Relacorilant plus nab-paclitaxel for the treatment of metastatic pancreatic ductal adenocarcinoma: results from the open-label RELIANT study.

BACKGROUND: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines. PATIENTS AND METHODS: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed. RESULTS: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest. CONCLUSION: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation.

LESSONS LEARNED: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation. BACKGROUND: Cediranib, a vascular endothelial growth factor receptor inhibitor, suppresses expression of BRCA1/2 and RAD51 inducing homologous recombination DNA repair deficiency (HRD) in several cancer cell lines and xenograft models [1]. Olaparib provides a clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPDAC) with germline BRCA mutation (gBRCAmt) [2]. We hypothesized that cediranib induces HRD in the absence of gBRCAmt and synergizes with olaparib, resulting in an objective response in patients with mPDAC. METHODS: Patients with mPDAC with at least one prior systemic chemotherapy were enrolled. Patients with known gBRCAmt were excluded. Patients took cediranib 30 mg daily and olaparib 200 mg twice daily, orally. The primary endpoint was objective response (OR) rate. RESULTS: Nineteen patients received the study drugs. Seven patients came off treatment before the first restaging scan: six because of clinical progression and one because of an adverse event. No OR was observed. Six patients had stable disease (SD) as a best overall response. The median duration of SD was 3.1 months. The median overall survival was 3.4 months. Common treatment-related adverse events were fatigue, hypertension, and diarrhea. CONCLUSION: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.

Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

A Phase II, Single-Arm, Open-Label, Bayesian Adaptive Efficacy and Safety Study of PBI-05204 in Patients with Stage IV Metastatic Pancreatic Adenocarcinoma.

LESSONS LEARNED: This trial evaluating a novel plant extract, PBI-05204, did not meet its primary endpoint of overall survival but did show signals of efficacy in heavily pretreated mPDA. PBI-05204 was generally well tolerated, with the most common side effects related to treatment being vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Additional trials are needed to explore the role of PBI-05204 in cancer treatment. BACKGROUND: Survival for metastatic pancreatic ductal adenocarcinoma (mPDA) is dismal, and novel agents are needed. PBI-05204 is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a cardiac glycoside that has demonstrated antitumor activity in various tumor cell lines with a mechanism involving inhibition of Akt phosphorylation and through downregulation of mTOR. METHODS: A phase II, single-arm, open-label study to determine the efficacy of PBI-05204 in patients with refractory mPDA therapy was conducted. The primary endpoint was overall survival (OS), with the hypothesis that 50% of patients would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Patients received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or patient withdrawal. Radiographic response was assessed every two cycles. RESULTS: Forty-two patients were enrolled, and 38 were analyzed. Ten patients were alive at 4.5 months (26.3%) with a median PFS of 56 days. One objective response (2.6%) was observed for 162 days. Grade ≥ 3 treatment-emergent adverse events occurred in 63.2% of patients with the most common being fatigue, vomiting, nausea, decreased appetite, and diarrhea. CONCLUSION: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate a role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy and radiotherapy. A randomized phase II trial is currently being designed.

Immune-Related Adverse Events and Immune Checkpoint Inhibitor Efficacy in Patients with Gastrointestinal Cancer with Food and Drug Administration-Approved Indications for Immunotherapy.

INTRODUCTION: Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. MATERIALS AND METHODS: The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. RESULTS: Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. CONCLUSION: Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. IMPLICATIONS FOR PRACTICE: Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer.

Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (n = 16).

Targeting DNA Damage Repair Pathways in Pancreatic Adenocarcinoma.

OPINION STATEMENT: Metastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from tumor tissue, to assess for the presence of DNA damage repair (DDR) defects, microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor kinase (NTRK) fusions, anaplastic lymphoma kinase (ALK) rearrangements, or human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose tumors harbor DDR defects, benefit from treatment with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and WEE1 have demonstrated promising anti-tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting therapies into rational clinical trial combinations and sequence PARP inhibitors in relation to platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for mPDA patients, in all treatment lines, so that novel therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.

Pancreatic Adenocarcinoma, Version 1.2019.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer: phase I results : A phase I clinical trial.

Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m2) of a 28-day cycle (L0). Nineteen patients were enrolled, yet 18 evaluable for dose-limiting toxicities (DLTs). One DLT observed at L0, however dasatinib was reduced to 50 mg (L-1) given side effects observed in the first two patients. At L-1, a DLT occurred in 1/6 patients and dose was re-escalated to L0, where zero DLTs reported in next four patients. Dasatinib was escalated to 100 mg (L1) where 1/6 patients experienced a DLT. Although L1 was tolerable, dose escalation was stopped as investigators felt L1 was within the optimal therapeutic window. Most frequent toxicities were anemia (89%), elevated aspartate aminotransferase (79%), fatigue (79%), nausea (79%), elevated alanine aminotransferase (74%), lymphopenia (74%), leukopenia (74%), neutropenia (63%), and thrombocytopenia (63%), most Grade 1/2. Stable disease as best response was observed in 69% (9/13). Median progression-free and overall survival was 3.6 and 8 months, respectively. Dasatinib, erlotinib, and gemcitabine was safe with manageable side effects, and with encouraging preliminary clinical activity in advanced pancreatic cancer.

