Metastatic Pancreatic Adenocarcinoma Research Articles

Clonal hematopoiesis of indeterminate potential (CHIP), treatment outcomes and adverse events in gastrointestinal cancers: A pooled analysis of clinical trial and real-world data.

169 Background: Clonal hematopoesis of indeterminate potential (CHIP) is the acquisition of somatic mutations leading to clonal expansion of hematopoietic stem cells and is a common incidental finding in circulating tumor DNA (ctDNA). Inflammation from these cells or a reduced marrow reserve may impact treatment outcomes or adverse events. We investigated the incidence of CHIP in ctDNA from patients with gastrointestinal (GI) cancers and explored its association with outcomes and adverse events (AEs). Methods: We collected ctDNA results from a local prospective metastatic colorectal cancer (mCRC) cohort (PREDICT-L) and ctDNA data from two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care [BSC] in mCRC) and CCTG PA.7 (gemcitabine and nab-paclitaxel [GN] with or without D+T in metastatic pancreatic adenocarcinoma [mPDAC]). CHIP+ was defined as the presence of a variant of ≥2% variant allele frequency annotated in the ctDNA report in any of the genes DNMT3A, TET2, ASXL1 and ATM, and not annotated as germline by respective sequencing platforms. The first line of treatment after ctDNA was reviewed, and grade ≥3 or dose-limiting adverse events were documented. Results: The prevalence of CHIP varied from 10% to 18% (see table). CHIP+ patients were older than CHIP- in the CO.26 cohort (p=0.011), and ECOG was higher in CHIP+ patients in the PREDICT-L cohort. There was no difference between CHIP+/- patients with regards to sex. DNMT3A was the gene most frequently mutated in all three cohorts. There was no significant difference in PFS or OS between the CHIP+/- groups, both in those treated with chemotherapy (Chemo) or immunotherapy (IO). The most common AEs were rash, GI toxicities and bleeding/clotting abnormalities. There was no significant difference in the rates of AEs between the CHIP+/- groups for those treated with Chemo or IO. Conclusions: CHIP is a common alteration in ctDNA but did not impact PFS, OS, or the chance of developing an AE. [Table: see text]

Preliminary results of a phase II study of surufatinib plus sintilimab, nab-paclitaxel and gemcitabine (AG) as first-line therapy in patients (pts) with locally advanced or metastatic pancreatic adenocarcinoma (mPDAC).

659 Background: Advanced pancreatic adenocarcinoma (PDAC) had poor survival and limited therapeutic options. Surufatinib is a potent, small-molecule tyrosine kinase inhibitor (TKI), selectively targeting VEGF receptors (VEGFR) 1, 2, and 3, FGFR 1, and CSF-1R. Recent studies showed that small molecule anti-vascular inhibitor combined with a PD-1 inhibitor exhibited encouraging efficacy in PDAC. This study is to assess the efficacy and safety of surufatinib plus sintilimab (an anti-PD-1 antibody),nab-paclitaxel and gemcitabine(AG) as first-line therapy for mPDAC pts. Here we report the preliminary results. Methods: Eligible pts ≥18 years old with histologically confirmed mPDAC, ECOG PS 0-1, with at least one measurable lesion were enrolled. Pts received surufatinib (250mg, orally daily), sintilimab (200mg, I.V., D1, Q3W), nab-paclitaxel (125mg/m2, I.V., D1, D8, Q3W) and gemcitabine (1000mg/m2,I.V.,D1, D8, Q3W). Based on Simon’s Two-stage design, 11 patients would be enrolled in stage 1; if 3 or more responses were observed, the trial would continue to stage 2, and additional 21 patients would be enrolled. The total sample size was 32. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. Results: At cutoff date of Aug 25, 2023, 15 pts were enrolled and received at least one time treatment. Median age was 60 years (range 45-68), male 53.3%, ECOG PS 1 100%, 66.7% of pts had more than 3 sites of metastasis. The most common metastatic sites were lymph nodes (66.7%) and liver (60.0%). 12 pts had received at least one tumor assessment. Six out of 11 evaluable pts responded during stage 1, allowing for enrollment to continue with a planned 21 additional patients in stage 2. Eight pts achieved partial response (PR), 3 pts achieved stable disease (SD), and the confirmed ORR (c-ORR) was 50.0% (6/12) (95% confidence interval [CI]: 21.1-78.9), and the DCR was 91.7% (11/12) (95% CI: 61.5-99.8). The median time to response (TTR) was 2.95 months (95% CI: 2.79-3.06), and median PFS was not reached yet. 15 pts underwent safety evaluation. The most common AEs of all grades were white blood cell count decreased (66.7%), neutrophil count decreased (60.0%), and anemia (53.3%), and grades ≥ 3 were blood cell count decreased (33.3%), neutrophil count decreased (33.3%), and diarrhea (13.3%). Conclusions: Surufatinib plus sintilimab, along with AG showed preliminary anti-tumor activity and manageable toxicity for the 1L treatment of mPDAC. This trial is ongoing and warrants further exploration in mPDAC. Clinical trial information: NCT05481476 .

A phase 1b/2 trial of pepinemab and avelumab as second line therapy for patients with metastatic pancreatic adenocarcinoma.

