Combination Of Nab-paclitaxel Research Articles

Leveraging chemotherapy-induced PD-L1 upregulation to potentiate targeted PD-L1 degradation using nanoparticle-based targeting chimeras

The combination of nab-paclitaxel and the programmed death-ligand 1(PD-L1) antibody atezolizumab showed limited benefits in clinical trials involving PD-L1-positive triple-negative breast cancer patients. This observed lack of success is attributed to the upregulation of PD-L1 on tumor cells induced by paclitaxel, leading to resistance against PD-L1 antibodies. Here, we introduce nanoparticle-based PD-L1 targeting chimeras (NanoTACPD-L1) to induce PD-L1 degradation instead of blockade. NanoTACPD-L1 initiates endocytosis independent of specific lysosome-targeting receptors, and delivers membrane-bound PD-L1 to lysosomes for targeted degradation. Furthermore, the efficiency of degradation is directly correlated with the PD-L1 expression level. NanoTACPD-L1 effectively leverages paclitaxel-induced PD-L1 upregulation to enhance PD-L1 degradation, employing a “Meet-Plot-With-Plot” strategy. In a series of in vivo models, NanoTACPD-L1 demonstrates superior therapeutic efficacy and immune activation, both when administered individually and in combination with paclitaxel, surpassing the effects of anti-PD-L1 antibody treatment. Collectively, our study provides a nanotechnology-based tool that can be enhanced by paclitaxel for PD-L1 degradation and validates its potential application in overcoming chemo-immunotherapy resistance.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study

BackgroundPlatinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate...

Phase II study of nab-paclitaxel with gemcitabine for relapsed/refractory small cell lung cancer.

Patients with small cell lung cancer (SCLC) often respond to first-line chemoimmunotherapy. However, relapse is inevitable and is associated with a poor prognosis. Treatments for relapsed SCLC, such as lurbinectedin and topotecan, are limited by modest efficacy and significant hematologic adverse events, leaving a need for newer therapeutic agents or regimens. The combination of gemcitabine and nab-paclitaxel is active and safe in other types of malignancies, such as pancreatic cancer. We conducted a phase II trial evaluating the efficacy and safety of gemcitabine and nab-paclitaxel in patients with relapsed/refractory SCLC. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with confirmed complete or partial response. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety. Between October 2016 and May 2021, 32 patients were enrolled. Patients were followed for a median of 9.3 months (range 1.8-65.2). Median age was 65 years (range 48-81). Fifty percent of patients were female. Fifty-three percent of patients had platinum-resistant/refractory relapsed SCLC. The ORR was 28.1% (95% confidence interval [CI] 15.5-100%). Median PFS was 2.9 months (95% CI 2.4-3.6), and median OS was 9.3 months (95% CI 5.2-12.4). Seven patients (21.9%) developed grade 3 or 4 neutropenia. Our study showed that the combination of gemcitabine and nab-paclitaxel led to encouraging outcomes in relapsed/refractory SCLC. Further studies are needed to compare this combination with other treatments used for relapsed SCLC, including lurbinectedin, temozolomide, and topotecan. https://clinicaltrials.gov/study/NCT02769832?cond=NCT02769832&rank=1, identifier NCT02769832.

Early tumor shrinkage as a prognostic predictor in chemotherapy-naïve patients with locally advanced pancreatic cancer treated with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel combination therapy: An exploratory analysis of JCOG1407

BackgroundEarly tumor shrinkage (ETS) is a prognostic predictor for patients treated with chemotherapy in colorectal cancer, although scarce studies evaluated its potential in locally advanced pancreatic cancer (LAPC). In this exploratory analysis of JCOG1407, a randomized phase II study comparing modified 5-fluorouracil, levofolinate, irinotecan, and oxaliplatin (mFOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP), we evaluated whether ETS can predict prognosis of patients with LAPC. MethodsOf the 126 patients enrolled in JCOG1407, 112 with measurable lesions were included in this study. ETS was defined as a ≥20 % reduction in tumor diameter compared with baseline at the initial imaging assessment 6–10 weeks after initiating chemotherapy. Patients were divided into the ETS (achieved ETS) and non-ETS (failed to achieve ETS) groups based on their ETS status. The impact of ETS on overall survival (OS) was compared using multivariable Cox regression analysis. ResultsFourteen of 55 (25.5 %) and 24 of 57 (42.1 %) patients in the mFOLFIRINOX and GnP arms, respectively, achieved ETS. In the overall population, mFOLFIRINOX arm, and GnP arm, the median OS in the ETS and non-ETS groups was 27.1 and 20.4, 29.8 and 20.6, and 24.1 and 20.4, months, respectively. The adjusted hazard ratios of OS for the ETS group in the overall population, mFOLFIRINOX arm, and GnP arm were 0.451 (95 % confidence interval [CI]: 0.270–0.754), 0.371 (95 % CI: 0.149–0.926), and 0.508 (95 % CI: 0.255–1.004), respectively. ConclusionsETS may be a prognostic predictor in chemotherapy-naïve patients with LAPC treated with mFOLFIRINOX or GnP.