Harnessing the Immune System in Pancreatic Cancer.

OPINION STATEMENT: Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS.

Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS. Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC. Methods Patients received the anti-angiogenic agent linifanib at the recommended phase II dose of 17.5 mg. Primary endpoint was objective response rate (ORR), with a goal of 10%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Simon's optimal two-stage design was used to assess futility. Linifanib was considered inactive if two or fewer patients among the first 30 achieved an objective response. Results Thirty patients were enrolled on study. Grade 3 treatment-related toxicities occurring in at least two patients were fatigue, hypertension, proteinuria, diarrhea, nausea, oral pain, vomiting, thrombocytopenia, and arthralgia. Although no responses were observed, 63.5% of patients achieved stable disease. The median PFS and OS were 4.7 months and 9.5 months, respectively. Stopping rules for lack of clinical efficacy led to study closure. Conclusion Despite observing zero responses, a majority of patients had stable disease and eight patients had stable disease lasting longer than 5 months. These results suggest that linifanib has some anti-tumor activity in KRAS mutant metastatic and refractory CRC.

A phase I trial investigating pulsatile erlotinib in combination with gemcitabine and oxaliplatin in advanced biliary tract cancers.

Advanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX. This was a single-institution phase Ib study that enrolled adult patients with unresectable or metastatic biliary tract, pancreas, duodenal, or ampullary carcinomas that have not received any prior treatment for their disease. Dose escalation followed a standard 3 + 3 design, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity, except nausea/vomiting, or grade 4 hematologic toxicity. A dose expansion cohort in ABTC was treated at the MTD. Twenty-eight patients were enrolled and 4 dose levels were explored. The MTD was erlotinib 150 mg + GEM 800 mg/m2 + OX 85 mg/m2. DLTs were diarrhea and anemia. Most frequent toxicities were nausea (78 %), fatigue (71 %), neuropathy (68 %), and diarrhea (61 %), predominantly grade 1-2. In the ABTC patients, the objective response and disease control rates were 29 % and 94 %, respectively, and median overall survival was 18 months. Erlotinib plus GEMOX was well tolerated. Encouraging anti-tumor activity was seen as evidenced by a high disease control rate and longer median OS than standard chemotherapy in the patients with ABTC.

Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

Trends in the Incidence and Treatment of Early-Onset Pancreatic Cancer.

BACKGROUND: Early-onset pancreatic cancer (EOPC) is relatively uncommon. It is unclear if the incidence of EOPC is evolving and how these patients are treated. METHODS: We conducted a retrospective, population-based study using SEER 2004-2016. We evaluated annual age-adjusted incidence rate (AAIR), stage at presentation, and race/ethnicity among 7802 patients plus treatment patterns in 7307 patients (excluding neuroendocrine tumors) younger than 50. RESULTS: The AAIR was higher in males while the rate increased faster in females. The AAIR was highest in Non-Hispanic Black patients and increased for all races/ethnicities over time. The percentage of patients diagnosed with distant-stage disease decreased over time but increased for localized-stage disease. Hispanic patients made up a larger proportion of patients over time compared to other groups. For localized-stage disease, primary surgery alone was the most utilized modality of therapy. For regional-stage disease, chemotherapy with radiation was the most utilized modality from 2004-2010, whereas chemotherapy alone was the most utilized from 2011-2016. For distant-stage disease, chemotherapy alone was the most utilized and used increasingly over time. Patients with EOPC received radiation and chemotherapy at similar rates to, and underwent surgery more frequently, than patients 50-69. CONCLUSIONS: The AAIR of EOPC increased over time, faster so in females. Groups who experience a higher burden of pancreatic cancer, particularly African Americans, experienced a higher burden of EOPC. Treatment of localized and regional-stage disease did not follow standard treatment guidelines for pancreatic cancer. Our findings indicate that EOPC patients received more treatment than their older counterparts.

Safety and Efficacy of Avelumab in Small Bowel Adenocarcinoma.