TPS712 Background: Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor prognosis despite maximal therapy and is unresponsive to immune checkpoint blockade (ICB). This failure of response is hypothesized to be driven in part by the characteristic immunosuppressive tumor microenvironment. In PDAC, Semaphorin 4D (SEMA4D) expression is prognostic in patients who have undergone surgical resection and correlates with tumor infiltration of activated CD8+ T-cells. Additionally, preclinical models suggest that antibody-mediated SEMA4D blockade promotes tumoral infiltration and activation of CD8+ T-cells and sensitizes PDAC to ICB, with improved overall survival with standard of care chemotherapy and ICB in combination with pepinemab (humanized anti-SEMA4D). Thus, we hypothesized that pepinemab may improve clinical outcomes in PDAC by sensitizing tumors to ICB. Methods: We designed a phase Ib/II single-arm clinical trial to evaluate the safety, tolerability, and efficacy of humanized anti-SEMA4D (pepinemab) with anti-PD-L1 (avelumab) in patients with chemotherapy-refractory PDAC. Patients must have failed first-line 5-fluorouracil or gemcitabine-based combination chemotherapy. The study follows a dose de-escalation schema starting at a dose combination of 20mg/kg pepinemab and 800mg avelumab every two weeks. Patient accrual for phase 1b utilizes the Bayesian Optimal Interval Design (BOIN) targeting a dose-limiting toxicity rate of 30% or less. After 16 subjects receive a given combination dose, a Simon’s two stage assessment of futility will be undertaken with expansion to phase 2 if 2 or more subjects demonstrate response. The trial is designed to evaluate a total cohort of 40 subjects and powered to detect a response rate of 23% or greater, with alpha set at 0.1% and 80% power. Treatment response is assessed via RECIST 1.1 criteria with surveillance CT prior to enrollment and after completion of two cycles (8 weeks). Baseline and on-treatment tumor biopsies (after completion of one cycle, 4 weeks) are performed to analyze changes in immune, stromal, and genomic profiles to elucidate mechanisms of treatment response and failure. Patient reported outcomes are incorporated (FACT-Hep and FAACT subdomains) to assess disease-specific symptoms. To date, 7 patients have been enrolled (Clinical Trial NCT05102721). Clinical trial information: NCT05102721 .

Results of the safety and tolerability of ivaltinostat plus capecitabine in the phase 1b portion of a phase 1b/2, dose-escalation, randomized, multi-center study in the maintenance (maint) setting in patients with metastatic pancreatic adenocarcinoma (mPDAC).

666 Background: The standard of care for patient (pts) with advanced or mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel used in the front-line setting until disease progression (prog) or toxicity. A tolerable maint therapy (tx) that can effectively delay disease prog while preserving quality of life with minimal cumulative toxicity is highly desirable. There is no standard main tx. Ivaltinostat (ival) is a pan-HDAC (histone deacetylation) inhibitor that increases histone acetylation (HA), suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines. Preclinical data demonstrated synergy with 5-FU/capecitabine in mouse models. The phase 1b study will determine an optimal combination of ival and cape followed by a randomized P2 trial of ival plus cape vs cape alone in the maint setting for pts with mPDAC who have not progressed on front-line mFOLFIRINOX. Methods: Key eligibility criteria for P1b include: locally advanced or mPDAC; at least 1 prior line of tx regardless disease prog; ECOG PS 0-1; and no known gBRCA1/2 mutation. Dose-limiting toxicities (DLT) in 3 dose levels of ival, (60, 125, and 250mg/m2 iv weekly on days 1 and 8) in combination with cape (1000mg/m2 po BID on days 1-14) of a 21-day cycle will be evaluated. The primary objective is to evaluate the safety, tolerability and determine the recommended phase 2 dose (RP2D) as well as pharmacokinetics (PK) of ival and cape. Results: As of the date of data-cut, 32 pts had been enrolled at the 60 (7 pts), 125 (14 pts) and 250 (11 pts) mg/m2 dose level, 8 were screen failures and 9 still ongoing with a goal of at least 6 DLT-evaluable pts per dose level. Average prior lines of tx was 3.6 (range 1-5). The median age was 68 (range 51-83) and 21(66%) were males. No DLTs were observed across the 3 dose levels. SAEs occurred in 2 pts that were not related to study drugs. Both ival and cape-related TEAEs were similar except palmar-plantar erythrodysesthesia syndrome (PPES) 9(28%) attributed to cape; fatigue, diarrhea and nausea were the only TEAEs occurred >15%. Two pts had ³grade 3 diarrhea, another pt had cape-related PPES. The TEAE profile was similar across the dose levels. At the time of data-cut there were 6 deaths among pts who discontinued study due to prog. Among 15 pts who had been evaluated for response since baseline, the best ORR were 11 SD(73.3%), 1(6.7%) no RECIST-measurable evidence of disease and 3 PD(20%). PK evaluations for ival indicated dose proportionate increases. The trend of PK observed in this study was similar to the PK trend observed in previous studies. Conclusions: Combination therapy of ival with cape has been well tolerated and the safety and PK/PD data support a RP2D of ival of 250 mg/m2. Clinical trial information: NCT05249101 .

Comparison between different therapeutic sequences in patients affected by metastatic pancreatic ductal adenocarcinoma.

674 Background: The first-line treatment of metastatic pancreatic cancer involves different therapeutic regimens, among them, mFOLFIRINOX and gemcitabine-nabpaclitaxel. However, it remains to be clarified which sequence might correlate with better outcomes. The aim of our work was to evaluate which sequence leads to better overall survival in this setting. Methods: We retrospectively collected data from 358 patients affected by stage IV pancreatic ductal adenocarcinoma from 3 different Italian Institutions. Patients received mFOLFIRINOX or gemcitabine plus nabpaclitaxel as first-line chemotherapy, followed by a second-line non-cross-resistant chemotherapy (gemcitabine or fluoropyrimidine-based combinations). Survival distribution was assessed by Kaplan-Meier curves. The primary endpoint was median overall survival. Statistical analysis was performed with MedCalc package. Results: The median age was 66 (± 9), 195 (54,4%) were male and 163 (45,6%) were female. 292 (81,5%) patients start gemcitabine plus nabpaclitaxel as first line treatment, while 66 (18,5%) patients start mFOLFIRINOX first-line therapy. No statistically significant differences in terms of mOS were observed between the two mFOLFIRINOX and gemcitabine-nabpaclitaxel groups: 16 versus 15 months, respectively, p = 0,2). No significant differences were found in terms of mPFS either: 7 versus 8 months, respectively, p = 0,3). Conclusions: The results of our retrospective study showed no statistically significant survival advantage between the sequences starting with mFOLFIRINOX or with gemcitabine-nabpaclitaxel. Further studies will be necessary to establish the effectiveness of new therapeutic schemes to be introduced into clinical practice in order to define a better therapeutic algorithm.

PANOVA-4 (EF-39): Pilot study of tumor treating fields (TTFields) therapy with atezolizumab, gemcitabine (GEM), and nab-paclitaxel (NabP) as first-line (1L) treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC).