Efficacy and safety of apatinib combined with nab-paclitaxel for second-line treatment of metastatic triple negative breast cancer (TNBC): An open-label phase II trial.

e13127 Background: Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. Preclinical studies have demonstrated that apatinib can enhance the anti-tumor effect of taxanes in TNBC via promoting apoptosis and suppressing migration and invasion of tumor cells. Previous studies have also shown the role of apatinib in combination with chemotherapy for treating TNBC. However, combinational treatment of apatinib and nab-paclitaxel for metastatic TNBC has not been reported. Therefore, the objective of this study was to evaluate the safety and efficacy of apatinib in combination with nab-paclitaxel as a second-line treatment for TNBC. Methods: This is a single-center, single-arm, and open-label prospective study. The patients enrolled in this study had metastatic TNBC, ECOG PS 0-2, at least one measurable lesion, and had previously received one systemic therapy except apatinib and nab-paclitaxel. They were treated with apatinib (250mg, PO, QD) plus nab-paclitaxel (125mg/m2, IV, day 1, 8 and 15) every 3 weeks as second-line treatment until disease progression, unacceptable toxicity, or consent withdrawal. The study utilized RECIST v1.1 to assess efficacy and NCI-CTCAE 5.0 to report adverse events. The study's primary endpoints were tolerability and progressive free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Twenty patients were enrolled by the cut-off date of December 1st, 2023. The median age was 55 years (range 31-76) and all had an ECOG PS of 0-1. Ninety percent of the sample had a Ki67 of 30% or higher, while 85% tested negative for PD-L1. All patients had distant metastases, with 35.0% having visceral metastasis and 35% having metastatic sites of 3 or more. 70% of patients had undergone surgery on the primary tumor. All patients received apatinib plus nab-paclitaxel treatment, with a median of 9 cycles (range 2-25), were included in the safety dataset. All patients experienced grade 1-2 treatment-related adverse events (TRAEs). Haematological toxicity of grade 3-4 with neutropenia occurred in 25.0% of patients. In addition, non-haematological toxicities were observed in 10% of patients, including abnormal hepatic function (5.0%) and hypertension (5.0%). No treatment-emergent adverse event (TEAE) resulted in death during the study. Out of the 20 evaluated patients, the median progression-free survival (PFS) was 6.7 months (95% CI: 6.0-NR). The objective response rate (ORR) was 65.0% (13/20), and the disease control rate (DCR) was 90.0% (18/20), according to RECIST v1.1. The median overall survival (OS) has not yet been reached. Conclusions: The combination of apatinib and nab-paclitaxel showed promising antitumor activity in patients with metastatic TNBC as a second-line treatment, with a manageable safety profile. Clinical trial information: NCT05019690 .

Sequential neoadjuvant chemotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma.

TPS4209 Background: Patients with borderline resectable (BRPC) and locally advanced unresectable (LAPC) pancreatic cancer have a median OS of 8-20 months unless they undergo margin negative resection. Despite advances in systemic therapy, the prognosis is dismal. The locoregional and distant failure rates are high in post-surgery and therefore neoadjuvant chemotherapy emerged as standard-of-care practice to select the patients for surgery and improve overall clinical outcomes. An effective and tolerable neoadjuvant regimen can facilitate R0 resection by tumor down staging and mitigating the risk for positive margins. A recent SEQUENCE-2 study on sequential treatment with combination of Gemcitabine and nab-paclitaxel (GA) GA followed by modified FOLFOX (mFOLFOX) improved OS (13.2 months) and PFS (9.5 months) in patients with metastatic PDC, compared with the standard GA regimen, with comparable safety profile. Current guidelines suggest modified FOLFIRINOX (mFFX, infusional 5-fluorouracil, oxaliplatin, irinotecan) or GA as the first-line systemic chemotherapeutic regimen in neoadjuvant, adjuvant and palliative setting. These regimens are associated with modest pathological complete response rate. However, there is significant unmet need for management of BRPC and LAPC as the optimal treatment strategy remains undefined. As both of the aforementioned regimens are active and feasible in BRPC and LAPC, we conceptualize that by using both regimens alternating in sequence the rate of R0 resection and pathological response could be improved by overcoming possible resistance to a single backbone. Methods: The aim of this study is to demonstrate the efficacy and feasibility of sequential chemotherapy (GA followed by mFFX) in patients with BRPC (n=34) and LAPC (n=30). To achieve this, we are conducting a non-randomized prospective interventional clinical study with BRPC and LAPC patients treated with alternating cycles of GA and mFFX for 4 months and assessed for clinical outcomes, feasibility and toxicity. The primary objective of this study is to evaluate the efficacy of sequential GA followed by mFFX in improving R0 resection rate in patients with BRPC and LAPC. After four months of sequential neoadjuvant therapy, the patients will proceed to surgery, radiation, or extended course of chemotherapy, off study, as determined by multidisciplinary tumor board consensus or the treating physician. These results will have high translational potential for providing mechanistic insight into tumor response, optimizing current management strategies for pancreatic cancer that could be generalizable to other stages of this cancer. The key eligibility criteria include treatment naive histologically diagnosed BRPC or LAPC with measurable disease, ECOG 0,1, optimal organ function. Clinical trial information: NCT05776524 .

Alliance A022106: A phase II/III trial of NABPLAGEM vs nab-paclitaxel/gemcitabine as second-line treatment for BRCA1/2 or PALB2 mutant metastatic pancreatic ductal adenocarcinoma (PLATINUM).

TPS4205 Background: Multiple lines of evidence support the use of platinum-based chemotherapy for patients with homologous recombination deficiency-associated pancreatic adenocarcinoma (HRD PDAC; 15-20%). However, the impact of the specific platinum agent used remains uncertain. Mechanistically, oxaliplatin and cisplatin act distinctly on cancer cells, reflected in disparate toxicity profiles and target disease indications; furthermore, preclinical studies have shown that BRCA2-deficient cell lines and mice demonstrate significantly greater sensitivity to cisplatin compared to oxaliplatin. While oxaliplatin, part of the FOLFIRINOX regimen, represents the most commonly used platinum analogue for PDAC, clinical data shows that cisplatin (in combination with gemcitabine) can produce robust response rates (~70%) specifically in patients with germline BRCA/PALB2-mutated metastatic PDAC. We therefore designed a randomized clinical trial (PLATINUM) through the Alliance for Clinical Trials in Oncology cooperative group to assess the optimal chemotherapy regimen in patients with HRD-associated metastatic PDAC following front-line FOLFIRINOX and to test the hypothesis that a platinum switch strategy will be beneficial. Methods: The study consists of a seamless phase II/III design, with the primary endpoint of the phase III component being overall survival. Eligible patients will have metastatic PDAC, a confirmed pathogenic BRCA1/2 or PALB2 mutation (somatic or germline), and demonstrated disease progression on front-line FOLFIRINOX, with or without subsequent PARP inhibitor maintenance. Patients will be randomized 1:1 to receive (1) the de facto standard of gemcitabine plus nab-paclitaxel; or (2) the experimental 3-drug combination of gemcitabine, nab-paclitaxel, and cisplatin (NABPLAGEM), which has been previously studied in non-biomarker-selected patients with advanced biliary tract cancer (SWOG1815) and metastatic PDAC. Both treatment arms will use a once every other week dosing schedule. A total of 100 patients will be enrolled, which provides 90% power to detect an effect size of hazard ratio 0.5 (median OS of 18 vs 9 months) at a one-sided alpha of 0.05. Reports containing efficacy, adverse events, and administrative information will be provided to the Alliance DSMB every 6 months. Planned correlatives include ctDNA analysis for BRCA reversion mutations in all patients, as well as whole genome and transcriptome sequencing in an optional biopsy cohort. This study was activated in December 2023. Clinical trial information: NCT06115499 .

Abstract PS08-06: A Phase Ib/II Study to Assess the Safety and Efficacy of PM8002 (Anti-PD-L1 x VEGF-A Bispecific Antibody) in Combination with Nab-Paclitaxel for First Line Treatment of Locally Advanced or Metastatic Triple-Negative Breast Cancer

