Diab, Maria

Abstract Background: Pancreatic adenocarcinoma (PDAC) is an aggressive malignancy with dismal prognosis. Most patients present with advanced stages. Heightened levels of serum interleukin-6 (IL-6) are associated with carcinogenesis, immune suppression, and poor prognosis in PDAC. Preclinical data of dual inhibition of IL-6 and programmed death ligand-1 (PD-L1) facilitates CD8+ T-cell migration into pancreatic tumors and was effective in controlling tumor growth in syngeneic and genetically engineered PDAC mouse models. Siltuximab (Sil) is a chimeric monoclonal antibody which targets the IL-6 molecule specifically. Spartalizumab (Sparta) is a high-affinity ligand-blocking humanized IgG4 antibody against the PD-1 receptor. We developed a phase Ib/II trial to evaluate the safety, immunogenicity and preliminary antitumor activity of Sil and Sparta in metastatic PDAC (mPDAC). Methods: Patients (pts) with mPDAC who have progressed on at least one line of systemic chemotherapy were eligible for the trial. Other selected inclusion criteria were ≥18 years of age, ECOG PS 0-1 and measurable disease per RECIST v1.1. The phase Ib trial design is standard 3+3, with a primary endpoint of recommended phase II dose (RP2D). An additional 24 patients were planned for an expansion cohort. Sil was administered at escalating dose levels of 6 mg/kg (DL1) and 11 mg/kg (DL2), in combination with Sparta at 300 mg IV on day 1 of each 21-day cycle. Key secondary endpoints included overall response rate (ORR = CR + PR), progression-free survival (PFS) and overall survival (OS). Results: We enrolled 4 patients on DL1 and escalated to DL2/RP2D in the absence of a dose limiting toxicity (DLT). A total of 31 patients were subsequently treated at the RP2D (escalation + expansion). The median age was 68 years, 42% were male. Majority were White (63%) and 20% were Black. About 43% had head of pancreas primary tumors and 86% had liver involvement. The median number of lines of prior therapy was 3 (range 1-4). There was no objective response among the 4 patients on DL1; 1 had stable disease (SD) for 11 weeks as best response. 17 of 31 patients on RP2D had only a baseline assessment and came off study for progression of disease, prior to follow-up imaging assessment for response evaluation. Of the 14 RP2D patients with a follow-up assessment, ORR was 0% (3 were SD and 11 had progression of disease (PD) as best response), mPFS - 2.2 mos (95% CI: 1.9, 2.6), mOS - 5.5mos (95% CI: 2.8, 6.5). Treatment related adverse events (TRAEs) of any grade included fatigue (23%), anemia (18%), and increased liver enzymes (9.5%). There were no grade 4-5 TRAEs. Conclusions: The combination Sil/Sparta had an acceptable safety profile but did not elicit responses in advanced PDAC pts. Correlative studies using paired biopsies and blood are ongoing to determine how dual IL-6/PD-1 blockade impacts stromal and immune biomarkers in relationship to the clinical outcome measures. Funding and medications for the study were provided by Novartis and Recordati Rare Diseases Inc (NCT04191421) and NIH/NCI (R21CA266088). Citation Format: Olatunji B. Alese, Olumide Gbolahan, Kathleen M. Coleman, Yichun Cao, Sujata Kane, Sarah Craven, Emily Greene, Natalie Horvat, Andrew McDonald, Walid L. Shaib, Christina S. Wu, Mehmet Akce, Maria Diab, Jeffrey M. Switchenko, Gregory B. Lesinski, Bassel F. El-Rayes. Phase Ib study of siltuximab and spartalizumab in advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT136.

Background Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study. Methods Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry. Results A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475). Conclusions Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.