TPS718 Background: TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is noninvasive, locoregional, and is delivered via a portable electric field generator and skin-placed arrays. TTFields therapy has low risk of systemic toxicity and is approved for glioblastoma (and grade 4 glioma in Europe), and pleural mesothelioma. In vitro, TTFields (150 kHz) application decreased pancreatic cancer cell proliferation and clonogenicity; in vivo, TTFields concomitant with chemotherapy (chemo) had greater antitumor effect than chemo alone in orthotopic pancreatic tumors. Co-application of TTFields with immune checkpoint inhibitors (ICIs) significantly decreased tumor volume, increased tumor infiltration and IFN-γ production, and did not impede ICI-induced effector memory T-cell production versus in vivo controls. The pilot (phase 2) PANOVA clinical study (NCT01971281) showed safety and feasibility with TTFields therapy plus NabP and GEM in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). The randomized, pivotal (phase 3) PANOVA-3 clinical study (NCT03377491), evaluating TTFields therapy with GEM and NabP in LAPC, is ongoing. Methods: PANOVA-4 (pilot, single-arm clinical study) assesses the safety and efficacy of TTFields therapy (NovoTTF-200T device) concomitant with atezolizumab, GEM, and NabP as 1L treatment for mPDAC. Eligible patients (pts) are ≥18 years of age and have a new mPDAC diagnosis, measurable abdominal disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, and no prior systemic PDAC therapy. Atezolizumab (1680 mg, IV infusion) is given before chemo on day 1 of each 28-d cycle, with NabP (125 mg/m2 IV) and GEM (1000 mg/m2 IV) given on days 1, 8, and 15. TTFields therapy (150 kHz) is delivered for ≥18 h/d until disease progression per RECIST v1.1 or loss of clinical benefit. Clinical follow-up occurs every 4 weeks (q4w) with CT scans q8w. Survival is assessed every 3 mo post last on-site visit. The primary endpoint is disease control rate (DCR). Secondary endpoints include overall survival (OS), progression-free survival (PFS), 1-year OS rate, objective response rate, PFS at 6 mo, duration of response, and safety. 76 pts are required to achieve 80% power (1-sided α level 0.05) to detect a 63% DCR vs historical 48% DCR in pts with mPDAC receiving 1L GEM and NabP. Clinical trial information: EUCTR2022-003157-55 .

Are adverse events (AEs) during first-line FOLFIRINOX (FFX) more frequent in real-world (RW) patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not proceed to second-line therapy?

630 Background: mPDAC patients (pts) that tolerate 1L FFX may increase their survival with 2L therapy, most often gemcitabine + nab-paclitaxel (GnP). However, some pts discontinue treatment due to the toxic effects of 1L FFX and consequently experience disease progression and reduced survival. Reasons for discontinuation are typically not available in RW sources. To assess whether AEs are more frequent per unit time in pts that stop treatment after 1L, we calculated the RW incidence rates (IRs) of AEs during 1L treatment for two RW cohorts: mPDAC pts treated with 1L FFX and no 2L (FFX-only) vs. pts treated with 1L FFX and 2L GnP (FFX + GnP). Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2021 who initiated treatment with 1L FFX ≤90 days from their metastatic diagnosis were included. Diarrhea, fatigue, nausea and vomiting, and neuropathy were available in the data as ungraded AEs abstracted from clinician notes. Hematologic and hepatic AEs were based on observed lab values and were graded according to the Common Terminology Criteria for AEs v5. Pts were required to have ≥1 year of follow-up unless death occurred first. We evaluated differences in IRs of AEs per pt-month of 1L treatment for statistical significance using the test-based method. Results: 587 pts met study inclusion criteria. 300 pts received FFX-only prior to death or end of follow-up, while 287 received FFX + GnP. For FFX-only vs. FFX + GnP pts, median age was 66 vs. 64 (IQR: 59–71 vs. 57–69), 57% in both groups were male, 70% vs. 69% were white, 55% vs. 62% had an ECOG of 0–1, and 8% vs. 3% had an ECOG of 2. Median 1L duration of therapy (DoT) was 2.1 (IQR: 0.7–5.0) vs. 4.6 months (IQR: 2.1–7.4). Among ungraded AEs, fatigue was more frequent per pt-month of 1L therapy for FFX-only vs. FFX + GnP pts (IR=0.037 vs. 0.027; p=.041). AEs based on lab values were higher per pt-month of 1L therapy for FFX-only vs. FFX + GnP pts for grade 3/4 thrombocytopenia (IR=0.012 vs. 0.006, p=.013), grade 1/2 anemia (IR=0.203 vs. 0.142, p<.001), grade 1/2 and 3/4 hypokalemia (IR=0.099 vs. 0.074, p<.001; IR=0.040 vs. 0.028, p=.010), grade 1/2 elevated ALT (IR=0.138 vs. 0.098, p<.001), grade 1/2 and 3/4 elevated AST (IR=0.150 vs. 0.109, p<.001; IR=0.018 vs. 0.011, p=.021), and grade 1/2 and 3/4 elevated ALP (IR=0.172 vs. 0.123, p<.001; IR=0.034 vs. 0.025, p=.035). IRs of all other AEs were numerically higher for FFX-only pts but differences were not statistically significant. Conclusions: A RW cohort of mPDAC pts receiving FFX-only experienced more AEs per pt-month of 1L and reduced likelihood of proceeding to subsequent lines of therapy compared to pts treated with FFX + GnP. Identifying predictive biomarkers may distinguish FFX non-responders and obviate AEs.

ARC-8: Phase 1/1b randomized study of quemliclustat + gemcitabine/nab-paclitaxel ± zimberelimab in patients with treatment-naive metastatic pancreatic adenocarcinoma.