INTRODUCTION: Small bowel adenocarcinomas (SBAs) are rare and frequently treated like large intestinal adenocarcinomas. However, SBAs have a very different microenvironment and could respond differently to the same therapies. Our previous data suggested that SBAs might benefit from targeting the PD-1/PD-L1 axis based on PD-L1 staining in almost 50% of SBA tissue samples tested. Thus, we designed a phase 2 study to explore safety and efficacy of avelumab in SBA. PATIENTS AND METHODS: Patients with advanced or metastatic disease were enrolled; ampullary tumors were considered part of the duodenum and allowed. Prior PD-1/PD-L1 inhibition was not allowed. Avelumab (10 mg/kg) was given every 2 weeks, and imaging was performed every 8 weeks. Primary endpoint was response rate. RESULTS: Eight patients (n = 5, small intestine; n = 3, ampullary) were enrolled, with a majority (88%) being male and a median age of 61 years. Of 7 efficacy-evaluable patients, 2 (29%) experienced partial responses; stable disease occurred in 3 additional patients (71%). Median progression-free survival was 3.35 months. Most frequent, related toxicities were anemia, fatigue, and infusion-related reaction (25% each), mostly grade ≤2; grade 3 hypokalemia and hyponatremia occurred in one patient, and another reported grade 4 diabetic ketoacidosis. CONCLUSIONS: Despite the observed benefit, accrual was slower than expected and the study was closed early due to feasibility. A general clinic observation was that patients were receiving immunotherapy off-label as the availability of these agents increased. Off-label availability and disease rarity were likely drivers of insufficient accrual.

First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors.

BACKGROUND: OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. METHODS: Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. RESULTS: Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. CONCLUSION: No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT02923349.

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study.

PURPOSE: Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study. PATIENTS AND METHODS: Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1). RESULTS: Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including BRAF or KRAS mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events. CONCLUSION: Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted.

First-in-Human PET Imaging and Estimated Radiation Dosimetry of l-[5-11C]-Glutamine in Patients with Metastatic Colorectal Cancer.

Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Noninvasive imaging via PET may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. l-[5-11C]-glutamine (11C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of 11C-glutamine for oncologic PET imaging. Methods: Nine patients with confirmed metastatic colorectal cancer underwent PET/CT imaging. Patients received 337.97 ± 44.08 MBq of 11C-glutamine. Dynamic PET acquisitions that were centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. After the dynamic acquisition, a whole-body PET/CT scan was acquired. Volume-of-interest analyses were performed to obtain estimates of organ-based absorbed doses of radiation. Results:11C-glutamine was well tolerated in all patients, with no observed safety concerns. The organs with the highest radiation exposure included the bladder, pancreas, and liver. The estimated effective dose was 4.46E-03 ± 7.67E-04 mSv/MBq. Accumulation of 11C-glutamine was elevated and visualized in lung, brain, bone, and liver metastases, suggesting utility for cancer imaging. Conclusion: PET using 11C-glutamine appears safe for human use and allows noninvasive visualization of metastatic colon cancer lesions in multiple organs. Further studies are needed to elucidate its potential for other cancers and for monitoring response to treatment.

External Validation of a Clinical Score for Patients With Neuroendocrine Tumors Under Consideration for Peptide Receptor Radionuclide Therapy.

Importance: Despite the benefit of peptide receptor radionuclide therapy (PRRT) for patients with well-differentiated neuroendocrine tumors (WD NETs), no clinical metric to anticipate benefit from the therapy for individual patients has been previously defined. Objective: To assess whether the prognostic ability of the clinical score (CS) could be validated in an external cohort of patients with WD NETs. Design, Setting, and Participants: This multicenter cohort study's analysis included patients with WD NETs who were under consideration for peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-dotatate between March 1, 2016, and March 17, 2020. The original cohort included patients from Vanderbilt-Ingram Cancer Center. The validation cohort included patients from Ochsner Medical Center, Markey Cancer Center, and Rush Medical Center. Patients with paragangliomas, pheochromocytomas and neuroblastomas were excluded. Statistical analysis was performed from June to November 2021. Exposures: PRRT with 177Lu-dotatate or alternate therapies such as everolimus, sunitinib, or capecitabine plus temozolomide. Main Outcomes and Measures: The primary outcome was progression-free survival (PFS) and was estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusting for primary tumor site, tumor grade, and number of PRRT doses administered was used to analyze association between CS and outcomes. Results: A total of 126 patients (median age [IQR] age: 63.6 [52.9-70.7] years; 64 male individuals) were included in the validation cohort, and the combined cohort (validation and original cohorts combined) had a total of 248 patients (median [IQR] patient age: 63.3 [53.3-70.3] years; 126 male individuals). In the validation cohort, on multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.61; 95% CI, 1.64-4.16). After finding an association of the CS with PFS in the validation cohort, the original and validation cohorts were combined into the cohort for this analysis. On multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.52; 95% CI, 1.89-3.36). Conclusions and Relevance: Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT.