Explore the vast range of titles available.

SummaryBackground A single center phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) was conducted (NCT02331251). Methods PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% received GNP until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months. Changes in tumor cell-free DNA copy number instability (CNI) was retrospectively evaluated. Results 17 pts. with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Grade 3 events occurred in 53% of patients. The phase II portion was completed for chemotherapy naïve PDAC pts. Of the 11 evaluable chemotherapy naïve PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 3 with PR on treatment for 8+, ~11, and 15 months; respectively. The primary endpoint of >15% complete response was not met. The median progression-free survival (PFS) and overall survival (OS) was 9.1 and 15.0 months for chemotherapy naïve treated patients. Of 9 patients evaluable for CNI change, a greater reduction in CNI correlated with longer PFS and improved OS. Conclusions GNP can be safely given to chemotherapy naïve PDAC patients. Efficacy appears to be slightly improved over previously reported results for standard weekly × 3 every 28 day gemcitabine and nab-paclitaxel dosing. CNI change may be prognostic for OS.

Introduction/BackgroundLenvatinib plus pembrolizumab is a standard of care for patients with advanced endometrial cancer (EC), following prior systemic therapy in any setting including neo/adjuvant. The randomized, open-label, phase 3 ENGOT-en9/LEAP-001 trial (NCT03884101) compares first-line lenvatinib plus pembrolizumab versus chemotherapy in patients with advanced/recurrent EC.MethodologyEligible patients had stage III-IV or recurrent, radiographically apparent, EC with no prior chemotherapy (hormonal therapy and chemoradiation permitted) or disease progression (PD) ≥6 months after neo/adjuvant chemotherapy. Patients were randomized 1:1 to lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 weeks (Q3W) or paclitaxel 175 mg/m2 Q3W plus carboplatin AUC 6 Q3W. Randomization was stratified by proficient versus deficient mismatch repair (MMR) status (pMMR versus dMMR), and in the pMMR stratum by prior adjuvant chemotherapy/chemoradiation (yes/no), measurable disease (yes/no), and ECOG performance status (0/1). Treatment continued for up to 35 cycles of pembrolizumab, 7 cycles of chemotherapy, or until PD/unacceptable toxicity. Dual primary endpoints were PFS (RECIST v1.1, blinded independent central review) and OS in the pMMR and intention-to-treat populations. Secondary endpoints included objective response rate and safety. Duration of response was an exploratory endpoint.ResultsOverall, 842 patients were randomized. At final analysis (data cutoff, October 2, 2023), after median follow-up of 38.4 (range, 30.3–52.9) months, OS was not statistically significant for non-inferiority of lenvatinib plus pembrolizumab versus chemotherapy in the pMMR population (HR, 1.02 [95% CI, 0.83–1.26]; non-inferiority P=0.2459875), thus no further statistical testing was performed (additional efficacy results in table 1). Treatment-related AEs occurred in 411/420 (97.9%) versus 398/411 (96.8%) treated patients in the lenvatinib plus pembrolizumab versus chemotherapy groups.ConclusionLenvatinib plus pembrolizumab did not meet the prespecified statistical criterion for OS or PFS versus chemotherapy in patients with pMMR advanced/recurrent EC in the first-line setting. The safety profile was manageable and consistent with that established for the combination in EC.DisclosuresDisclosures provided.Abstract #88 Table 1

The authors would like to note an error in Figures 1 and 2 of this paper. The graph in Figure 1 incorrectly reflected the overall survival (OS), when it should have displayed the progression-free survival (PFS). The caption and median PFS values were correct.

It is widely acknowledged that there is value in examining cancers for genomic aberrations via next-generation sequencing (NGS). How commercially available NGS platforms compare with each other, and the clinical utility of the reported actionable results, are not well known. During the course of the current study, the Foundation One (F1) test generated data on a combination of somatic mutations, insertion and deletion polymorphisms, chromosomal abnormalities, and deoxyribonucleic acid (DNA) copy number changes at ~250× coverage, while the Paradigm Cancer Diagnostic (PCDx) test generated the same type of data at >5,000× coverage, plus provided messenger RNA (mRNA) expression levels. We sought to compare and evaluate paired formalin-fixed paraffin-embedded tumor tissue using these two platforms. Samples from patients with advanced solid tumors were submitted to both the F1 and PCDx vendors for NGS analysis. Turnaround time (TAT) was calculated. Biomarkers were considered clinically actionable if they had a published association with treatment response in humans and were assigned to the following categories: commercially available drug (CA), clinical trial drug (CT), or neither option (hereafter referred to as \"None\"). The demographics of the 21 unique patient tumor samples included ten men and eleven women, with a median age of 56 years. Due to insufficient archival tissue from the same collection period, in one case, we used samples from different collections. PCDx reported first results faster than F1 in 20 cases. When received at both vendors on the same day, PCDx reported first results for 14 of 15 cases, with a median TAT of 9 days earlier than F1 (P<0.0001). Categorization of CA compared to CT and none significantly favored PCDx (P=0.012). In the current analysis, commercially available NGS platforms provided clinically relevant actionable targets (CA or CT) in 47%-67% of diverse cancer types. In the samples analyzed, PCDx significantly outperformed F1 in TAT, and had statistically significant higher clinically relevant actionable targets categorized as CA.

