Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E.

BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.

Examination of Wnt signaling as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using a pancreatic tumor organoid library (PTOL).

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

A Phase Ib Expansion Cohort Evaluating Aurora A Kinase Inhibitor Alisertib and Dual TORC1/2 Inhibitor Sapanisertib in Patients with Advanced Solid Tumors.

BACKGROUND: This study further evaluated the safety and efficacy of the combination of alisertib and sapanisertib in an expansion cohort of patients, including a subset of patients with refractory pancreatic adenocarcinoma, with further evaluation of the pharmacodynamic characteristics of combination therapy. METHODS: Twenty patients with refractory solid tumors and 11 patients with pancreatic adenocarcinoma were treated at the recommended phase 2 dose of alisertib and sapanisertib. Adverse events and disease response were assessed. Patients in the expansion cohort were treated with a 7-day lead-in of either alisertib or sapanisertib prior to combination therapy, with tumor tissue biopsy and serial functional imaging performed for correlative analysis. RESULTS: Toxicity across treatment groups was overall similar to prior studies. One partial response to treatment was observed in a patient with ER positive breast cancer, and a patient with pancreatic cancer experienced prolonged stable disease. In an additional cohort of pancreatic cancer patients, treatment response was modest. Correlative analysis revealed variability in markers of apoptosis and immune cell infiltrate according to lead-in therapy and response. CONCLUSIONS: Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.

Population-level comparisons of gene regulatory networks modeled on high-throughput single-cell transcriptomics data.

Single-cell technologies enable high-resolution studies of phenotype-defining molecular mechanisms. However, data sparsity and cellular heterogeneity make modeling biological variability across single-cell samples difficult. Here we present SCORPION, a tool that uses a message-passing algorithm to reconstruct comparable gene regulatory networks from single-cell/nuclei RNA-sequencing data that are suitable for population-level comparisons by leveraging the same baseline priors. Using synthetic data, we found that SCORPION outperformed 12 existing gene regulatory network reconstruction techniques. Using supervised experiments, we show that SCORPION can accurately identify differences in regulatory networks between wild-type and transcription factor-perturbed cells. We demonstrate SCORPION's scalability to population-level analyses using a single-cell RNA-sequencing atlas containing 200,436 cells from colorectal cancer and adjacent healthy tissues. The differences between tumor regions detected by SCORPION are consistent across multiple cohorts as well as with our understanding of disease progression, and elucidate phenotypic regulators that may impact patient survival.

Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment.

Defining feature of pancreatic ductal adenocarcinoma (PDAC) that participates in the high mortality rate and drug resistance is the immune-tolerant microenvironment which enables tumors to progress unabated by adaptive immunity. In this study, we report that PDAC cells release CSF-1 to induce nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) activation in myeloid cells. Increased NLRP3 expression was found in the pancreas of patients with PDAC when compared with normal pancreas which correlated with the formation of the NLRP3 inflammasome. Using human primary cells and an orthotopic PDAC mouse model, we show that NLRP3 activation is responsible for the maturation and release of the inflammatory cytokine IL1ß which selectively drives Th2-type inflammation via COX2/PGE2 induction. As a result of this inflammation, primary tumors were characterized by reduced cytotoxic CD8+ T-cell activation and increased tumor expansion. Genetic deletion and pharmacologic inhibition of NLRP3 enabled the development of Th1 immunity, increased intratumoral levels of IL2, CD8+ T cell­mediated tumor suppression, and ultimately limited tumor growth. In addition, we observed that NLRP3 inhibition in combination with gemcitabine significantly increased the efficacy of the chemotherapy. In conclusion, this study provides a mechanism by which tumor-mediated NLRP3 activation exploits a distinct adaptive immunity response that facilitates tumor escape and progression. Considering the ability to block NLRP3 activity with safe and small orally active molecules, this protein represents a new promising target to improve the limited therapeutic options in PDAC. SIGNIFICANT: This study provides novel molecular insights on how PDAC cells exploit NLRP3 activation to suppress CD8 T-cell activation. From a translational perspective, we demonstrate that the combination of gemcitabine with the orally active NLRP3 inhibitor OLT1177 increases the efficacy of monotherapy.

Biomarker Testing Trends in Patients With Metastatic Colorectal Cancer Who Live in Rural Areas and Urban Clusters in the US.

BACKGROUND: There is a paucity of data on biomarker testing rates in rural populations with metastatic colorectal cancer (mCRC). To assess biomarker testing practices, oncologists in rural areas and urban clusters in the US were surveyed. MATERIALS AND METHODS: A web-based survey was administered to oncologists spending ≥40% of their time practicing in rural areas or urban clusters and who had treated ≥2 patients with stage IV mCRC in the prior month. RESULTS: Ninety-nine oncologists completed the quantitative survey and 17 the qualitative interview. Among respondents, 97% reported ordering biomarker tests. Oncologists reported testing for KRAS, NRAS, BRAF, HER2, and mismatch repair deficiency/microsatellite instability in 72%, 65%, 63%, 56%, and 66% of patients with metastatic disease, respectively. Forty-one percent reported performing reflex testing. The most cited testing barriers were lack of insurance coverage, insufficient tissue samples, and long turnaround times. CONCLUSION: Further assessment of rural testing practices is needed.

The Local Microbiome in Esophageal Cancer and Treatment Response: A Review of Emerging Data and Future Directions.

The incidence of esophageal cancer is increasing worldwide, with established risk factors explaining only a small fraction of cases. Currently, there are no established screening protocols in most countries, and treatment options are limited. The human microbiome has been implicated in carcinogenesis and the cancer treatment response. The advent of nucleic acid sequencing technologies has enabled more comprehensive, culture-independent bacterial identification. Across several tumor types, studies of tissue-specific microbiomes have shown associations between the overall microbiome composition, the relative abundance of specific bacteria, and tumorigenesis. Furthermore, in the era of cancer immunotherapy, several studies have demonstrated that the microbiome and specific bacteria may modify treatment responses and the risk of immune-related adverse events. DESIGN: peer-reviewed, published studies describing the role of local, gastrointestinal-specific microbiota or the role of the gut microbiome in treatment responses were reviewed. PubMed was searched from 1 September 2022 to 1 November 2022, using the following terms in combination: "microbiome", "tumor microbiome", "esophageal cancer", "cancer", "cancer treatment", and "immunotherapy". Original research articles were considered, and other reviews or editorials were discarded. In total, approximately 250 articles were considered. RESULTS: over 70 studies describing microbiome research in either gastrointestinal carcinogenesis or the systemic treatment response were identified and reviewed. CONCLUSIONS: a growing body of evidence supports the role of the esophageal microbiome in both esophageal tumorigenesis and the immune checkpoint inhibitor response. More well-designed, comprehensive studies are required to collect the appropriate clinical, microbial, and immunophenotype data that are needed to clarify the precise role of the microbiome in esophageal carcinogenesis and treatment.

Pulmonary metastasectomy is associated with survival after lung-only recurrence in pancreatic cancer.

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma, 14% of patients have lung-only recurrence. We hypothesize that in patients with isolated lung metastases from pancreatic ductal adenocarcinoma, pulmonary metastasectomy offers a survival benefit with minimal additional morbidity after resection. METHODS: This was a single-institution, retrospective study of patients who underwent definitive resection of pancreatic ductal adenocarcinoma and later developed isolated lung metastases between 2009 and 2021. Patients were included if they carried a diagnosis of pancreatic ductal adenocarcinoma, underwent pancreatic resection with curative intent, and subsequently developed lung metastases. Patients were excluded if they developed multiple sites of recurrence. RESULTS: We identified 39 patients with pancreatic ductal adenocarcinoma and isolated lung metastases, 14 of whom underwent pulmonary metastasectomy. During the study period, 31 (79%) patients died. Across all patients, there was an overall survival of 45.9 months, a disease-free interval of 22.8 months, and survival after recurrence of 22.5 months. Survival after recurrence was significantly longer in patients who underwent pulmonary metastasectomy than those who did not (30.8 months vs 18.6 months, P < .01). There was no difference in overall survival between groups. However, patients who underwent pulmonary metastasectomy were significantly more likely to be alive 3 years after their diagnosis (100.0% vs 64%, P = .02) and 2 years after recurrence (79% vs 32%, P < .01) than those in who did not undergo pulmonary metastasectomy. No mortalities occurred related to pulmonary metastasectomy, and procedure-related morbidity was 7%. CONCLUSION: Patients who underwent pulmonary metastasectomy for isolated pulmonary pancreatic ductal adenocarcinoma metastases had significantly longer survival after recurrence and clinically meaningful survival benefit with minimal additional morbidity after pulmonary resection.

