Effect of a MUC5AC Antibody (NPC-1C) Administered With Second-Line Gemcitabine and Nab-Paclitaxel on the Survival of Patients With Advanced Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial

Importance: Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. Objective: To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC. Design, setting, and participants: This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022. Interventions: Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks. Main outcomes and measures: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis. Results: A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival. Conclusions and relevance: In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. Trial registration: ClinicalTrials.gov Identifier: NCT01834235

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Exceptional responses to ipilimumab/nivolumab (ipi/nivo) in patients (pts) with refractory pancreatic ductal adenocarcinoma (PDAC) and germline BRCA or RAD51 mutations

754 Background: Immune checkpoint inhibitors (ICI’s) have not shown meaningful clinical activity in unselected pts with PDAC. BRCA-deficient tumors have increased genomic instability, including increased tumor mutation burden (TMB), more tumor-infiltrating immune cells, and enrichment of a T cell-inflamed signature. We hypothesized that pts with mutations in BRCA or other homologous recombination repair genes may be sensitive to ICI’s. Methods: Utilizing the IRB-approved PDAC database at the University of Miami, we identified pts with relapsed/refractory PDAC with pathogenic germline mutations who were treated with combination ICI’s (ipi 1mg/kg and nivo 3mg/kg every 21 days followed by nivo 240mg every 2 weeks). Results: Five pts were identified (1 BRCA1, 2 BRCA2, 1 RAD51C and 1 RAD51D). Among the 3 evaluable pts, there was one complete response (CR), one partial response (PR) and one had progressive disease (PD). The pt with a CR had BRCA1; he had resection followed by adjuvant gem/cape and had a biopsy-proven recurrence in the lung and retroperitoneum 1y after the end of adjuvant therapy. He received ipi/nivo at recurrence and achieved a CR, ongoing for 17m on nivo maintenance. The patient with a PR had RAD51C; he was diagnosed with mPDAC and received FOLFIRINOX for 6m, followed by olaparib on a trial for 12m. Upon PD, the disease quickly progressed on 5FU/liposomal irinotecan, gemcitabine/nab-paclitaxel/cisplatin and FOLFIRINOX. He then started ipi/nivo with immediate improvement in pain and tumor markers. A radiological PR was seen after 2 doses and is ongoing for 3m with continued clinical and tumor marker improvement. The 3rd evaluable pt had BRCA2 and had PD with an exponential rise in tumor markers accompanied by clinical deterioration. Response data on the final two pts were pending at the time of submission and will be presented at the meeting. Conclusions: In this biomarker selected cohort, 2 out of 3 evaluable pts with PDAC had impressive responses to ipi/nivo. PDAC has generally been refractory to ICI therapy but this series suggests that this subgroup may be responsive to ICI’s. Further evaluation is warranted

Gemcitabine (G) and nab-paclitaxel (nab-P) in patients with refractory advanced pancreatic cancer (PC).

373 Background: There is no standard chemotherapy regimen for PC patients who have progressed on G and fluoropyrimidine-based therapy. Single agent nab-P had limited activity on a second-line phase II trial in PC. Synergistic preclinical studies with G and taxanes have been reported. Nab-P targets stromal cells and leads to improved delivery of chemotherapy to PC cells. The combination of G + nab-P might be an effective approach in pretreated PC. Methods: A retrospective analysis of advanced refractory PC patients treated from Sep 2010 to Aug 2011 with the combination of G + nab-P was performed at the Sylvester Comprehensive Cancer Center. Patients received G 1000mg/m2 and nab-P 100mg/m2 on D1, 8 and 15 of a 28 day cycle. Treatment response was assessed by review of imaging studies using the RECIST criteria, CA19-9 response and symptomatic improvement. The progression-free survival (PFS) and overall survival (OS) were calculated from time of commencement of G + nab-P until documented progression or death respectively. Results: 10 patients were treated with G + nab-P; 60%, 30% and 10% of patients had received 3, 2 and 1 prior chemotherapy regimen. 90% and 80% received prior G or fluoropyrimidine-based regimen respectively. Therapy was discontinued in one patient following only one dose of G + nab-P (Cycle 1, day 1) due to grade 2 thrombocytopenia. The remaining 9 patients received a median of 4 cycles. Two (22.2%) patients had confirmed PR, 3(33.3%) patients had confirmed stable disease while 4 (44.4%) patients progressed on therapy. The median PFS was 13.7 weeks. The median PFS was 20 weeks in patients with PR or SD and 9.9 weeks in patients with PD. Recurrent malignant ascitis resolved in a patient with peritoneal carcinomatosis. Treatment was well tolerated; grade 3-4 hematologic toxicity included anemia, thrombocytopenia and neutropenia in 2, 1 and 2 patients respectively. 70% of patients required G-CSF support. Non hematologic Grade 3-4 toxicities included fatigue, peripheral neuropathy; nausea and vomiting in 3, 2 and 1 patient respectively. Conclusions: G + nab-P resulted in clinical benefit in half of this group of advanced PC patients who had previously progressed on G and fluoropyrimidine-based regimens

Impact of Hispanic ethnicity on the clinical presentation and survival of esophageal and gastric cancer in south Florida.