665 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) remains a challenging cancer to treat, with median survival of <1 year. In PDAC, extracellular adenosine (eADO) produced from ATP is released from tumor cells and suppresses antitumor immune responses. Quemliclustat (Q) is a potent and selective small-molecule inhibitor of soluble and cell-bound CD73, a key enzyme involved in the production of eADO within the tumor microenvironment. Elevated CD73 expression is found in 40-60% of PDAC and correlates with poor clinical outcome. ARC-8 evaluated Q ± anti-PD-1 antibody zimberelimab (Z) in combination with gemcitabine/nab-paclitaxel (G/nP). Methods: ARC-8 (NCT04104672) is a phase 1b dose escalation and expansion study in patients (pts) with treatment-naive mPDAC. Q 100mg was previously determined as the recommended dose for expansion (Manji et al., 2021). Q 100 mg is administered with standard doses of G/nP with Z (240 mg IV Q2W) in the dose expansion (Cohort A; QZ+G/nP) and in randomized (2:1) cohorts either with Z (Cohort A1; QZ+G/nP) or without Z (Cohort A2; Q+G/nP). Adverse events (AEs) are recorded and graded per NCI CTCAE 5.0. Clinical activity is assessed every 8 weeks per RECIST v1.1. Endpoints include measures of safety and median overall survival (OS). Results: As of June 19, 2023, 122 patients with untreated mPDAC were treated with Q 100mg, including 93 pts treated with QZ+G/nP (dose escalation, n=6; cohort A, n=26; and randomized cohort A1, n=61) and 29 pts treated with Q+G/nP (Cohort A2). Median age was 66 years, 66% ECOG of 1, and 65% had liver metastasis at baseline. Median survival follow-up was 21 months (mos). Efficacy is summarized in Table 1. All patients reported AE, 85% Grade 3+ AE, and 23% discontinued study treatment due to AE. Most common Grade 3+ AE was neutrophil count decreased (31%) and anemia (25%). Conclusions: Results from ARC-8 demonstrate the addition of Q 100 mg ± Z to G/nP was safe and tolerable, with no significant added toxicity to GnP. Modulation of eADO with Q may confer benefit beyond radiographic measures of disease. The OS is promising and supports further development of Q in mPDAC. Clinical trial information: NCT04104672 . [Table: see text]

Clinical and prognostic characteristics of early onset metastatic pancreatic cancer.

702 Background: In the last decade several studies have shown an increase in the incidence of early-onset PDAC (EO-PDAC), conventionally defined as cancer that occurs in adults between the ages of 18 and 49. Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, and prognostic differences in a large group of patients with early onset mPDAC. Methods: We retrospectively collected data from 368 patients affected with metastatic pancreatic ductal adenocarcinoma, from 3 different Italian Institutions. All patients had one or more metastatic sites, and received first-line chemotherapy. The main objective of the study was to evaluate the median overall survival in EO-PDAC patients compared to late onset PDAC (LO-PDAC), while secondary endpoint was evaluations of mPFS. Statistical analysis was performed with the MedCalc package. Results: 30 (8,1%) patients were early onset and 338 (91,9%) were late onset; median age was 46 (±5) and 68 (±8), respectively. M/F ratios were 1:1 in both group. In the overall population mOS was significantly lower in EO-PDAC patients: 10,0 versus 15,0 months ( p = 0,03). Furthermore, mPFS was significantly lower in EO-PDAC patients: 5,0 versus 8,0 months ( p = 0,04). ORR obtained from 244 pts were: 11% in EO-PDAC and 24,7% in LO-PDAC. Conclusions: The results of our work, although limited by the retrospective nature of the study, showed a worse prognosis for patients with early onset PDAC compared to late onsets. Further investigations will be needed to better understand this growing group of patients from a molecular and therapeutic point of view.

Real-world overall survival and time to next treatment in patients with metastatic pancreatic ductal adenocarcinoma who received FOLFIRINOX and modified FOLFIRINOX in the first line.

629 Background: FOLFIRINOX (FFX) is a recommended first line (1L) treatment option for patients (pts) with mPDAC but is known for its high toxicity. Efforts to balance pts’ quality of life (QoL) during treatment with treatment effectiveness have led to the use of modified FOLFIRNOX (mFFX) regimens that employ decreased doses of FFX components. Further evidence is needed to assess OS and progression-free survival (PFS) among pts who receive FFX or mFFX treatment in the real world compared to the trial setting. We identified a real-world (RW) sample of pts with mPDAC treated with FFX and mFFX in 1L and assessed their OS, and, as a RW proxy for PFS, TTNT. Methods: This retrospective observational study utilized the Flatiron Metastatic Pancreatic Cancer Enhanced Data Mart. Adult pts diagnosed with mPDAC between January 2014 and May 2022 who initiated treatment with FFX or mFFX in 1L within 90 days of their diagnosis for metastatic disease were included in the study. mFFX was defined as administration of <150mg/m2 of irinotecan or <2,720mg/m2 5-FU total (bolus+infusion) during cycle 1; doses greater than these were considered FFX. TTNT was defined as duration between 1L treatment initiation and the start of second line therapy or death. Kaplan-Meier analyses were used to assess median OS and TTNT from the start of 1L FFX or mFFX treatment and log-rank tests for the statistical significance of differences in OS and TTNT. Results: 2,212 mPDAC pts met the study inclusion criteria, with 507 pts (23%) receiving FFX and 1,705 pts (77%) receiving mFFX in 1L. For FFX vs. mFFX, the median age at 1L initiation was 63yr vs. 65yr, 72% vs. 56% were male, 67% vs. 63% were white, 36% vs. 30% had an ECOG score of 0, 31% vs. 32% had an ECOG score of 1, and 83% vs. 81% received treatment at community oncology centers. For FFX vs. mFFX, median OS was 9.5 (95% CI: 8.9–10.7) vs. 9.0 months (95% CI: 8.4–9.7) (p=.452) and median TTNT was 4.8 (95% CI: 4.5–5.5) vs. 4.8 months (95% CI: 4.5–5.2) (p=.256). Conclusions: In a RW sample of 2,212 pts receiving 1L FFX and mFFX at primarily community oncology practices in the United States from 2014–2022, more than three-quarters received mFFX. Pts experienced similar median OS and TTNT across the two regimens, indicating that full-strength FFX may provide little benefit to OS in exchange for its increased toxicity. In the PRODIGE 4/ACCORD 11 trial of unmodified FFX, conducted earlier (2005–2009) among a group of 342 French pts, median OS was 11.1 months (95% CI: 9.0–13.1) and median PFS was 6.4 months (95% CI: 5.5–7.2). The median RW OS of FFX and mFFX pts in our study was numerically lower than the trial, as was RW TTNT compared with trial PFS. Future research should seek to understand the factors driving differences in RW and clinical trial outcomes as well as to assess the tradeoff between regimen toxicity and survival benefit.

De-escalation and dose density in real-world patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.

628 Background: FOLFIRINOX (FFX) is a recommended first-line (1L) treatment for patients (pts) with mPDAC and good performance status but is known for high toxicity. To make the regimen more tolerable for pts, clinicians may omit components and/or reduce doses (referred to as “de-escalation”). To better understand the frequency and degree of de-escalation in outpatient clinical practice, we examined real-world (RW) treatment patterns among mPDAC pts receiving FFX in 1L. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2022 who initiated treatment with FFX in 1L within 90 days of their diagnosis for metastatic disease were included in the study. Receipt of FFX was defined as receiving all four regimen components within 28 days of 1L initiation. Modified FFX (mFFX) was defined as administration of <150mg/m2 of irinotecan or <2,720mg/m2 5-FU total (bolus + infusion) during cycle 1. 6-week dose density was defined as the actual dose received of each component in the 6 weeks following treatment initiation as a percent of the expected dose over 3 two-week cycles [expected FFX dose defined as 2800 mg/m2 of 5-FU (bolus + infusion), 400 mg/m2 of leucovorin, 180 mg/m2 of irinotecan, and 85 mg/m2 of oxaliplatin per cycle]. Results: 1,215 mPDAC pts met the study inclusion criteria, with >99% receiving mFFX. The median age at 1L initiation was 65yr (IQR: 58–71), 57% were male, 68% were white, 15% had an ECOG score of 0, 39% had an ECOG score of 1, and 6% had an ECOG of 2. The median number of FFX cycles was 5 (IQR: 2–9). In the first administration, 97% of pts received FFX/mFFX, 2% received FOLFIRI (omitting oxaliplatin), and 1% received other combinations. The number of pts in treatment declined over subsequent administrations, as did the number receiving FFX: by the 10th administration, 390 pts were treated, with 74% receiving mFFX, 13% FOLFIRI, 5% FOLFOX (omitting irinotecan), and 7% other combinations. At the 15th administration, 149 pts continued treatment, with 36% receiving mFFX, 44% FOLFIRI, 5% FOLFOX, 8% 5FU + leucovorin, and 7% other (either 5FU alone or with oxaliplatin and/or irinotecan). Median 6-week dose density was 69% for 5FU (IQR: 40–93%), 100% for leucovorin (IQR: 66–133%), 83% for irinotecan (IQR: 56–130%), and 99% for oxaliplatin (IQR: 68–127%). Conclusions: De-escalation was common among pts continuing FFX/mFFX treatment, with oxaliplatin the most frequently omitted component in later administrations. Over the 6 weeks following FFX treatment initiation, the actual vs. standard dose was lowest for 5FU, followed by irinotecan, while median leucovorin and oxaliplatin doses were close to standard dose over 3 two-week cycles. The omission of components of the regimen may indicate that mFFX lacks tolerability for many pts.

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 .

The economic impact of short-term imaging with metastatic pancreatic ductal adenocarcinoma.

643 Background: Although modern cancer treatment has significantly improved overall survival, this comes with a high financial cost. Based on an NIH report on Financial Burden of Cancer Care, treating pancreatic adenocarcinoma (PDAC) costs $108K, $18K, and $125K for initial treatment, during follow-up, and in last year of life, respectively. During the course of treatment, patients will visit the hospital for acute symptoms for which cross-sectional imaging is obtained within 45 days of subsequent scheduled follow-up imaging. This presents an opportunity for cost saving if data could be collected to identify an algorithm to avoid unnecessary duplication of imaging in a short interval. The purpose of this pilot study is to evaluate tumor growth trajectory within this short time span of 45 days to guide future trials to clarify the circumstances for which a subsequent follow up study is necessary. Methods: We retrospectively identified patients from our tumor registry from 2016 to 2019 who were diagnosed with metastatic PDAC (mPDAC). Subjects were included for analysis if they met the following criteria: 1) diagnosed with mPDAC; 2) had at least 2 CT abdomen/pelvis (CTAP) within 45 days of each other with one of the studies being obtained in the emergency department; and 3) had at least 1-3 measurable lesions as defined by RECIST 1.1 criteria. Tumor dimension was measured on axial images with the largest cross-section. For our primary outcome we used paired t-tests to evaluate the difference in mean size of all lesions (primary and metastatic). We also performed sub-group analyses comparing mean size of primary and metastatic lesions separately. An alpha level of 0.05 was used to determine statistical significance. Results: We screened 383 subjects from the tumor registry and identified 28 subjects suitable for our study. 18 subjects were female and 10 were male. We identified 69 target lesions, 23 of which were primary and 46 were metastatic. The mean sum of the largest dimension of target lesions was 2.82 cm on the initial study and 3.23 on the latter study (p<0.001). The mean sum of the largest dimension of the primary lesion was 3.62 cm on the initial study and 3.89 on the latter study (p=0.01). For metastatic lesions, the initial sum was 2.38 cm while the latter was 2.85 (p<0.001). Conclusions: Our finding of increase in tumor size in 45 days for mPDAC suggests that mPDAC is aggressive and can grow even in short time span. This suggests that if progression is identified on a study obtained within 45 days of scheduled follow-up, the follow-up study could be cancelled to avoid added cost to the patient. However, if the earlier study is stable or shows response, the scheduled follow-up may still be necessary to demonstrate continued stability/response.

Impact of site of metastases in pancreatic ductal adenocarcinoma.

708 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a 5-year survival rate of 3%. We examined the clinical significance of the metastatic site on outcomes in mPDAC using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We analyzed the data on mPDAC from SEER database from 2010-2020 and categorized into three groups: mPDAC with, liver-only (LO) metastasis (mets), multi-organ mets including the liver (IL), and multi-organ mets excluding the liver (EL). Patient demographics and disease characteristics were summarized using the mean for continuous variables and proportions for categorical variables. Overall survival (OS) was calculated from time of diagnosis to death or censored at a loss to follow-up. The survival curve was plotted using the Kaplan-Meier method and log-rank p-value was reported. The Cox regression model was used to study the association of site of distant metastasis on overall survival, controlling for potential confounders (age, race, treatment, etc.) Results: We identified 22642 patients with mPDAC; 15844, 4250, and 2548 with LO, IL, EL mets respectively. The mean age at diagnosis was 66 years with the majority being white (78.4%), non-Hispanic (87.1%), and from metropolitan counties (88.5%). The median OS was 4 months, 3 months, and 6 months (log-rank p<0.001) for LO, IL, and EL groups respectively, with 2-year survival being 4.84%, 2.56% and 7.89% respectively (log-rank p<0.001). Multivariate analysis showed a higher risk of mortality in LO (31.5%, hazards ratio (HR)=1.315, p<0.001) and IL groups (69.2% HR=1.692, p<0.001) than EL group (Table). Conclusions: The site of distant metastasis is an independent prognostic factor for survival in patients with mPDAC, with liver-only mets or multi-organ mets including liver having worse OS than extrahepatic mets. [Table: see text]

Updated results of a phase 1b/2 study of surufatinib plus camrelizumab, nab-paclitaxel and S-1 (NASCA) as first-line therapy for metastatic pancreatic adenocarcinoma (mPDAC).

671 Background: This prospective, randomized controlled phase 1b/2 clinical study was designed to explore the efficacy and safety of surufatinib combined with camrelizumab, nab-paclitaxel and S-1 as first-line treatment compared with nab-paclitaxel and gemcitabine (AG) in mPDAC. Preliminary data was reported (Guanghai Dai, 2023 ASCO, 4142). Here we presented the updated data as more patients (pts) were recruited. Methods: In phase 1b, pts with mPDAC received surufatinib (200mg to 300mg, qd po), camrelizumab (200mg, I.V., D1, Q3W), nab-paclitaxel (125mg/m2, I.V., D1, D8, Q3W), and S-1 (40mg bid, D1-14, Q3W). Phase 2 is a prospective, open-label, randomized (1:1) trial comparing NASCA with AG in the first-line setting. The primary objective was the RP2D and overall response rate (ORR) per RECIST v1.1. Tumor tissue samples were collected at diagnosis and were subjected to mIHC to evaluate tumor immune microenvironment. Results: From Aug 2021 to Jun 2023, 49 pts were enrolled. As previously reported, 6 pts were enrolled in phase 1b and RP2D was determined as surufatinib 200mg. Of the 49 pts, 48 were evaluable for efficacy (28 in NASCA and 20 in AG group). ORR was 53.6% (15/28) (95% CI: 35.8-70.5) in pts receiving NASCA (pts in phase 1b included) and 15.0% (3/20) (95% CI: 5.2-36.0) in AG group. In NASCA group, pts with liver metastases exhibited higher ORR than those without liver metastases (71.4% vs 35.7%, p=0.13). Median progression-free survival and overall survival was 9.17m (95% CI: 5.5-NA) and 15.57m (95% CI: 9.27-NA) in NASCA group, 6.3m (95% CI: 4.87-NA) and 8.63m (95% CI: 7.90-NA) in AG group at the median follow-up of 13.7m. The most frequent adverse events (AEs) of all-grade in NASCA were neutropenia (57.1%), hepatotoxicity (42.9%), and neuropathy (39.3%). Immune-related AEs were observed in 5 pts with grade 3 hepatotoxicity in 4 pts and grade 2 enteritis in 1 pt. Safety was comparable in two groups except for hepatotoxicity and diarrhea. Using mIHC, the tissue of 13 pts treated with NASCA were stained for multiple markers of immune cells. CD3+ T cells infiltrated the tumor core at the highest level, followed by CD68+CD163- (M1) macrophages, and FOXP3+ T cells. Majority of immune cells and ICI biomarkers were expressed at higher proportion in the stroma. Pts with liver metastases displayed elevated tumoral FOXP3+ T cells (p=0.031), PD-L1+CD68+ macrophages (p=0.014), and decreased infiltration of stromal CD8+ T cells (p=0.064) than pts without liver metastases. In pts with liver metastases, responders displayed a higher stromal PD-1+ cells than nonresponders (p=0.036). Conclusions: Updated results proved that NASCA regimen presented higher clinical activity than the standard AG treatment, especially in pts with liver metastases, with a manageable safety profile. This trial is ongoing and NASCA regimen deserves further exploration in mPDAC. Clinical trial information: NCT05218889 .

Maintenance therapy with olaparib or selumetinib plus durvalumab (S+D) according to genetic profile of metastatic pancreatic adenocarcinoma (m-PDAC) controlled with modified FOLFIRINOX (mFFX): A phase II randomized MAZEPPA GERCOR D19-02 PRODIGE-72 study.