3580 Background: TAS-102 (FTD/TPI) is a combination of a nucleoside analogue and a thymidine phosphorylase inhibitor, and has showed activity in 5FU-resistant CRC. Nal-IRI achieves higher intra-tumor concentrations than irinotecan (Iri; 142-fold) and its major metabolite, SN-38 (9-fold). This resulted in superior anti-tumor activity compared to free Iri in multiple tumor xenografts. Furthermore, multiple clinical trials have established the activity of nal-IRI in combination with 5FU in pancreaticobiliary cancers. The combination of nal-IRI with the more potent nucleoside analogue TAS-102 may thus result in a more effective systemic therapy. We conducted this study to define the safety and efficacy of the combination of TAS-102 and nal-IRI in advanced CRC. Methods: Eligible patients (pts) on this investigator-initiated phase II study had advanced CRC and must have had disease progression on at least one prior therapy. Additional inclusion criteria - measurable disease, ECOG PS 0-1 & adequate organ function. Based on previously published dose escalation phase I data, the pts were treated at the recommended phase II dose of TAS-102 (given orally at 35mg/m2 bid on days 1-5) and nal-IRI (60mg/m2 IV on day 1) in 14-day cycles. The primary endpoint was objective response rate (ORR) = complete (CR) + partial (PR) response per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DoR). Results: Twenty-two pts were enrolled, of whom 20 were evaluable for response. Male - 50%; ECOG PS 1 – 75%; African Americans – 38%; median age - 58yrs (interquartile range [IQR] 49-67). Median line of prior therapy was 1 (IQR 1-2) and 13.6% (3 pts enrolled during the dose escalation phase) had received prior Iri. 47.6% received concurrent Bevacizumab. ORR was 15% (3 PR, 0 CR). 60% had stable disease (SD) as best response; DCR of 75%. mPFS - 9.7 mos (95% CI: 5.6, 14.2); mOS - 10.1 mos (95% CI: 7.3, 15.9). 12-month PFS and OS rates were 34.6% and 39.5% respectively. At a median follow up of 11.9 mos, DoR was yet to be determined and 50% of the pts had maintained response for 12 mos. Median duration of progression free among pts with SD was 7.6 mos (95% CI: 4.6, 13.2), with a 12-month survival rate of 47.7% (95% CI: 15.5%, 74.5%). Median time to response (TTR) was 4.8mos. Most common treatment related toxicities included fatigue and neutropenia (G3; 27.3% each); anemia and leucopenia (G3; 18.2% each). Other G3 AEs included febrile neutropenia, diarrhea, hypokalemia, lymphopenia and nausea (4.5% each). Conclusions: We demonstrated that the combination of TAS-102 and nal-IRI had an acceptable safety profile, and showed antitumor activity in patients with advanced CRC. Additional biomarker analyses such as survival correlation with UGT1A1 phenotype and RAS mutational status are ongoing. (NCT03368963). Clinical trial information: NCT03368963 .

3579 Background: Panitumumab (Pmab) is a recombinant monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR) and it is indicated for the treatment of metastatic colorectal carcinoma (mCRC). However, the objective response rates (ORR) for the single agent are historically about 8-11%. EGFR inhibition induces synthetic lethality with poly ADP ribose polymerase inhibitors (PARPi) such as Niraparib, by attenuating DNA repair pathways. Combining PARP and EGFR inhibition has the potential to confer synergistic benefit, while also ameliorating resistance mechanism to EGFRi. We conducted this study to define the safety and efficacy of the combination of Niraparib and Pmab in RAS wildtype (WT) mCRC. Methods: Patients (pts) with RAS WT mCRC who have progressed on at least one line of systemic chemotherapy were eligible for the trial. Other selected inclusion criteria were ≥18 years of age, ECOG PS 0-1 and measurable disease per RECIST 1.1. Pmab was administered at 6 mg/kg IV on days 1 & 15 of each 28-day cycle, while Niraparib was taken orally at 200mg or 300mg (based on body weight and platelet count) daily throughout the cycle. The primary endpoint was clinical benefit rate (CBR) defined as complete (CR) + partial (PR) response + stable disease (SD) per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, ORR, progression-free survival (PFS), overall survival (OS), and duration of response (DoR). Results: A safety run-in cohort of 6 pts was initially enrolled. Following a preplanned safety analysis showing an acceptable toxicity profile, an additional 19 pts were enrolled. Of the total 25 enrolled pts, 24 were evaluable for response. Male - 50%; Whites/African Americans/Asians – 65.2%/21.7%/13%; median age – 58.5yrs. The majority had left sided tumor (92%) and the median line of prior therapy was 2 (range 1-4). CBR was 83.3% (0 CR, 6 PR, 14 SD) and ORR was 25%. mPFS – 5.6mos (95% CI: 3.7, 6.9); mOS – 20.9mos (95% CI: 9.2, NR). Six-month PFS and OS rates were 48.4% and 100% respectively. At a median follow up time of 7.5mos (95% CI: 4.2, 10.4), 3 patients remained on treatment and DoR was yet to be determined. Muco-cutaneous adverse events (AEs) of any grade included rash (58.4%), oral mucositis (20.8%), dry skin (16.7%) and paronychia (4.2%). Most common (grade > 2) treatment related AEs (TRAEs) were anemia (G3; 12.5%), dermatitis, oral mucositis, hypertension and neutropenia (G3; 4.2% each). There were no grade 4-5 TRAEs. Conclusions: The combination of Pmab and Niraparib had an acceptable safety profile, and showed considerable antitumor activity in pts with advanced RAS WT mCRC compared to historical rates. Additional biomarker analyses such as survival correlation with immune cell infiltration in paired skin biopsies and HER2/BRAF mutational status are ongoing. Funding and product (Niraparib) for the study were provided by GSK (NCT03983993). Clinical trial information: NCT03983993 .

Abstract Background: Tyrosine kinase inhibitors (TKI) are associated with marked improvements in molecular response and survival compared with previous therapies for patients with chronic myelogenous leukemia (CML) in chronic phase (CP). We previously reported efficacy and safety of TKI at 12-month follow-up (Firwana et. al.JCO. 2014; 32(15_suppl): 7054). Here, we summarize the evidence of TKI efficacy and safety of TKI, comparing them directly and in-directly, in the mature follow-up for patients with newly diagnosed CP-CML. Methods: We included randomized controlled trials (RCTs) evaluating TKI in adults with newly diagnosed CP-CML. TKI (imatinib, dasatinib and nilotinib) were included if used as an initial treatment. Studies on bosutinib were excluded as it is only approved in the US for the treatment of CP-CML after failure of initial therapy. Studies that included patients with accelerated- or blast-phase CML, intolerant or resistant patients to first-line treatment, those on IFN-α, older agents or stem cell transplantation were excluded. Main outcomes are efficacy, represented by major molecular response (MMR, ≤ 0.1% BCR-ABLIS) and deeper molecular responses (MR4.5, ≤ 0.0032%IS), survival, represented by overall survival (OS) and progression free survival (PFS), and safety represented by medication discontinuation rate due to adverse events. Latest period of reporting outcome data were considered. As available trials provides direct comparison with imatinib, with no head-to-head trials to compare other TKI, we conducted a mixed treatment comparison (MTC) analysis which pools evidence from direct and indirect comparisons to facilitate simultaneous inference regarding all treatments. Bayesian mixed-treatment comparison method was used to rank TKI in terms of effectiveness. Results: Four landmark trials reported in 15 published articles and conference abstracts were identified involving 1647 patients with CP-CML. Follow-up times ranged from 3 months to 6 years. Table-1 depicts the results of MTC for imatinib, dasatinib and nilotinib. MTC analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy and safety. Nilotinib ranked first in efficacy with better improvement in MMR and MR4.5 at 48-month follow-up despite its different regimens, followed by dasatinib. Dasatinib has the highest medication discontinuation rate due to adverse events or drug-related toxicity. Among TKI, nilotinib was found to have the best survival profile; however, it was statistically nonsignificant. Conclusion: Both nilotinib and dasatinib are associated with significantly better efficacy and safety profiles compared to imatinib. At 48-month follow-up period, nilotinib ranked first to achieve MMR and MR4.5, with lower discontinuation rate due to adverse events. This analysis shows that new generation TKI are not only showing faster response, but also maintaining a more potent one through longer follow up period. It is important to note out that MTC is not a substitute for well conducted RCTs investigating direct comparisons. Table-1: Results of mixed treatment comparison for imatinib, dasatinib and nilotinib using fixed-effect Bayesian method. Comparison Mean risk difference (95% CrI) compared to from reference standard (Imatinib) Rank* MMR MR 4.5 PFS OS Discontinuation due to adverse events 48 months 48 months 36 months 48 months 48 months Imatinib Reference Reference Reference Reference Reference 4 Dasatinib 0.62 (0.26 to 1.01) 0.32 (-0.05 to 0.69) 0.21 (-0.43 to 0.85) 0.17 (-0.49 to 0.83) 0.59 (-0.05 to 1.25) 3 Nilotinib 300 0.92 (0.56 to 1.28) 0.81 (0.45 to 1.18) 1.02 (0.24 to 1.86) 0.19 (-0.51 to 0.89) -0.11 (-0.66 to 0.43) 1 Nilotinib 400 0.76 (0.41 to 1.12) 0.68 (0.31 to 1.05) 0.05 (-0.57 to 0.65) 0.81 (0.01 to 1.67) 0.30 (-0.20 to 0.81) 2 *Reported rank is valid for all outcomes, except for PFS and OS, where Nilotinib 400 ranks #1 and Nilotinib 300 ranks #2. Also, for rate of medication discontinuation due to adverse events, Dasatinib has the highest rate for discontinuation, followed by Nilotinib, both doses. Abbreviations: CrI, credible intervals; MMR, major molecular response, BCR-ABLIS ≤ 0.1%; MR4, deeper molecular responses, BCR-ABLIS ≤ 0.0032%; PFS, progression free survival; OS, overall survival. Disclosures No relevant conflicts of interest to declare.

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP‐CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP‐CML and enrolling 2,456 patients were included. Follow‐up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%IS) achievement with second‐generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed‐treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR4.5 ≤ 0.0032%IS) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new‐generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow‐up period. It is important to note out that MTC is not a substitute for well‐conducted RCTs investigating direct comparisons.