Faculty Bibliography

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/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/CONCLUSIONS: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.

PURPOSE/OBJECTIVE:The benefit of adjuvant therapy for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) remains unclear because of severely limited evidence. Although biologically distinct entities, adjuvant therapy practices for IPMN-derived PDAC are largely founded on pancreatic intraepithelial neoplasia-derived PDAC. We aimed to evaluate the role of adjuvant chemotherapy in IPMN-derived PDAC. METHODS:This international multicenter retrospective cohort study (2005-2018) was conceived at the Verona Evidence-Based Medicine meeting. Cox regressions were performed to identify risk-adjusted hazard ratios (HR) associated with overall survival (OS). Kaplan-Meier curves and log-rank tests were employed for survival analysis. Logistic regression was performed to identify factors motivating adjuvant chemotherapy administration. A decision tree was proposed and categorized patients into overtreated, undertreated, and optimally treated cohorts. RESULTS:> .05). Based on this model, we observed undertreatment in 18.1% and overtreatment in 61.2% of patients. Factors associated with chemotherapy administration included younger age, R1-margin, poorer differentiation, and nodal disease. CONCLUSION/CONCLUSIONS:Almost half of patients with resected IPMN-derived PDAC may be overtreated or undertreated. In patients with node-negative disease or normal CA19-9, adjuvant chemotherapy is not associated with a survival benefit, whereas those with node-positive disease and elevated CA19-9 have an associated benefit from adjuvant chemotherapy. A decision tree was proposed. Randomized controlled trials are needed for validation.

Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Herein, we report clinical and translational results from a phase Ib trial testing whether IL1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n = 10) were treated with canakinumab, a high-affinity monoclonal human antiinterleukin-1β (IL1β), the PD1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSC) by flow cytometry for patients in the trial but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor, we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD1 and IL1β blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.

OBJECTIVES/OBJECTIVE:We sought to determine the yield of somatic mutational analysis from EUS-guided biopsies of pancreatic adenocarcinoma compared to that of surgical resection and to assess the impact of these results on oncologic treatment. METHODS:We determined the yield of EUS sampling and surgical resection. We evaluated the potential impact of mutational analysis by identifying actionable mutations and its direct impact by reviewing actual treatment decisions. RESULTS:Yield of EUS sampling was 89.5%, comparable to the 95.8% yield of surgical resection. Over a quarter in the EUS cohort carried actionable mutations, and of these, over one in six had treatment impacted by mutational analysis. CONCLUSIONS:EUS sampling is nearly always adequate for somatic testing and may have substantial potential and real impact on treatment decisions.

PURPOSE/OBJECTIVE:Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC. METHODS:total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS). RESULTS:11.5%), respectively. CONCLUSION/CONCLUSIONS:Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.

The human oral microbiome may alter oral and systemic disease risk. Consuming high sugar content beverages (HSB) can lead to caries development by altering the microbial composition in dental plaque, but little is known regarding HSB-specific oral microbial alterations. Therefore, we conducted a large, population-based study to examine associations of HSB intake with oral microbiome diversity and composition. Using mouthwash samples of 989 individuals in two nationwide U.S. cohorts, bacterial 16S rRNA genes were amplified, sequenced, and assigned to bacterial taxa. HSB intake was quantified from food frequency questionnaires as low (< 1 serving/week), medium (1-3 servings/week), or high (> 3 servings/week). We assessed overall bacterial diversity and presence of specific taxa with respect to HSB intake in each cohort separately and combined in a meta-analysis. Consistently in the two cohorts, we found lower species richness in high HSB consumers (> 3 cans/week) (p = 0.027), and that overall bacterial community profiles differed from those of non-consumers (PERMANOVA p = 0.040). Specifically, presence of a network of commensal bacteria (Lachnospiraceae, Peptostreptococcaceae, and Alloprevotella rava) was less common in high compared to non-consumers, as were other species including Campylobacter showae, Prevotella oulorum, and Mycoplasma faucium. Presence of acidogenic bacteria Bifodobacteriaceae and Lactobacillus rhamnosus was more common in high consumers. Abundance of Fusobacteriales and its genus Leptotrichia, Lachnoanaerobaculum sp., and Campylobacter were lower with higher HSB consumption, and their abundances were correlated. No significant interaction was found for these associations with diabetic status or with microbial markers for caries (S. mutans) and periodontitis (P. gingivalis). Our results suggest that soft drink intake may alter the salivary microbiota, with consistent results across two independent cohorts. The observed perturbations of overrepresented acidogenic bacteria and underrepresented commensal bacteria in high HSB consumers may have implications for oral and systemic disease risk.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