125 Background: Race and ethnicity are associated with differences in survival among patients with esophageal and gastric cancer (EGC); outcomes are better in Asian patients but worse for African-Americans compared to Caucasians and Asians. Limited data exist for Hispanics (Hisp) compared to non-Hispanic whites (NHW) or African-Americans (AA). Because of the large Hisp population in South Florida, we compared the clinical presentation and survival of patients with EGC by race and ethnicity. Methods: Using a cross-sectional study design, this IRB-approved analysis of the Florida Cancer Data System database identified all patients diagnosed at the University of Miami and Jackson Memorial Hospital between January 2000 and December 2012 with squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the esophagus, and adenocarcinomas of the gastro-esophageal junction (GEJ) or stomach (STO). Demographic, treatment and survival data were extracted from the registry. Survival was analyzed using the Kaplan-Meier method and variables associated with survival were analyzed using a Cox proportional hazards model. Results: Data from 2,170 patients were available; 44% were Hisp, 19% AA and 38% NHW. Compared to NHW's and AA's, Hisp's were more likely to have the following features: male gender, advanced age at cancer diagnosis, esophageal site of malignancy, adenocarcinoma histology, earlier stage at presentation, history of smoking and alcohol use, private insurance, surgical resection and receipt of chemotherapy (p < 0.001 in each case). Hisp were less likely to have STO (p<0.001). In a multivariate model, race and ethnicity were not independently associated with survival but age, stage, surgical resection and chemotherapy administration were all independently associated with survival (p < 0.01 in each case). Country of birth did not influence results among Hispanic patients. Conclusions: Race and ethnicity were not independently associated with survival in this large registry study. However, significant differences in the tumor location, histology and stage of presentation exist, and further studies to elucidate the biological or environmental reasons for these disparities are warranted

Frameshift mutations (Fsindel) complement tumor mutation burden (TMB) in predicting survival after immune checkpoint inhibitors (ICI) in a pancancer analysis

2617 Background: ICI benefit certain patients (pts) with various malignancies and discovering biomarkers for response is an active research field. Recently, higher TMB (top 20% in each histology) based on nonsynonymous single nucleotide variants from MSK-IMPACT was shown to correlate with superior survival in a pancancer cohort. Fsindels may generate more immunogenic neoantigens and robust T cell infiltrates, thus predicting better responses to ICI. We previously demonstrated the clinical implication of fsindel in lung cancer pts on ICI. However, its value in other solid cancers has not been evaluated. Methods: Comprehensive genomic profiling (CGP) of the tumors was performed by FoundationOne to derive fsindel and TMB as previously described. Pts with advanced solid cancers who received ICI and had CGP available were included. We categorized pts into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). Also, they were categorized into TMB high (top 20%) and TMB low (bottom 80%) within their own histology. Progression free survival (PFS) and overall survival (OS) were compared. Results: One hundred thirty-one pts excluding lung cancer were included. There were 11 histology groups: 14 soft tissue sarcomas, 19 GU, 23 GI, 23 skin, 10 HEENT, 10 RCC, 9 GYO, 6 pancreas, 5 mucosal melanoma, 4 breast, and 8 others. 74 pts received pembrolizumab, 25 nivolumab, 29 ipilimumab/nivolumab, and 3 atezolizumab. All pts had metastatic disease, mean age was 61 years and 55 (42%) were women. Among the 131 pts, 74 were FS- and 57 FS+. The presence of fsindel (FS+) was significantly correlated with overall response (p = 0.032) and clinical benefit rates (p = 0.025). TMB-high did not show any significant difference in PFS (p = 0.1) or OS (p = 0.28) when compared to the TMB low. However, in a combined model of TMB and fsindel, TMB high and FS+ patients had significantly better PFS compared to patients who had either TMB high or FS+ or neither (TMB low and FS-) (p = 0.021). Conclusions: Combined model of TMB high and fsindel (+) correlated with superior PFS in advanced solid cancer pts on ICI, in concordance with previous report for lung cancer. Validation in a larger cohort is underway

A retrospective cohort study to determine the prognostic factors in metastatic colorectal cancer (mCRC) patients (pts) undergoing lung metastatectomy.

