ cells (P = 0.01). CONCLUSIONS: The combination of cetuximab and pembrolizumab is inactive in patients with RASwt mCRC, despite its partial local immunologic efficacy. Further development of immuno-oncology combinations with enhanced efficacy and/or targeting additional or alternative immune checkpoints merits investigation.

Immunotherapy in colorectal cancer.

The immune tumor microenvironment (TME) of colorectal cancer (CRC) is a crucial contributor to disease biology, making it an important target for therapeutic intervention. The diversity of immune cell populations within various subsets of CRC has led to the discovery that immune characterization of the TME has both prognostic and predictive value for patients. The convergence of improved molecular and cellular characterization of CRC along with the widespread use of immunotherapy in solid tumors has led to a revolution in the approach to clinical care. Monoclonal antibodies (mAbs) which target key immune checkpoints, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), have demonstrated remarkable clinical activity in microsatellite instability-high (MSI-H) CRCs and are now used in routine practice. The observation that MSI-H cancers are highly infiltrated with immune cells and carry a high neoantigen load led to the successful targeting of these cancers with immunotherapy. More recently, the Food and Drug Administration (FDA) approved a PD-1 inhibitor for microsatellite stable (MSS) cancers with high tumor mutation burden. However, the anti-tumor activity of immunotherapy is rare in the majority of CRC. While immune cell characterization does provide prognostic value in these patients, these observations have not yet led to therapeutic interventions. By delineating factors that predict efficacy, resistance, and therapeutic targets, ongoing research will inform the development of effective combination strategies for the vast majority of MSS CRC and immunotherapy-resistant MSI-H cancers.

First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study.

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.

ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma.

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.

Outcomes of patients with borderline resectable and resectable pancreatic adenocarcinoma treated with neoadjuvant three-week course chemoradiotherapy using capecitabine-based versus gemcitabine-based concurrent chemotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy can provide downstaging and improve margin negativity for borderline resectable and resectable pancreatic adenocarcinoma [(B)RPC]. Little is known about the relative efficacy of capecitabine (CAPE)-based vs. gemcitabine (GEM)-based 3-week chemoradiation (3WCRT) with 36 Gy in 15 fractions. This study aimed to compare the odds of achieving surgical resection, time to progression (TTP), and overall survival (OS) of patients treated with 3WCRT with concurrent CAPE versus GEM. METHODS: A retrospective cohort study was conducted, examining medical records from a single center for patients with (B)RPC treated with 3WCRT between 1/2009-12/2020. Odd ratios (OR) of achieving surgical resection were estimated using logistic regression for univariable and multivariable analyses. Median TTP (mTTP) and median OS (mOS) were estimated using the Kaplan-Meier method. Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) of progression and survival in univariable and multivariable analyses. RESULTS: Thirty-one patients were included in the analysis. Twenty-two (71%) patients were treated with CAPE, while 9 (29%) were treated with GEM. All patients in the GEM group were borderline resectable, vs. 18 (82%) patients in the CAPE group, P=0.30. Nineteen (86%) patients in the CAPE group were treated with neoadjuvant FOLFIRINOX, vs. 4 (44%) patients in the GEM group, P=0.03. The CAPE group had higher odds of achieving surgical resection [OR =9.33; 95% confidence interval (CI): 1.50-58.20]. Adjusting for covariates, the odds of achieving surgical resection were still statistically higher in the CAPE group vs. the GEM group (OR =25.34; 95% CI: 1.14-563.72). The CAPE group had superior mTTP compared to the GEM group (15.4 months, 95% CI: 4.9-71.1 vs. 4.0 months, 95% CI: 0.4-14.5; P=0.01), corresponding to a hazard ratio of 0.33 (95% CI: 0.14-0.81). Adjusting for covariates this effect persisted; the adjusted hazard ratio (AHR) for progression was 0.24 (95% CI: 0.08-0.77). Cox proportional hazards analysis also demonstrated that the CAPE group had superior OS compared to the GEM group in unadjusted (HR =0.13; 95% CI: 0.04-0.40) and adjusted models (HR =0.13, 95% CI: 0.03-0.52). CONCLUSIONS: For neoadjuvant 3WCRT, this hypothesis-generating study suggests concurrent CAPE may be a more effective radiosensitizer than GEM for patients with (B)RPC.

Ovarian transposition and metachronous ovarian metastasis in a premenopausal colorectal carcinoma patient: a case report.

Colon cancer has a high incidence of metastasis, with an estimated 0.8-7.4% of colorectal adenocarcinoma (CRC) cases metastasizing to the ovary. The role of prophylactic bilateral oophorectomy in CRC is contested in the literature, particularly in premenopausal patients. Further, it is unclear if prophylactic removal of the contralateral ovary is indicated in cases of direct involvement of one ovary to reduce recurrence. Facing a lack of evidence for survival benefit, hormonal complications, and sterilization, some choose to pursue fertility sparing options. For female patients interested in additional pregnancies, the ovaries can be surgically relocated in a prophylactic procedure known as ovarian transposition; as even small doses of radiation to the ovary can effectively sterilize women in their 30 s. We present a case of a 29-year-old female who underwent ovarian transposition of the right ovary before initiating chemoradiation for primary left sided colon adenocarcinoma with direct invasion of the left ovary. Months later, she presented to the emergency department (ED) with abdominal pain suspicious for ovarian torsion. On restaging computerized tomography (CT), she was diagnosed with symptomatic right ovarian metastasis in the transposed ovary, requiring reoperation and oophorectomy. For this patient, and for others facing critical decisions about ovarian preservation in advanced colorectal cancer, the question remains how to balance fertility concerns with optimal minimization of metastasis and recurrence.

Use of Fecal Microbial Transplantation for Immune Checkpoint Inhibitor Colitis.

Immune checkpoint inhibitors (ICIs) can result in immune-related adverse events which require rapid identification and treatment. Gastrointestinal immune-related adverse events are among the most frequent and severe of these events. ICI colitis can be refractory to current therapies such as corticosteroids and biologic therapy. Fecal microbiota transplantation (FMT) is currently used in cases of recurrent Clostridioides difficile colitis. Many investigations are underway to test the utility of FMT for additional indications, including inflammatory bowel disease (IBD). We present a 71-year-old man with ICI colitis that was nonresponsive to currently defined management options and treated with benefit from FMT.

Erratum: Boland, P.M., et al. Immunotherapy for Colorectal Cancer, Cancers 2017, 9, 50.

The authors wish to make the following corrections to this paper [...].