Abstract Background: PD-L1 and VEGF play important roles in immune evasion and pro-tumor angiogenesis promoting cancer growth and metastasis. PM8002 is a bispecific antibody targeting PD-L1 and VEGF-A for treating cancer. Here, we present results from a Phase Ib/II study of PM8002 in combination with nab-paclitaxel in patients with locally-advanced or metastatic triple-negative breast cancer (TNBC). Methods: 42 patients with locally-advanced or metastatic TNBC (without prior systemic treatment) were enrolled in this Phase Ib/II study to test the safety and efficacy of PM8002 in combination with nab-paclitaxel. The first 6 patients were enrolled during Phase Ib with safety as the primary endpoint, and the remaining patients were enrolled during Phase II with objective response rate (ORR) as the primary endpoint. Each treatment cycle lasts 28 days. All patients received PM8002 at 20 mg/kg (Q2W) and nab-paclitaxel at 100 mg/m2 on the 1st, 8th, and 15th days of each cycle until unacceptable toxicity or disease progression were observed. Tumor responses were evaluated every 8 weeks according to RECIST 1.1. Safety was evaluated according to CTCAE 5.0. Nab-paclitaxel dose was reduced according to toxicity, while PM8002 dose was kept consistent according to body weight. PD-L1 expression in tumors was tested, and subgroup analysis of ORR data stratified by PD-L1 expression was also included. Results: As of June 30, 2023, 42 patients were treated and evaluated at least once for treatment efficacy. The median duration of drug exposure was 4.6 months (min, max: 2.0, 7.6). The best overall ORR was 76.2% (32/42), including 1 complete response (CR) and 31 partial responses (PRs) with 29 objective responses occurring at the patient's first evaluation. The confirmed ORR was 57.2% (24/42) and the overall disease control rate (DCR) was 95.2% (40/42). The median time to response (TTR) was 1.9 months (95% CI:1.8~2.0) and the median best percentage change from baseline for target lesions was -47.2% (Q1, Q3: -56.9%, -33.5%). Among 13 patients with PD-L1 combined positive scores (CPS) < 1, the best ORR and DCR were 69.2% (9/13) and 100.0% (13/13), respectively. Among 25 patients with PD-L1 CPS ≥1, the best ORR and DCR were 80.0% (20/25) and 96.0% (24/25), respectively. Among 9 patients with PD-L1 CPS ≥10, the best ORR and DCR were both 100.0% (9/9). At the cut-off date of data analysis, 38 patients were still on treatment with a median progression-free survival (mPFS) of 7.4 months (95% CI: 7.4~NA); 38 patients were censored due to no disease progression or death. The incidence of treatment-related adverse events (TRAEs) was 95.2%, of which 26.2% were Grade 3 or 4; no Grade 5 TRAEs were observed. The incidence of drug-related TRAEs related to PM8002 was 92.9%, of which 23.8% were Grade 3 or 4. The incidence of drug-related TRAEs related to nab-paclitaxel was 95.2%, of which 26.2% were Grade 3 or 4. 1 patient (2.4%) reduced nab-paclitaxel dose due to diarrhea. 1 patient (2.4%) discontinued PM8002 and nab-paclitaxel treatment due to diarrhea. The most common TRAEs related to PM8002 and nab-paclitaxel included neutropenia (69.0%), leukocytopenia (59.5%), anemia (52.4%) and proteinuria (26.2%). The incidence of immune-related adverse events (irAEs) was 11.9%, which included hyperthyroidism, hypothyroidism, and rash. No ≥ Grade 3 irAEs were observed. AEs related to targeting VEGF were also analyzed, including hypertension 19.0% (4.8% at Grade 1, 11.9% at Grade 2, and 2.4% at Grade 3) and proteinuria 26.2% (9.5% at Grade 1, and 16.7% at Grade 2). Conclusions: Rapid, deep, and durable tumor responses were observed for the combination of PM8002 and nab-paclitaxel in patients with first line TNBC. PM8002 did not enhance toxicity that is typically observed for nab-paclitaxel. This Phase II study is still ongoing with plans for entering late-stage clinical development for solid tumors. Citation Format: Jiong Wu, Jian Zhang, Zhongsheng Tong, Qingyuan Zhang, Yong-Sheng Wang, Qiao Cheng, Xin Chen, Zhihua Li, Yongmei Yin. A Phase Ib/II Study to Assess the Safety and Efficacy of PM8002 (Anti-PD-L1 x VEGF-A Bispecific Antibody) in Combination with Nab-Paclitaxel for First Line Treatment of Locally Advanced or Metastatic Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-06.

A single arm Phase I/II trial on the combination of carboplatin, nab-paclitaxel and avastin as first-line treatment for advanced non-squamous non-small cell lung cancer (TORG1424/OLCSG1402: CARNAVAL).

Bevacizumab with platinum doublet therapy including paclitaxel+carboplatin improves the survival of patients with non-squamous non-small cell lung cancer. However, in a previous trial (CA031), paclitaxel+carboplatin led to Grade>3 neutropenia in a Japanese population. Nanoparticle albumin-bound paclitaxel exhibits an improved toxicity profile. We evaluated the safety, dosage and response rate of the nanoparticle albumin-bound paclitaxel+carboplatin + bevacizumab combination in a Japanese population. Chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer were included. The dosage schedule was established in the Phase I trial as follows: 4-6cycles of carboplatin (area under the concentration-time curve=6 on Day 1)+nanoparticle albumin-bound paclitaxel (100mg/m2 on Days 1, 8 and 15)+bevacizumab (15mg/kg on Day 1), followed by maintenance therapy (nanoparticle albumin-bound paclitaxel+bevacizumab). The response rate and presence of adverse effects were evaluated in the Phase II trial. The overall response rate was 56.5% (90% confidence interval: 44.5-68.5), and 93% of patients (43/46) showed tumor shrinkage or maintained a stable disease course. The primary endpoint was achieved. At the median follow-up duration of 42months, the median overall survival was 18.9 (range: 10.5-32.4) months. The most frequently observed Grade≥3 adverse effects were neutropenia (72%), leukopenia (50%) and anemia (30%). All adverse effects were manageable and none resulted in patient death. In conclusion, the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination is favorable and well tolerated in Japanese patients as first-line treatment for advanced non-squamous non-small cell lung cancer.

A phase II/III randomized clinical trial of CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative chemotherapy versus immediate resection in patIents with resecTable BiliarY Tract Cancers (BTC) at high risk for recurrence: PURITY study

BackgroundBiliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1–3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20–40% and recurrence rates are up to ~ 75%(4–6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4–6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8).MethodsPURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study.Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate.Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis.DiscussionConsidering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients’ outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery.Trial registrationPURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023–503295-25–00).