565 Background: Resection of liver metastases is now accepted as a potentially curative strategy in some pts with mCRC. Resection of lung metastases (LMs) may also be beneficial but this is not well established. We hypothesized that resection of LMs may lead to prolonged survival in highly selected pts with mCRC. Methods: In this IRB-approved retrospective cohort study, cases were defined as mCRC pts with LMs as their only site of disease who underwent metastatectomy. Controls consisted of mCRC pts who had LMs but did not undergo resection. Charts were reviewed for clinical characteristics; survival data was obtained from the institutional tumor registry. The primary endpoint was overall survival (OS) in the cases versus controls. The secondary endpoint was to determine prognostic factors associated with better survival. Results: We included 26 consecutive cases of mCRC undergoing resection of LMs and randomly selected 26 controls. All pts in the both groups were treated with contemporary chemotherapy, as well as bevacizumab and anti-EGFR monoclonals when appropriate. The median OS from the time of diagnosis with LMs was 29.8 months (95% CI 22.9-36.6) in the control group versus 56.6 months (95% CI 47.3-65.8) for the cases who underwent resection (log rank p=0.04). A number of baseline factors were significantly different between the cases and controls. The control group contained more pts with poorly differentiated tumors (p=0.016); had more pts with synchronous versus metachronous presentation of LM's (p=0.001); had more pts with multiple vs solitary LM's (p<0.001); and had more pts with bilateral vs unilateral LMs (p<0.001). The interval from initial diagnosis to the onset of LMs was significantly longer in the resection group vs controls (22.9 vs 2.9 months, p<0.001). Conclusions: In this retrospective study, pts with mCRC to the lung who were referred for resection were more likely to have well differentiated, solitary, unilateral tumors, with a long interval between the original diagnosis and the onset of LMs. Pts selected using these criteria may have a significant survival benefit from surgical resection of their LMs

A retrospective study of neoadjuvant DCF (docetaxel, cisplatin, 5-fluorouracil) for locally advanced gastric or gastro-esophageal junction adenocarcinoma (GC)

138 Background: Perioperative chemotherapy (chemo) with ECF (epirubicin/cisplatin/5-fluorouracil) plus surgery improved survival over surgery alone in GC in the MAGIC trial. Herein we report our experience using DCF in the perioperative setting in patients (pts) with locally advanced GC. Methods: We conducted a retrospective IRB-approved study of pts with potentially resectable locally advanced GC who were treated with DCF with neoadjuvant intent. Pts received 3 cycles of preoperative (pre-op) DCF every 3 weeks, followed by surgery, then 3 cycles of postoperative (post-op) DCF. Patients with a poor pathologic response could be changed to radiation (RT) or an alternate chemo regimen postop. Results: A total of 41 pts were identified, 24 with gastric and 17 with GEJ adenocarcinoma. All pts received at least 1 cycle of DCF and 78% received at least 3 cycles pre-op. Five pts progressed during neoadjuvant DCF, 4 were unresectable by CT after neoadjuvant DCF and 2 were lost to follow-up. The remaining 30 pts had surgery with curative intent. Post-op, 2 pts were lost to follow-up, 12 received DCF (with 6 of these also receiving RT), 11 received a different chemo regimen due to a poor response to neoadjuvant DCF (including 6 pts who also received RT). Two pts received post-op RT only. The median PFS was 16.8 months (95% CI 7.7 - 25.9) and the median OS was 26.9 months (95% CI 18.7–35.1). The PFS was longer for pts who had a radiological or pathological response to neoadjuvant DCF (log rank p = 0.005 and 0.02 respectively) and for pts who received DCF post-op (log rank p = 0.005). Among pts who did not receive DCF post-op, there was no survival difference between the pts who were switched to an alternative chemo or chemoRT regimen post-op compared to those who received no further therapy. The most common chemo-related adverse events were anemia (27% grade 3 or 4), nausea/vomiting (17% G3 or 4), and febrile neutropenia (12%). Conclusions: The DCF regimen is well tolerated in locally advanced GC. Patients who do not have a good response (either radiologic or pathologic) to pre-op DCF appear to have a poor prognosis regardless of the post-op treatment given