Early-Onset GI Cancers: Rising Trends, Genetic Risks, Novel Strategies, and Special Considerations.

Cancers in young adults (commonly described as early-onset [EO] cancer) represent a group of malignancies that have unique and challenging biology and genetic, treatment, social, and psychological implications. Even more concerning is a rising trend of EO cancers in multiple tumor types. Research and investigation in EO cancers will help elucidate mechanisms of carcinogenesis, differences in biology and response to treatment, and the need for multidisciplinary care to ensure comprehensive treatment and support for young patients.

Podcast article: Biomarker testing in colorectal cancer.

Christopher Lieu, co-director of gastrointestinal medical oncology and the associate director for clinical research at the University of Colorado Cancer Center (CO, USA) discusses the importance of biomarker testing in metastatic colorectal cancer to inform personalized patient care.

Improved Survival After Adjuvant Therapy in Locally Advanced Rectal Cancer Patients With Pathologic Complete Response.

BACKGROUND: The benefit of adjuvant therapy is unclear in patients with rectal cancer achieving a pathologic complete response after neoadjuvant chemoradiotherapy and total mesorectal excision. OBJECTIVE: This study aimed to assess the benefit of adjuvant chemotherapy on survival among rectal cancer patients with a pathologic complete response after neoadjuvant chemoradiation. DESIGN: Retrospective cohort study. SETTING: National Cancer Database (2004-2017). PATIENTS: Patients with clinical stage 2 or 3 rectal adenocarcinoma who underwent neoadjuvant chemoradiation (50-50.4 Gy in 25-28 fractions) followed by total mesorectal excision with a pathologic complete response were included. INTERVENTION: Adjuvant chemotherapy. MAIN OUTCOME MEASURES: Overall survival. RESULTS: There were 20,518 patients and 2221 (11%) had a pathologic complete response after neoadjuvant chemoradiation. Of 2221 patients, 1441 (65%) did not receive adjuvant therapy and 780 (35%) did. Patients who received adjuvant therapy were more likely to be younger (median 58 vs 62 y), have private insurance (61% vs 49%), and have node-positive disease (57% vs 48%) (all p < 0.05). There were no differences in sex, race, Charlson-Deyo score, clinical T-stage, tumor size and differentiation, adequate lymphadenectomy (12 or more), or sphincter preservation between groups (all p > 0.05). Overall survival at 5, 10, and 14 years was significantly longer in the adjuvant group (93%, 85%, 83%, respectively) compared to patients who did not receive adjuvant therapy (87%, 67%, 51%, respectively) ( p < 0.001). In a subgroup analysis, adjuvant therapy was associated with improved survival in patients with clinical stage 2 and 3 rectal cancer ( p < 0.001). After adjusting for patient and tumor characteristics, omission of adjuvant chemotherapy was associated with significantly worse survival (HR 1.53, 95% 1.08-2.16). LIMITATIONS: Selection bias, unknown perioperative morbidity, chemotherapy regimen, recurrence status, and other unidentified factors limiting survival analysis. CONCLUSIONS: In patients with clinical stage 2 or 3 rectal cancer, adjuvant chemotherapy was associated with improved overall survival in patients achieving a pathological complete response after neoadjuvant chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/C139 . SOBREVIDA MEJORADA DESPUS DE LA TERAPIA ADYUVANTE EN PACIENTES CON CNCER DE RECTO LOCALMENTE AVANZADO CON RESPUESTA PATOLGICA COMPLETA: ANTECEDENTES:En los pacientes con cáncer de recto que logran una respuesta patológica completa después de la quimiorradioterapia neoadyuvante y la escisión total del mesorrecto, el beneficio de la terapia adyuvante no está claro.OBJETIVO:Evaluar el beneficio de la quimioterapia adyuvante en la sobrevida de los pacientes con cáncer de recto con una respuesta patológica completa después de la quimiorradioterapia neoadyuvante.DISEÑO:Estudio de cohorte retrospectivo.ESCENARIO:Base de Datos Nacional de Cáncer (2004-2017).PACIENTES:Pacientes con adenocarcinoma rectal en estadio clínico 2 ó 3 que se sometieron a quimiorradiación neoadyuvante (50-50,4 Gy en 25-28 fracciones) seguida de escisión mesorrectal total con una respuesta patológica completa.INTERVENCIÓN:Quimioterapia adyuvante.PRINCIPALES MEDIDAS DE RESULTADO:Sobrevida global.RESULTADOS:Hubo 20.518 pacientes y 2.221 (11%) tuvieron una respuesta patológica completa después de la quimiorradiación neoadyuvante. Entre estos 2221 pacientes, 1441 (65%) no recibieron terapia adyuvante y 780 (35%) sí. Los pacientes que recibieron terapia adyuvante tenían más probabilidades de ser más jóvenes (mediana de 58 frente a 62 años), tener un seguro privado (61% frente a 49%) y tener enfermedad con linfonodos positivos (57% frente a 48 %) (todos p < 0,05). No hubo diferencias en género, raza, puntuación de Charlson-Deyo, estadio T clínico, tamaño y diferenciación del tumor, linfadenectomía adecuada (≥12) o preservación del esfínter entre los grupos (todos p > 0,05). La sobrevida general a los 5, 10 y 14 años fue significativamente mayor en el grupo adyuvante (93%, 85%, 83%, respectivamente) en comparación con los pacientes que no recibieron terapia adyuvante (87%, 67%, 51% respectivamente) ( p < 0,001). En un análisis de subgrupos, la terapia adyuvante se asoció con una mejor sobrevida general en pacientes con cáncer de recto en estadio clínico 2 y 3 ( p < 0,001). Después de ajustar por las características del paciente y del tumor, la omisión de la quimioterapia adyuvante se asoció con una sobrevida global significativamente peor (HR 1,53, IC del 95%, 1,08-2,16).LIMITACIONES:Sesgo de selección; morbilidad perioperatoria desconocida, régimen de quimioterapia, estado de recurrencia y otros factores no identificados que limitan el análisis de sobrevida.CONCLUSIONES:En pacientes con cáncer de recto en estadio clínico 2 ó 3, la quimioterapia adyuvante se asoció con una mejor sobrevida general en pacientes que lograron una respuesta patológica completa después de la quimiorradioterapia neoadyuvante. Consulte Video Resumen en http://links.lww.com/DCR/C139 . (Traducción-Dr. Felipe Bellolio ).

Phase 1 study of the safety, pharmacokinetics, and preliminary efficacy of CA102N as monotherapy and in combination with trifluridine-tipiracil in patients with locally advanced or metastatic solid tumors.