Background: Amivantamab, a fully human EGFR and MET bispecific antibody, has shown clinical activity against tumors with primary activating EGFR mutations, EGFR resistance mutations, or MET pathway activation. Amivantamab has demonstrated activity in both EGFR- and MET-driven non-small cell lung cancer, with preclinical evidence demonstrating its ability to recruit immune effector cells. While two anti-EGFR antibodies are incorporated as part of the standard of care (SoC) for metastatic colorectal cancer (mCRC) patients, MET is highly expressed or amplified in subsets ofmCRC and additionally plays a role in mediating resistance to anti-EGFR therapies; therefore, amivantamab may provide benefit in this setting.
Method(s): This open-label, multicenter, global Ph1b/2 study will assess the safety and anti-tumor activity of amivantamab as a monotherapy and characterize the safety and tolerability of amivantamab in addition to SoC chemotherapy in KRAS, NRAS, BRAF, and EGFR ectodomain wild type participants with advanced or metastatic CRC. The Ph2 amivantamab monotherapy Cohorts A and B will assess the antitumor activity in participants with left-sided CRC who have progressed on or after SoC fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and an anti-VEGF treatment, without (Cohort A) or with (Cohort B) prior exposure to anti-EGFR treatment. The Ph2 amivantamab monotherapy Cohort C will assess the antitumor activity in participants with right-sided CRC who have progressed on or after SoC fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and an anti-VEGF treatment, with or without an anti-EGFR treatment. The Ph1b dose confirmation cohorts (Ph1b-D and Ph1b-E) will assess the safety and confirm the recommended Ph2 combination dose (RP2CD) of amivantamab in addition to SoC chemotherapy regimens (mFOLFOX6 or FOLFIRI). Upon confirmation of the RP2CD, the Ph2 Cohorts D and E, which are distinct cohorts from Ph1b-D or Ph1b-E, will further characterize the safety, tolerability, and preliminary anti-tumor activity of amivantamab in addition to SoCmFOLFOX6 or FOLFIRI in mCRC patients who have progressed after front-line therapy. The primary objectives are to assess the anti-tumor activity of amivantamab as a monotherapy and characterize the safety of amivantamab when added to SoC chemotherapy in participants with mCRC (Ph2 cohorts), as well as to assess the RP2CD of amivantamab when added to SoC chemotherapy (Ph1b). The key secondary objectives are to characterize the safety of amivantamab as a monotherapy and to assess the anti-tumor activity of amivantamab when added to SoC chemotherapy in participants with mCRC. This study is currently enrolling (NCT05379595) as of August 2022 in 12 countries, with goal enrollment of 225 participants

Background: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors (NCT05453825). Cohort A will enroll colorectal cancer (CRC) patients. Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human deltalike ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aggressive CRC remains difficult to treat owing to the aberrant activation of oncogenic signaling pathways including the NOTCH pathway. Preclinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway inhibition. We postulate that navicixizumab will demonstrate anticancer efficacy against CRC.
Method(s): Eligible CRC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 3 prior lines of standard therapy for metastatic disease, including an anti-VEGF monoclonal antibody. Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap ExTra with the Xerna TME Panel where patient samples will be classified into one of four tumor microenviroment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m² on Days 1 and 15 of a 28-day cycle, Cohort A2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of <5% and a 25% PFS rate at 4 months, with targets of 15% and 50% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel biomarker subtypes