Plasma biomarkers to predict pembrolizumab response in HCC patients

e14043 Background: Pembrolizumab (PEM) has been approved as second line therapy for the treatment of hepatocellular carcinoma (HCC). We conducted a single institution investigator-initiated clinical/biomarkers trial to assess potential biomarkers to predict response in unresectable HCC patients (pts) receiving PEM. Methods: PEM was administered at 200mg iv. every 3 weeks for advanced HCC pts who progressed on, were intolerant of, or refused sorafenib. The circulating levels of cytokines/chemokines included IL-1β, IL-6, IL-8, IL-12, IL-18, IFN-γ, TGF-β, IL-10, CXCL9, CCL4, CCL5, as well as PD-1, PD-L1, PD-L2 were measured by ELISA at baselines and at day 60-90. PD-L1 expression in tumor was also assessed by histopathological staining. Results: 29 pts have been treated and 28 were evaluated for response. One pt had complete response, 8 had partial response and 4 had stable disease. Among all the biomarkers tested, only TGF-β at baseline predict response. The mean of plasma TGF-β in responders were 141.9pg/ml vs. 1071.8pg/ml in nonresponders. The cut-off values was determined based on the near medians. The plasma concentration of TGF-β of ≥200pg/ml was an index for nonresponder (P = 0.003). Kaplan-Meier analysis showed that the median overall survival (OS) and progression-free survival (PFS) in pts with TGF-β ≥200pg/ml were 7 months and 2 months, respectively, while in pts with TGF-β < 200 pg/ml, the OS and PFS were over 25 months(P = 0.005 and P = 0.008, respectively). Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1/PD-L-1 (P < 0.05). Since tumor PD-L1 expression is upregulated by IFN-γ, and IL-10, and interacts with PD-1 to suppress T cell, to confirm these relationships, the linear regression was used to analyze the data. Plasma IFN-γ or IL-10 levels positively correlated with plasma PD-1 and PD-L1 levels ( P < 0.05). Nine of these 24 patients had tumor available for PD-L1 scoring (PD-L1-positive:3 pts and PD-L1-negative:6pts). Similar to plasma PD-L1 concentration, pts with positive tumor PD-L1 had high levels of plasma IFN-γ or IL-10 ( P < 0.05). Conclusions: Our study confirmed that PEM is active in HCC and TGF-β is a predictive markers for tumor response, PFS, and OS. Support by grant from Merc

A phase 1 trial of combined MEK, STAT3 and PD-1 inhibition in metastatic pancreatic ductal adenocarcinoma (PDAC)

TPS713 Background: PDAC is characterized by its innate and acquired resistance to both MAPK pathway inhibition and immune checkpoint (e.g. PD-1/PD-L1) inhibition (ICI) via multiple mechanisms. In preclinical models of PDAC, combined MEK and STAT3 inhibition (MEKi+STAT3i) uncovers stromal plasticity by attenuating cancer-associated fibroblasts (CAF) with IL-6/CXCL1-secretory phenotypes while enriching for Ly6a/CD34-expressing CAF phenotypes with mesenchymal stem cell-like features. This remodeling of CAF heterogeneity is associated with a striking attenuation in and reprogramming of tumor-associated macrophages (TAMs) as well as enhanced trafficking of CD8 T cells, which exhibit a distinct effector and anti-apoptotic transcriptional program. The addition of MEKi+STAT3i to PD-1 blockade overcomes ICI resistance by significantly enhancing the recruitment, degranulating capacity, and functional cytotoxicity of CD8 + T-cells, thereby augmenting antitumor responses and dramatically improving survival in these models. Furthermore, a patient with refractory PDAC treated off-label with this combination achieved a meaningful response. Based on this strong rationale, a phase 1 trial was initiated to test the combination of MEKi+STAT3 and PD1 inhibition in patients with metastatic PDAC. Methods: NCT05440942 is an open-label, prospective, single-institution phase 1 trial testing the safety, preliminary efficacy, and biomarkers of response to the combination of trametinib (MEKi), ruxolitinib (JAK2/STAT3 inhibitor) and retifanlimab (PD-1 inhibitor) in patients with metastatic PDAC. Patients with metastatic PDAC who have had disease progression on at least one line of prior therapy, with good organ function, preserved performance status, and without major intercurrent illness are eligible. Patients must have an accessible lesion for biopsy and must be willing to undergo this research biopsy at baseline and on treatment. Part 1 of the study is a dose-escalation phase with 3 dose levels and a target dose of trametinib 2mg orally daily, ruxolitinib 15mg orally twice daily, and retifanlimab 500mg intravenously every 28 days. The dose escalation is being done using the novel Bayesian keyboard design and 9-15 patients will be treated to get to the potential maximum tolerated dose (MTD). Dose level 1 has been completed without any dose-limiting toxicities seen. Part 2 is an expansion phase which will accrue an additional 20 patients. All patients in part 1 and 2 will have core-needle biopsies pre-treatment and after 4 weeks. Serial blood samples will be collected at baseline and on treatment. Biopsies are being analyzed by multiparameter immune profiling using mass cytometry and bulk RNA sequencing; blood is being analyzed for circulating tumor DNA and immune profiling. These results will be correlated with clinical response to therapy to determine biomarkers of response and resistance. Clinical trial information: NCT05440942