CA102N is a covalently bound conjugate of modified nimesulide (Nim) and NaHA, the sodium salt of hyaluronic acid (HA). HA is a natural ligand of cluster of differentiation 44 (CD44), which is over-expressed in colorectal cancer (CRC). CA102N is designed to deliver nimesulide directly to the tumor via the interaction of HA and CD44. A Phase 1, 2-part (dose escalation, dose expansion), non-randomized, open-label, first-in-human study of CA102N, as monotherapy and in combination with trifluridine-tipiracil, was conducted in patients with locally advanced or metastatic solid tumors. The CA102N doses evaluated were 0.36 mg/kg, 0.54 mg/kg, and 0.72 mg/kg Nim equivalent. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 as well as serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) throughout the study; secondary endpoints were pharmacodynamics parameters, objective tumor response, and urinary pharmacodynamics markers of target inhibition. Between April 2019 and October 2021, 37 patients were enrolled in 3 US centers. No DLTs were observed in Part 1, and 0.72 mg/kg Nim equivalent was the dose selected for Part 2. In total, 52 TEAEs in 18 patients were CA102N-related; 4 (in 3 patients) were ≥ Grade 3. Exploratory analysis in the dose expansion cohort revealed a median progression-free survival of 3.7 (1.0, 6.77) months. Based on this study, CA102N as monotherapy or in combination with trifluridine-tipiracil, was safe and well-tolerated at the recommended Phase 2 dose of 0.72 mg/kg Nim equivalent in patients with locally advanced or metastatic solid tumors. Preliminary evidence of antitumor activity in CRC warrants further clinical development. (ClinicalTrials.gov registration number: NCT03616574. Registration date: August 6, 2018).

Treatment of Metastatic Colorectal Cancer: ASCO Guideline.

PURPOSE: To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC). METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria. RECOMMENDATIONS: Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti-vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti-epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive RAS wild-type mCRC; chemotherapy and anti-vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair RAS wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated BRAF V600E-mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Informational Needs of Surgical Oncology Patients: A Cross-Sectional Patient Survey.

INTRODUCTION: Patients newly diagnosed with cancer often seek information prior to being seen by a specialist. Little is known about the type of information desired and the sources used. We asked how patients find information about their new cancer diagnoses to improve information provision. METHODS: An anonymous seven-question survey was provided to new patients in the surgical and medical oncology clinics at a comprehensive cancer center from February 2021 to June 2021. RESULTS: Of 503 consecutive patients, 405 (81%) returned surveys; 49% female, 57% aged 51-75 y, and 71% Caucasian. Many (74%) sought information before their visit. Most (57%) relied on prior medical providers and 77% reported them as a trusted source. Nearly 80% of patients used at least one nonvalidated resource; 21% friends and relatives, 20% nongovernment or hospital resources, and 12% social media. Importantly, 23% found conflicting information. Respondents desired information on cancer treatment (58%), alternative therapies (35%), and nutrition and supplements (31%). CONCLUSIONS: Patients with cancer trust information from medical providers but seek information from a variety of sources that can provide conflicting information. These data support encouraging patients to use validated sources, providing robust organization-based resources, and engaging patients on topics such as alternative therapies and nutrition.

Rectal Cancer: Clinical and Molecular Predictors of a Complete Response to Total Neoadjuvant Therapy.

BACKGROUND: Total neoadjuvant therapy in rectal cancer may increase pathological complete response rates, potentially allowing for a nonoperative approach. OBJECTIVE: The objective of this study was to identify patient and tumor characteristics that predict a complete response following total neoadjuvant therapy. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at a university-based National Cancer Institute-designated Comprehensive Cancer Center. PATIENTS: The patients include those with stage 2 or 3 rectal adenocarcinoma. INTERVENTIONS: Interventions included total neoadjuvant therapy, total mesorectal excision, and nonoperative management. MAIN OUTCOME MEASURES: Complete response was defined as either patients with a clinical complete response undergoing nonoperative management who remained cancer-free or patients undergoing surgery with a pathological complete response. RESULTS: Among 102 patients, median age was 54 years, 69% were male, median carcinoembryonic antigen level was 3.0 ng/mL, and the median distance of the tumor above the anorectal ring was 3 cm. Thirty-eight (37%) patients had a complete response, including 15 of 18 (83%) nonoperative patients who remained cancer free at a median of 22 months (range, 7-48 months) and 23 of 84 (27%) patients who underwent surgery and had a pathological complete response. The incomplete response group consisted of 61 patients who underwent initial surgery and 3 nonoperative patients with regrowth. There were no differences in gender, T-stage, or tumor location between groups. Younger age (median, 49 vs 55 years), normal carcinoembryonic antigen (71% vs 41%), clinical node-negative (24% vs 9%), smaller tumors (median 3.9 vs 5.4 cm), and wild-type p53 (79% vs 47%) and SMAD4 (100% vs 81%) were more likely to have a complete response (all p < 0.05). LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSIONS: In patients with rectal cancer treated with total neoadjuvant therapy, more than one-third will achieve a pathological complete response or sustained clinical complete response with nonoperative management, making oncological resection superfluous in these patients. Smaller, wild-type p53 and SMAD4, and clinically node-negative cancers are predictive features of a complete response. See Video Abstract at http://links.lww.com/DCR/B889 . CNCER DE RECTO PREDICTORES CLNICOS Y MOLECULARES DE UNA RESPUESTA COMPLETA A LA TERAPIA NEOADYUVANTE TOTAL: ANTECEDENTES:La terapia neoadyuvante total en el cáncer de recto puede aumentar las tasas de respuesta patológica completa y permitir potencialmente un enfoque no quirúrgico.OBJETIVO:El objetivo fue identificar las características tanto del paciente y del tumor que logren predecir una respuesta completa después de la terapia neoadyuvante total.DISEÑO:Este fue un estudio de cohorte retrospectivo.AJUSTES:Este estudio se realizó en un Centro Integral de Cáncer designado por el Instituto Nacional del Cáncer con sede universitaria.PACIENTES:Los pacientes incluyen aquellos con adenocarcinoma de recto en estadio 2 o 3.INTERVENCIONES:Terapia neoadyuvante total, escisión total del mesorrecto, manejo conservador no quirúrgico.PRINCIPALES MEDIDAS DE RESULTADO:La respuesta completa se definió como pacientes con una respuesta clínica completa sometidos a tratamiento no quirúrgico que permanecieron libres de cáncer o pacientes sometidos a cirugía con una respuesta patológica completa.RESULTADOS:Entre 102 pacientes, la mediana de edad fue de 54 años, el 69% fueron hombres, la mediana del nivel de antígeno carcinoembrionario fue de 3.0 ng/ml y la mediana de la distancia del tumor por encima del anillo anorrectal fue de 3 cm. Thirty-eight (37%) pacientes tuvieron una respuesta completa que incluyó a 15 de 18 (83%) pacientes con manejo no operatorio y que permanecieron libres de cáncer en una mediana de 22 meses (rango 7- 48 meses) y 23 de 84 (27%) pacientes que fueron sometidos a cirugía y tuvieron una respuesta patológica completa. El grupo de respuesta incompleta consistió en 61 pacientes que fueron sometidos inicialmente a cirugía y 3 pacientes no quirúrgicos con recrecimiento. No se encontró diferencias de género, estadio T o ubicación del tumor entre los grupos. Edad más joven (mediana 49 frente a 55), antígeno carcinoembrionario normal (71% frente a 41%), ganglios clínicos negativos (24% frente a 9%), tumores más pequeños (mediana de 3,9 frente a 5,4 cm) y p53 de tipo salvaje (79 % vs 47%) y SMAD4 (100% vs 81%) tenían más probabilidades de tener una respuesta completa (todos p < 0,05).LIMITACIONES:Este fue un estudio retrospectivo y con un tamaño de muestra pequeño.CONCLUSIONES:En pacientes con cáncer de recto tratados con terapia neoadyuvante total, más de un tercio logrará una respuesta patológica completa o una respuesta clínica completa sostenida con manejo no operatorio, logrando que la resección oncológica sea superflua en estos pacientes. Los cánceres más pequeños, clínicamente con ganglios negativos, con p53 de tipo salvaje y SMAD4, son características predictoras de una respuesta completa. Consulte Video Resumen en http://links.lww.com/DCR/B889 . (Traducción-Dr. Osvaldo Gauto ).

First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors.

(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11-447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.

Prognostic Impact of the Presence of Barrett's Esophagus and Intestinal Metaplasia on Esophageal Adenocarcinoma Survival.