Abstract 1957: OPM-116, a highly potent and specific PI3Kγ inhibitor to enhance antitumor immunity

Abstract Tumor-associated macrophages are an integral part of the tumor microenvironment. They play a crucial role in cancer initiation and progression by orchestrating tumor proliferation, angiogenesis, extracellular matrix remodeling, metastasis, immunosuppression, and resistance to checkpoint blockade immunotherapy and chemotherapy (Gao J, 2022). On the other hand, when properly stimulated, macrophages can effectively interact with the innate and adaptive immune systems arms, promoting cancer cell phagocytosis and tumor destruction by T cell-mediated cytotoxicity (Mantovani A, 2022). PI3Kγ has a unique pattern of expression and biological function, and it has been investigated for a long time as a therapeutic target for different disorders, including cancer. Inhibition of PI3Kγ reprograms M2 macrophages into M1 cells in the tumor microenvironment which translates into the expansion of activated T cells by relieving macrophage suppression. Recent clinical data indicates the compelling role of PI3Ky in combination with PDL1 in anti-tumor activity, irrespective of PDL1 status (Hamilton E, 2021). PI3Ky selectivity has been difficult to achieve due to the high sequence homology across the class 1 PI3K isoforms (Drew SL, 2020). Macrocyclization of small molecules with a linear structure strongly reduces their conformational flexibility and alters a variety of their physicochemical and biological characteristics. The unexpected selectivity these compounds can exhibit, even amongst closely similar target molecules, is explained by the conformationally limited structure (Ma J, 2022). Here, we describe the discovery of a potent and selective, ATP-competitive inhibitor of PI3Kγ. OPM-116, macrocyclic compound display >300-fold selectivity for PI3Kγ over the other class I isoforms. Its selectivity in biochemical and cellular assays as well as in human PBMC assays is presented. In vitro, OPM-116 can inhibit the IL-4-induced polarization of M2 macrophages. Pharmacodynamic analysis performed in animals that received oral compound administration confirmed the absolute selectivity and good PK profiles of the drug. OPM-116 is a highly selective, PI3Kγ inhibitor that displays high potency and specificity and represents a promising step toward the identification of a clinical candidate. Drew S.L., et al. Discovery of potent and selective PI3Kγ inhibitors. J. Med. Chem. 2020. Ma J., et al. Development of small macrocyclic kinase inhibitors. Futur. Med. Chem. 2022. Gao J., et al. Shaping polarization of tumor-associated macrophages in cancer immunotherapy. Front. Immunol. 2022. Mantovani A, et al. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discovery. 2022. Hamilton E, et al. Mario-3 phase II study safety run-in evaluating a novel triplet combination of eganelisib, atezolizumab, and nab-paclitaxel as first-line therapy for locally advanced or metastatic TNBC. AACR, Cancer Res 2021. Citation Format: Kenji Shoji, Petra Blom, Maria Eugenia Riveiro, Jan Hoflack. OPM-116, a highly potent and specific PI3Kγ inhibitor to enhance antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1957.

Abstract 5275: Celecoxib and chloroquine enhance the antitumor effect of immune checkpoint blockade therapy, in a syngeneic mouse model for pancreatic cancer

Abstract Immune checkpoint inhibitors (ICIs) have shown impressive clinical activities in some cancer types, but they have yet to demonstrate any meaningful clinical benefit in patients with pancreatic ductal adenocarcinoma (PDAC) except those with microsatellite instability high (MSI-H) tumors. Several recent studies showed that concomitant use of NSAIDs such as celecoxib by patients with certain cancers could improve the survival benefit of ICI treatment (e.g., Sebastian et al, Clin Lung Cancer, 2023;). Furthermore, autophagy inhibitors such as chloroquine were also reported to sensitize pancreatic tumors to the treatment of ICIs in mouse models for PDAC (Yamamoto, et al, Nature, 2020). We recently reported that the combination of chemotherapy (triple combination of nab-paclitaxel + gemcitabine + cisplatin) and a mouse surrogate of the IFc-enhanced anti-CTLA-4 antibody botensilimab, showed significantly improved antitumor activity in immune competent KPC syngeneic mouse model for PDAC [Tanne, et al, Cancer Res (13_Supplement), 2020]. In this study, we sought to determine whether or not the addition of celecoxib and/or chloroquine further improve the antitumor activity of triple chemotherapy and ICI in the syngeneic KPC model. We first found that celecoxib (30mg/kg P.O. QDx21) significantly enhanced the tumor growth inhibition when added to triple chemotherapy (Gemcitabine 70mg/kg I.P., Cisplatin 4mg/kg I.P., Nab-paclitaxel 25mg/kg I.V. days 1,4 and 7) plus the murine equivalents of botensilimab (100ug I.P. BIW for three weeks) and balstilimab (200ug I.P. BIW for three weeks) (p=0.004, N=10). We then performed a pilot study to assess if adding chloroquine could further improve the activity. While adding chloroquine (60mg/kg I.P. QDx21) alone did not significantly affect tumor growth the addition of both chloroquine and celecoxib greatly improve the tumor growth inhibition compared to just the triple chemotherapy and ICIs (p=0.009, N=5). Overall, our data showed that celecoxib or the combination of celecoxib and chloroquine could substantially sensitize the mouse pancreatic tumors to the treatment of chemotherapy and ICIs. (This work was supported in part by the Seena Magowitz Foundation and the Purple Pansies) Citation Format: Jaeger Moore, Dhan Chand, Daniel Levey, Daniel Von Hoff, Haiyong Han. Celecoxib and chloroquine enhance the antitumor effect of immune checkpoint blockade therapy, in a syngeneic mouse model for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5275.

Development and Evaluation of a Quantitative Systems Pharmacology Model for Mechanism Interpretation and Efficacy Prediction of Atezolizumab in Combination with Carboplatin and Nab-Paclitaxel in Patients with Non-Small-Cell Lung Cancer.

Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential patient population that could benefit from combined therapy remain undetermined. Here, we developed an NSCLC model based on the published quantitative systems pharmacology (QSP)-immuno-oncology platform by making necessary adjustments. After calibration and validation, the established QSP model could adequately characterise the biological mechanisms of action of the triple combination of atezolizumab, nab-paclitaxel, and carboplatin in patients with NSCLC, and identify predictive biomarkers for precision dosing. The established model could efficiently characterise the objective response rate and duration of response of the IMpower131 trial, reproducing the efficacy of alternative dosing. Furthermore, CD8+ and CD4+ T cell densities in tumours were found to be significantly related to the response status. This significant extension of the QSP model not only broadens its applicability but also more accurately reflects real-world clinical settings. Importantly, it positions the model as a critical foundation for model-informed drug development and the customisation of treatment plans, especially in the context of combining single-agent ICIs with platinum-doublet chemotherapy.

Efficacy and safety of the combination of cisplatin plus nab-paclitaxel and nivolumab with radiotherapy after maximal tumor resection in non-metastatic muscle invasive bladder cancer (CNN-BC trial).

TPS723 Background: The therapeutic gold standard for muscle invasive bladder cancer (MIBC) is radical cystectomy (RC) preceded by neoadjuvant chemotherapy when appropriate. However, RC is a major surgery procedure with 13% rate of severe complication and a perioperative mortality rate of about 1.5 - 5 %. Trimodal therapy (TMT) is a “bladder sparing” option alternative to RC. TMT consists of complete transurethral bladder tumor resection (TURBT) followed by a combination of systemic chemotherapy and locoregional radiotherapy (RT), with the option of “salvage” cystectomy in case of local treatment failure. Immunotherapy with anti-PD1/PD-L1 monoclonal antibody significantly improves survival of metastatic BC patients, and it seems to potentiate the activity of RT without increased toxicity. Therefore, we investigate the role of a multimodal TMT strategy to increase the disease-free survival (DFS) and avoid or delay RC in non-metastatic MIBC pts. Methods: CNN-BC trial (NCT05203913) is a phase 2, open-label, mono-institutional study evaluating the activity and safety of TMT with cisplatin, nab-paclitaxel and nivolumab as systemic therapy in non-metastatic MIBC pts. Eligible pts should have undergone complete TURBT with diagnosis of T2-T3 N0M0 urothelial carcinoma, and no evidence of lymph nodes or metastatic disease at FDG-PET within 6 weeks from the start of treatments. TMT consists of nivolumab (480 mg IV every 4 weeks for a total of 13 doses), weekly nab-paclitaxel (60mg/m2) plus cisplatin (20mg/m2) administered concurrently with RT (60Gy in 25 fractions over 5 weeks on original bladder tumor, plus a concomitant boost of 50Gy in 25 fractions on whole bladder and pelvic nodes). The primary endpoint is the 1-year DFS rate, defined as the rate of survival free of recurrence in pelvic nodes or bladder, or appearance of distant metastases. Secondary endpoints include: the rate of pts who require salvage cystectomy, the rate of locoregional complete response (CR) and of locoregional DFS, median DFS, safety, and quality of life. Exploratory biomarkers analysis will be performed. The trial is actively recruiting. Clinical trial information: NCT05203913 .

NABNEC: A randomised phase II study of nab -paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas (GI-NECs).

589 Background: Neuroendocrine carcinomas (NEC) are rare and aggressive cancers. There are no randomised trials to date to establish standard therapy for advanced G3 gastrointestinal (GI) NENs. Extrapolating from small cell lung cancer data, standard practice is to treat G3 GI-NENs with etoposide and carboplatin. Paclitaxel is also active in NECs however there is no data on the role of nab -paclitaxel. NABNEC (ANZCTR # 12616000958482) aimed to determine the activity, safety and tolerability of carboplatin and nab -paclitaxel in advanced G3 GI-NENs and to enhance our understanding of the biology and imaging characteristics of such NENs. Methods: NABNEC was designed as a randomised non-comparative phase II study, evaluating the activity of nab- paclitaxel in patients with advanced and/or metastatic non-resectable G3 GI-NENs. The statistical plan was that 46 evaluable patients in the experimental arm would give 80% power and 95% confidence to rule out a 30% RR in favour of a more interesting RR of 50% at 6 months. Protocol version 3.0 was amended and randomisation to the control arm was suspended after 12 patients. Primary endpoint was objective response rate (RR) by RECIST 1.1. Secondary endpoints were progression free survival, overall survival, adverse events by NCI-CTCAE V4.03 and quality of life (EORTC QLQC30, QLQ-GINET21 questionnaires). Translational research endpoints include blood and tissue biomarkers including circulating tumour cells profiling, mutation profile (whole exome sequencing) and DNA methylation profile correlated with clinical endpoints. Correlation of 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) to early response has also been evaluated. Results: 60 patients were accrued between Sep 2016 and Dec 2021 from 16 centres, resulting in 58 evaluable patients, 12 (control arm), 46 (experimental arm). 43 patients (75%) had tumours with Ki-67>55%; the remainder had Ki-67 between 20 and 55%. About 20% had pancreatic primaries; more than half had liver metastases. The NABNEC trial met its primary endpoint. RR was 53% (38-69%) in the experimental treatment arm compared to 42% (16-71%) in the control group. Progression free survival was not different between the 2 treatments. 24m overall survival was 25% in the experimental group compared to 17% in the control. Grade 3 toxicity was worse in the nab-paclitaxel arms (52% v 42%). Quality of life and tertiary outcomes are being analysed. Conclusions: The combination of carboplatin and nab-paclitaxel is an active regimen for G3 GI-NENs. Further evaluation in a Phase III study is warranted. Clinical trial information: ACTRN12616000958482.

Abstract C003: RAMP 205: A phase 1b/2a study of gemcitabine, nab-paclitaxel, avutometinib, and defactinib in untreated metastatic pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) accounts for ~90% of pancreatic cancer. Surgery is the only curative treatment. Unfortunately, most patients are diagnosed with advanced disease and are not candidates for resection. Combination chemotherapy approaches have provided incremental improvements to PDAC outcomes. However, impact on survival for patients with inoperable disease remains modest, with a 2-year survival rate of less than 7%. Activating mutations in the KRAS oncogene are a key initiating event in ~80-90% of PDAC. Permanent activation of KRAS drives tumor cell proliferation and survival, tumor microenvironment modulation, and metabolic alterations in PDAC. Patients with KRAS mutant PDAC have worse outcomes compared to those with KRAS wild-type PDAC. In addition, hyperactivation of focal adhesion kinase (FAK) has been correlated with high stromal density, resulting in therapeutic resistance and poor survival. Avutometinib is a first-in-class oral RAF/MEK clamp that potently inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. Defactinib is a selective inhibitor of focal adhesion kinase (FAK), which has been shown to mediate resistance to multiple anticancer agents. Preclinical data have shown that the combination of avutometinib + FAK inhibition (FAKi) + chemotherapy (gemcitabine + paclitaxel as a surrogate for nab-paclitaxel) induced tumor regression in a autochthonous KRAS/TP53 mutant PDAC mouse model. Prior clinical experience of defactinib + pembrolizumab + chemotherapy was safe, showed responses, decreased stromal density, and increased CD8+ T cell infiltration in patients with PDAC (NCT02546531). Methods: RAMP 205 is a multi-center, open-label, single arm Phase 1b/2a study of gemcitabine and nab-paclitaxel in combination with avutometinib and defactinib in patients with previously untreated metastatic PDAC (NCT05669482). The study is being conducted in 2 parts: Parts A (dose evaluation) and Part B (dose expansion). The starting dose is 2.4 mg avutometinib orally (PO) twice weekly + 200 mg defactinib PO twice per day, in combination with standard once weekly gemcitabine/nab-paclitaxel (QW IV). All study drugs are dosed 3 weeks on, 1 week off. Following determination of the Recommended Phase 2 Dose (RP2D) in Part A, Part B will evaluate efficacy of the RP2D via objective response rate (primary endpoint). Mandatory tumor biopsies and blood samples will be collected for correlative studies, including circulating tumor DNA, molecular profiling and pharmacodynamic markers. Eligible patients must have histologic or cytologic evidence of metastatic PDAC and measurable disease according to RECIST v1.1. Patients with prior or concomitant treatment for metastatic PDAC or prior treatment with RAS/MAPK or FAK inhibitors are not eligible. The study will enroll ~35 patients with 6-12 patients in Part A, and 23 patients in Part B. Citation Format: Kian-Haut Lim, Manuel Hidalgo, Mark H. O'Hara, Kristen R. Spencer, Ignacio Garrido-Laguna, David G. DeNardo, Vijeta Bhambhani, Gloria Patrick, Yaofeng Cheng, Silvia Coma, Jonathan A. Pachter, Louis J. Denis. RAMP 205: A phase 1b/2a study of gemcitabine, nab-paclitaxel, avutometinib, and defactinib in untreated metastatic pancreatic ductal 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 C003.

NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer

The NAPOLI 3 trial showed the superiority of fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin (NALIRIFOX) over the combination of gemcitabine and nab-paclitaxel (GEM-NABP) as first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Analyses comparing NALIRIFOX and GEM-NABP with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) have not yet been reported. To derive survival, response, and toxic effects data from phase 3 clinical trials and compare NALIRIFOX, FOLFIRINOX, and GEM-NABP. After a systematic search of PubMed, Scopus, Embase, and American Society of Clinical Oncology and European Society for Medical Oncology meetings' libraries, Kaplan-Meier curves were extracted from phase 3 clinical trials conducted from January 1, 2011, until September 12, 2023. Phase 3 clinical trials that tested NALIRIFOX, FOLFIRINOX, or GEM-NABP as first-line treatment of metastatic PDAC and reported overall survival (OS) and progression-free survival (PFS) curves were selected. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses of Individual Participant Data reporting guidelines. Individual patient OS and PFS data were extracted from Kaplan-Meier plots of original trials via a graphic reconstructive algorithm. Overall response rates (ORRs) and grade 3 or higher toxic effects rates were also collected. A pooled analysis was conducted, and results were validated via a network meta-analysis. The primary end point was OS. Secondary outcomes included PFS, ORR, and toxic effects rates. A total of 7 trials with data on 2581 patients were analyzed, including 383 patients treated with NALIRIFOX, 433 patients treated with FOLFIRINOX, and 1756 patients treated with GEM-NABP. Median PFS was longer in patients treated with NALIRIFOX (7.4 [95% CI, 6.1-7.7] months) or FOLFIRINOX (7.3 [95% CI, 6.5-7.9] months; [HR], 1.21 [95% CI, 0.86-1.70]; P = .28) compared with patients treated with GEM-NABP (5.7 [95% CI, 5.6-6.1] months; HR vs NALIRIFOX, 1.45 [95% CI, 1.22-1.73]; P < .001). Similarly, GEM-NABP was associated with poorer OS (10.4 [95% CI, 9.8-10.8]; months) compared with NALIRIFOX (HR, 1.18 [95% CI, 1.00-1.39]; P = .05], while no difference was observed between FOLFIRINOX (11.7 [95% CI, 10.4-13.0] months) and NALIRIFOX (11.1 [95% CI, 10.1-12.3] months; HR, 1.06 [95% CI, 0.81-1.39]; P = .65). There were no statistically significant differences in ORR among NALIRIFOX (41.8%), FOLFIRINOX (31.6%), and GEM-NABP (35.0%). NALIRIFOX was associated with lower incidence of grade 3 or higher hematological toxic effects (eg, platelet count decreased 1.6% vs 11.8% with FOLFIRINOX and 10.8% with GEM-NABP), but higher rates of severe diarrhea compared with GEM-NABP (20.3% vs 15.7%). In this systematic review and meta-analysis, NALIRIFOX and FOLFIRINOX were associated with similar PFS and OS as first-line treatment of advanced PDAC, although NALIRIFOX was associated with a different toxicity profile. Careful patient selection, financial toxic effects consideration, and direct comparison between FOLFIRINOX and NALIRIFOX are warranted.

Camrelizumab combined with apatinib and nanoparticle albumin-bound paclitaxel in lung adenocarcinoma (CAPAP-lung): a single-arm phase II study

Platinum-doublet chemotherapy plus immunotherapy has been the standard of care for the first-line treatment of advanced non-small cell lung cancer lacking actional driver mutations. However, optimization of drug combinations is still needed to find a better balance between therapeutic efficacy and safety in the immunotherapy era. We aimed to investigate the efficacy and safety of platinum-free albumin bound paclitaxel (nab-paclitaxel) combined with camrelizumab and apatinib as first-line treatment for patients with advanced lung adenocarcinoma. In this multicenter open-label, single-arm phase II trial, patients with systemic treatment-naïve advanced lung adenocarcinoma without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations received a rational-based combination of camrelizumab (200mg intravenously, day one), apatinib (250mg, q.d., five continuous days per week), and nab-paclitaxel (135mg/m2 intravenously, days one and eight) every three weeks for four to six cycles in China. Patients with controlled disease were maintained with camrelizumab and apatinib. The primary end point was progression-free survival (PFS). This trial is registered with ClinicalTrials.gov (No. NCT04459078). Between August 26, 2020 and May 20, 2022, 64 patients were enrolled. The median PFS was 14.3 (95% CI: 9.9, not reached) months. The confirmed objective response rate was 64.1% (95% CI: 51.1, 75.7). The grade 3-4 hematologic treatment-related adverse events (TRAEs) were decreased neutrophil count (14.1%), decreased white blood cell count (7.8%), and anemia (3.1%). The most common non-hematologic TRAEs of grade 3-4 were increased alanine transaminase (18.8%) and aspartate transaminase (15.6%). No treatment-related death occurred. The quality of life was on average not clinically meaningful worse through treatment cycle14. Nab-paclitaxel plus camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a potential treatment option in patients with advanced lung adenocarcinoma lacking EGFR/ALK mutations. Heath Research Foundation of Chinese Society of Clinical Oncology, Hunan Provincial Natural Science Foundation of China, Hunan Cancer Hospital Climb Plan, Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, The Science and Technology Innovation Program of Hunan Province, and Suzhou Sheng Diya Biomedical Co., Ltd, a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Shanghai, China).

A case of contralateral vertebral artery dissection during ramucirumab plus nab-paclitaxel combination therapy with a history of unilateral vertebral artery dissection

A case of contralateral vertebral artery dissection during ramucirumab plus nab-paclitaxel combination therapy with a history of unilateral vertebral artery dissection

A Case of Advanced Squamous Cell Lung Cancer with Hemodialysis That Responded to Carboplatin and Nab-paclitaxel Combination Therapy After Progression on Pembrolizumab

A Case of Advanced Squamous Cell Lung Cancer with Hemodialysis That Responded to Carboplatin and Nab-paclitaxel Combination Therapy After Progression on Pembrolizumab