673 Background: Maintenance treatments in m-PDAC patients (pts) after FFX induction is discussed. We assessed the efficacy of genetic-driven maintenance in pts with controlled disease. Methods: In this multicenter, open-label, phase II study, PS 0-1 pts with histologically confirmed m-PDAC controlled after 4 months (mo) of mFFX received a genetically-driven maintenance therapy (centralized analysis): BRCAness - olaparib 300 mgx2/d (Arm A); no BRCAness, but KRAS mutation - randomization (2:1) to S+D (1500 mg IV q4w + 75 mg PO BID; Arm B) or FOLFIRI q2w (Arm C), until confirmed progression or toxicity. Statistical hypotheses: Arm A, PFS4mo rate after inclusion - H0: PFS4mo ≤40%, H1: PFS4mo ≥70%; Arm B and C, H0: PFSc=PFSb, H1: PFSc<PFSb (one-sided 2.5% α-type I-error and 10% β-type 2). A prespecified single interim analysis for futility using a-spending function with O’Brien-Fleming boundaries was planned after 33.1% of events (~93 pts). The Kaplan-Meier method and a swimmer plot were applied. Results: 124 pts were included in the study; Arm A: 16 pts (male: 9, median age: 67 years, PS 0: 9 pts) received olaparib; PFS 4mo: 50%; median PFS: 3.7 mo (1.7-9.4), ORR: 13%, median OS: 18 mo (5.5-21.5). Arm B/Arm C: at interim analysis (12/5/2022): 104 pts were randomized (Arm B/Arm C: 70/34); median PFS in Arms B and C: 3.5 mo (95% CI 2.1-3.9) vs 5.7 mo (95% CI 2.2-10.7), respectively. Due to futility, inclusions were stopped. At final analysis (data cutoff: 06/15/2023) with median follow up of 11.2 mo (95% Cl 9.4-13.1): 108 pts (male: 53%, age: 63.5 years, PS 0: 44%) were treated (Arm B/Arm C: 72/36). 123/124 pts (ITT population) had ≥1 cycle treatment (median: 4.0 [IQR, 2.0-6.0]). Primary endpoint was not met: median PFS 3.7 mo (95% Cl 2.1-5.0) in Arm B vs 6.6 mo in Arm C (95% Cl 2.6-8.7); HR=1.6 (0.99-2.58), P=0.0523. Median OS (entire population): 12.7 mo (95% CI 8.7-18.2); 10.1 mo (95% CI 8.3-20.6) in Arm B and 17.3 mo (95% CI 8.4-20.9) in Arm C. The toxicity profile: ≥1 grade 3-4 treatment-related arms (A/B/C) was as expected: 18.8%, 23.6%, 28.6% of pts. Conclusions: MAZEPPA study did not meet its primary endpoint of improving PFS4mo in m-PDAC pts treated with S+D maintenance vs those receiving FOLFIRI. Data on genomic alterations analyses will be presented at the congress. Clinical trial information: NCT04348045 .

Kinetics of CA19-9 decline in a randomized phase III study of irinotecan liposome injection, oxaliplatin, 5-fluorouracial/leucovorin (NALIRIFOX) or nab-paclitaxel plus gemcitabine (GEM+NABP) in patients who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas (NAPOLI 3).

687 Background: The NAPOLI 3 study (NCT04083235, N = 770) reported that NALIRIFOX improved overall survival (OS) vs Gem+NabP with manageable toxicity in 1L treatment of metastatic pancreatic adenocarcinoma. We explored changes in CA19-9 levels and their potential associations with efficacy as an important tumor marker in pancreatic adenocarcinoma. Methods: In NAPOLI 3, CA19-9 was evaluated at baseline and every 8 weeks until patients discontinued study treatment. The detection limit of CA19-9 was 8000 kU/L in this study. The Cox proportional hazards regression and logistic regression were employed to investigate the relationship between CA19-9 decrease and OS, progression-free survival (PFS), and overall response rate (ORR). Results: Patients with evaluable CA19-9 (levels =< 8000) at baseline and additional measurements at weeks 8 and 16 were included in the analysis (NALIRIFOX, n = 179; Gem+NabP, n = 194). The median baseline CA19-9 level was 378.0 and 409.7 kU/L for the NALIRIFOX and Gem+NabP arms, respectively. Overall, patients with (vs without) any CA 19-9 decrease by week 16 had a higher ORR (59.9% vs 35.2%; p = 0.002), a longer median PFS (9.2 vs 6.2 months; p < 0.001) and a longer median OS (14.2 vs 8.7 months; p = 0.005), respectively in a pooled analysis of the treatments. In the NALIRIFOX arm, patients with any CA19-9 decrease by week 16 had a higher confirmed ORR of 65.1% compared with those without at 42.4% ( p < 0.001), a median PFS of 9.5 vs 7.1 months ( p < 0.001) and a median OS of 15.4 versus 8.4 months ( p = 0.004), respectively. In the Gem+NabP arm, patients with CA19-9 decrease by week 16 had a higher ORR of 55.5% compared with those without at 23.8% ( p = 0.012), a median PFS of 7.6 versus 5.8 months ( p < 0.001) and a median OS of 13.7 versus 11.9 months ( p = 0.235), respectively. Conclusions: CA19-9 decrease by week 16 has the potential to be an early prognostic factor for OS, PFS and ORR. The results should be interpreted with caution as a considerable percentage of patients were excluded due to non-evaluable CA19-9 that exceeded the lab detection limit of 8000 kU/L. Clinical trial information: NCT04083235 .

Abstract B005: A phase 1 expansion cohort study evaluating the safety and efficacy of the CHK1 inhibitor LY2880070 with low-dose gemcitabine in metastatic pancreatic adenocarcinoma

Abstract Background: Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC. Methods: Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2–6, 9–13, and 16–20 of each 21-day cycle. Pre-treatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses. Results: Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiological responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and gamma-H2AX, as well as induction of replication fork instability. Conclusions: No evidence of clinical activity was observed for combined low dose gemcitabine and LY2880070 in this treatment refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients. Citation Format: Brandon M. Huffman, Hanrong Feng, Kalindi Parmar, Junning Wang, Kevin Kapner, Bose Kochupurakkal, David Martignetti, Thomas Abrams, Leah Biller, Marios Giannakis, Kimmie Ng, Anuj Patel, Kimberly Perez, Harshabad Singh, Douglas Rubinson, Benjamin Schlechter, Elizabeth Andrews, Alison Hannigan, Stanley Dunwell, Zoe Getchell, Srivatsan Raghavan, Brian Wolpin, Alan D'Andrea, Andrew Aguirre, Geoffrey Shapiro, James Cleary. A phase 1 expansion cohort study evaluating the safety and efficacy of the CHK1 inhibitor LY2880070 with low-dose gemcitabine in metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B005.