Background/Aims: Barrett's esophagus (BE), defined by the presence of intestinal metaplasia (IM) on histology, is thought to be the only identifiable precursor lesion for esophageal adenocarcinoma (EAC). Recent studies have suggested the possibility of an alternate, non-IM associated EAC that is a more aggressive form of EAC with worse survival. Among EAC patients, we aimed to compare survival of patients with and without IM at the time of diagnosis. Methods: This was a retrospective cohort study of all patients with histologic confirmed EAC evaluated at a tertiary care center from 2013 to 2019. Cases were categorized according to the presence or absence of IM on histologic specimens (Group I-IM-EAC and Group II-non-IM-EAC). We compared demographic characteristics, clinical stage, therapy, and survival between the 2 groups using the Chi-square and ANOVA tests (for categorical and continuous variables, respectively). We used Cox proportional hazards regression to determine the association of IM with overall survival, adjusting for sex, age at diagnosis, tumor location, histologic grade, and clinical stage. Results: A total of 475 patients were included in this analysis (mean age 64.8 years [SD 10.8], 89% white) and 109 (23.0%) had no evidence of IM. Compared with IM-EAC (Group I), individuals in the non-IM-EAC group were younger (P = .01) and had a greater proportion of patients diagnosed with advanced disease (49.5 vs 20.2% for stage 4, P < .001). These patients were less likely to undergo endoscopic therapy alone (0.92% vs 29.78%, P < .001) or surgery alone (0 vs 9.84%, P = .001). On multivariable analysis, the presence of IM-EAC was associated with improved overall survival compared to non-IM-EAC (HR 0.69, 95% CI 0.49-0.96). Additional factors associated with poor survival was increasing stage of diagnosis (HR 6.49: 95% CI 3.77-11.15 for stage 4, HR 2.19: 95% CI 1.25-3.84 for stage 3, HR 2.04: 95% CI 0.98-4.25 for stage 2 compared to stage 1) and more advanced histologic stage (HR 2.00, 95% CI 1.26-3.19) for poorly/undifferentiated compared to well differentiated). Conclusions: EAC without the presence of IM on histology was associated with worse survival compared to those with IM. Future prospective studies with detailed molecular sequencing are required to clarify if 2 separate phenotypes of EAC exist (IM-EAC and non-IM-EAC). If confirmed, this may have significant implications for screening and management strategies.

Cabozantinib sensitizes microsatellite stable colorectal cancer to immune checkpoint blockade by immune modulation in human immune system mouse models.

Immune checkpoint inhibitors have been found to be effective in metastatic MSI-high colorectal cancers (CRC), however, have no efficacy in microsatellite stable (MSS) cancers, which comprise the majority of mCRC cases. Cabozantinib is a small molecule multi-tyrosine kinase inhibitor that is FDA approved in advanced renal cell, medullary thyroid, and hepatocellular carcinoma. Using Human Immune System (HIS) mice, we tested the ability of cabozantinib to prime MSS-CRC tumors to enhance the potency of immune checkpoint inhibitor nivolumab. In four independent experiments, we implanted distinct MSS-CRC patient-derived xenografts (PDXs) into the flanks of humanized BALB/c-Rag2nullIl2rγnullSirpαNOD (BRGS) mice that had been engrafted with human hematopoietic stem cells at birth. For each PDX, HIS-mice cohorts were treated with vehicle, nivolumab, cabozantinib, or the combination. In three out of the four models, the combination had a lower tumor growth rate compared to vehicle or nivolumab-treated groups. Furthermore, interrogation of the HIS in immune organs and tumors by flow cytometry revealed increased Granzyme B+, TNFα+ and IFNγ+ CD4+ T cells among the human tumor infiltrating leukocytes (TIL) that correlated with reduced tumor growth in the combination-treated HIS-mice. Notably, slower growth correlated with increased expression of the CD4+ T cell ligand, HLA-DR, on the tumor cells themselves. Finally, the cabozantinib/nivolumab combination was tested in comparison to cobimetinib/atezolizumab. Although both combinations showed tumor growth inhibition, cabozantinib/nivolumab had enhanced cytotoxic IFNγ and TNFα+ T cells. This pre-clinical in vivo data warrants testing the combination in clinical trials for patients with MSS-CRC.