Abstract C038: Interim pharmacodynamic analyses of mitazalimab in combination with FOLFIRINOX in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) identify CD4 effector T cells as a correlate of treatment outcomes

Abstract CD40 agonists are being investigated in combination with standard of care chemotherapy as an approach to trigger anti-tumor immunity and improve outcomes for patients with cancer. Preclinical models suggest the importance of appropriate sequencing of chemotherapy and a CD40 agonist. Herein, we report interim pharmacodynamic analyses and their association with outcomes from a Phase 2 study evaluating mitazalimab, a CD40 agonist, in combination with modified (m) FOLFIRINOX chemotherapy as first line therapy in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients with newly diagnosed mPDAC were treated with mitazalimab on day 1 prior to beginning an every 2-week regimen on day 8 of mFOLFIRINOX followed by mitazalimab 48 hours later. Tumor response was determined by RECIST v1.1 imaging. Peripheral blood was analyzed for selected cytokines and chemokines and by flow cytometry to assess changes in leukocyte subsets including B cells, monocytes, T cells, and NK cells. The neutrophil-to-lymphocyte ratio was determined from complete blood counts. The analysis included 23 patients with associated response data and indicated a mitazalimab-specific contribution to tumor response. Mitazalimab triggered an expected immune response characterized by transient cytokine (IL-8, IP-10, MCP-1, and MIP1b) release and B cell depletion. Chemotherapy provoked a reduction in classical monocytes and proliferating CD4+ T cells. Both mitazalimab and chemotherapy caused a transient reduction in circulating dendritic cells and NK cells. Tumor response was associated with an expansion in the frequency of effector CD4 T cells (p < 0.0001) at day 8 after receiving mitazalimab but did not correlate with neutrophil-to-lymphocyte ratio (p = 0.851). In conclusion, mitazalimab and FOLFIRINOX modulate immune responses in patients with mPDAC in different ways. Interim results of pharmacological analyses identify CD4 effector T cells as a correlate of treatment outcomes suggesting the contribution of mitazalimab to tumor responses. Citation Format: Max M. Wattenberg, Karin Enell Smith, Yago Pico de Coana, David Gomez Jimenez, Malin Carlsson, Sumeet Vijay Ambarkhane, Peter Ellmark, Gregory L. Beatty. Interim pharmacodynamic analyses of mitazalimab in combination with FOLFIRINOX in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) identify CD4 effector T cells as a correlate of treatment outcomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C038.

Abstract A003: Preliminary safety results from a phase I study of autologous transgenic T cells expressing high affinity mesothelin-specific T cell receptor (TCR) (FH-TCR TMSLN) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDA)

Abstract Background: We previously demonstrated murine CD8+ T cells engineered to express a high affinity MSLN-specific TCR exhibit efficacy in the KPC mouse model, particularly with serial infusions, and thus developed a human TCR for expression in autologous T cells for targeting MSLN, which is overexpressed by 80% of PDAs. In this first-in-human phase I trial, we are determining safety, preliminary efficacy, as well as persistence, activation, localization, and functional capacity of autologous FH-TCR-TMSLN (T) cells in refractory, MSLN+ mPDA. Methods: Eligible pts have ECOG PS 0-1, ≥1 prior therapy for mPDA, life expectancy ≥12 weeks, MSLN 2+ expression in ≥30% tumor cells by IHC, HLA-A*2:01, no HLA-B*13:02. Pts undergo leukapheresis, and 3-4 weeks later receive the first T cell infusion. Three T-cell infusions, if sufficient T cells can be manufactured, are being administered every 21 days (d) at 3 dose level cohorts: 1 × 109, 3.3 × 109 and 1 × 1010 T cells, with a 3+3 design. Dose limiting toxicities (DLTs) are assessed during the 21d after each T cell dose. Only pts who receive ≥75% of the assigned T cell dose are DLT evaluable, but all pts are evaluable for safety. Lymphodepleting chemotherapy (LDC) with fludarabine/cyclophosphamide is administered prior to the last T cell infusion (cohorts 1-2) or prior to the first T cell infusion (cohort 3). Primary endpoints are safety and DLTs. Secondary endpoints are response rate, progression-free and overall survival. Exploratory endpoints include TCR-TMSLN cells in tumor biopsies and blood as biomarkers. Results: Between Dec 2021 to July 2023, 7 pts were enrolled, and 6 pts treated (n=3 at dose at level 1, n=3 at dose level 2), 4 women, median age 60 years (range 51-70), median 3 prior systemic therapies. All pts underwent research-related tumor biopsies at baseline, and 2-3 weeks post first T cell infusion, and 2 pts had biopsies after the last T-cell infusion. Treatment exposure was median 3 (range 1-3) T cell infusions. No DLTs occurred among 6 pts treated at dose levels 1 × 109 and 3.3 × 109 T cells. Treatment related adverse events (TRAE) thought at least possibly related to T cells infusions were fever [n=2 grade (gr) 1, n=1 gr 2], and gr 2 chills, cytokine release syndrome (CRS), dizziness, fatigue, hypertension, hypotension, nausea, acute generalized exanthematous pustulosis (AGEP) rash, and sinus tachycardia (n=1 each). TRAE due to LDC were transient leukopenia (n=2 gr 4, n=1 gr 3, n=2 gr 2), neutropenia (n=4 gr 4, n=1 gr 2), lymphopenia (n=3 gr 4), dysgeusia (n=2 gr 2), anemia (n=1 gr 3) and fatigue (n=1 gr 2). One patient had a serious adverse event with gr 2 CRS and gr 2 AGEP, which resolved. Due to anticipated difficulty attaining sufficient T cells doses for three high dose infusions, we amended the protocol to allow treatment with at least one T cell infusion, with the first dose preceded by LDC at the 1 × 1010 T cells dose level. Conclusions: FH-TCR-TMSLN cells are well tolerated with no on-target toxicity, and the study is open to accrual (NCT04809766). Citation Format: Elena G. Chiorean, Aude Chapuis, Andrew Coveler, Cecilia Yeung, Ted Gooley, David B. Zhen, Gentry King, Stacey Cohen, Lindsay Hannan, Rachael Safyan, Anthony Germani, Susan Ra, Jennifer Casserd, Tom Schmitt, Philip Greenberg. Preliminary safety results from a phase I study of autologous transgenic T cells expressing high affinity mesothelin-specific T cell receptor (TCR) (FH-TCR TMSLN) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDA) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A003.