Glen J Weiss, Vivek Khemka Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, AZ, USAIt has come to our attention that the second and fourth paragraph of our Authors' reply1 may be misconstrued as an endorsement of the Paradigm Cancer Diagnostics (PCDx) test by Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, AZ, USA. This was not our intention. We stand by the interpretation of the results of the original manuscript and the remainder of the content of the Authors' reply. We welcome a more robust clinical comparison of these two platforms, as well as any other platform that may improve the clinical decision-making and outcomes for patients with advanced cancer.Previous letter has been published

BackgroundCTLA-4 pathway blockade with ipilimumab (IPI) ± nivolumab (NIVO; anti–PD-1) is an effective treatment for several cancers. A nonfucosylated version of IPI, BMS-986218, was developed to increase the effects of CTLA-4 blockade and enhance intratumoral regulatory T-cell depletion via its increased affinity for Fcγ receptors (FcγR, CD16) on natural killer T cells and macrophages, resulting in enhancement of antibody-dependent cellular cytotoxicity. Preclinical data supported the mechanism of action of BMS-986218 and demonstrated greater antitumor activity in an MC38 tumor model vs IPI.1 Here, we present initial results from the first-in-human phase 1/2a trial of BMS-986218 ± NIVO in previously treated patients with advanced cancer (NCT03110107).MethodsPatients with ≥1 prior therapy received BMS-986218 2–70 mg intravenously Q4W. Safety, tolerability, pharmacokinetics, and pharmacodynamics were evaluated.ResultsAs of December 12, 2019, 65 patients (median age, 61 years [range, 24–85 years]) received BMS-986218 monotherapy. TRAEs occurred in 52% of patients; most were grade 1–2. The most common (≥10%) TRAEs (any grade; grade 3) were pruritus (12%; 0%) and diarrhea (11%; 3%). Eight patients (12%) had grade 3 TRAEs; most resolved with protocol-defined management. No grade 4 TRAEs were reported; 1 grade 5 TRAE (pneumonitis; 2 mg) occurred. Seven patients (11%) discontinued treatment due to TRAEs; 4 dose-limiting toxicities occurred. The maximum tolerated dose has not been reached. BMS-986218 exposure increased dose proportionally, and the half-life was ≈2 weeks. Increased levels of serum chemokine ligands 9 and 10 and interferon-γ indicate that pharmacodynamic changes occurred at the lowest dose tested (2 mg [≈0.03 mg/kg]), similar to previous findings with IPI 3 mg/kg, and at higher doses (40–70 mg [≈0.06–1 mg/kg]), consistent with findings with IPI 10 mg/kg. In a subset of patients with paired biopsies, BMS-986218 was associated with an increased gene signature linked to CD8+ T-cell infiltration and inflammation. In a highly heterogeneous population, as part of dose escalation, BMS-986218 monotherapy treatment was associated with clinical activity in some patients. Updated data based on a September 2020 data cutoff will be presented.ConclusionsBMS-986218 monotherapy demonstrated an acceptable safety profile and signs of clinical benefit in this heterogeneous patient population with select advanced cancers. Preliminary pharmacodynamic activity was consistent with enhanced effects of CTLA-4 blockade. Data from continuing dose escalation of BMS-986218 ± NIVO along with preclinical results provide support for ongoing monotherapy expansions and for BMS-986218 + NIVO expansions in patients with advanced cancer.AcknowledgementsThe authors acknowledge Dr Charles Drake while at Columbia University Medical Center, New York, NY, USA, for his contributions to the study.Trial RegistrationNCT03110107Ethics ApprovalThis study was approved by the WCG Independent Review Board, approval number 20170464ReferenceEngelhardt J, Akter R, Valle J, et al. Preclinical characterization of BMS-986218, a novel nonfucosylated anti–CTLA-4 antibody designed to enhance antitumor activity. Presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting II; June 22–24, 2020 [poster 4552].

Background: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy. Methods: Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted. Results: Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types. Conclusions: Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.

ObjectivesKEYNOTE-C93/GOG-3064/ENGOT-en15 (NCT05173987) is a phase 3, randomized, open-label study evaluating first-line pembrolizumab versus carboplatin-paclitaxel chemotherapy in patients with dMMR advanced or recurrent endometrial cancer (EC).MethodsPatients aged ≥18 years with histologically confirmed stage III/IV recurrent EC including carcinosarcoma (mixed Mullerian tumor), radiographically evaluable disease (measurable or nonmeasurable per RECISTv1.1), no prior systemic therapy (prior radiation with or without radiosensitizing chemotherapy >2 weeks before first dose or prior hormonal therapy ≥1 week before randomization is permitted), and ECOG PS ≤1 are eligible. Patients must have central confirmation of dMMR status. ~350 patients will be randomized 1:1 to pembrolizumab 400 mg IV Q6W for 18 cycles (~2 years) or carboplatin AUC 5 or 6 mg/mL/min IV Q3W and paclitaxel 175 mg/m2 IV Q3W for 6 cycles (with option for >6 cycles). Trastuzumab is permitted for patients in the chemotherapy arm with HER2+ serous EC. Randomization is stratified by disease status (newly-diagnosed advanced EC vs recurrent EC) and histology (endometrioid vs nonendometrioid). Treatment will continue for the specified number of cycles or until PD or unacceptable toxicity. Patients in the chemotherapy arm can receive pembrolizumab following confirmed PD by BICR. Dual primary endpoints are PFS per RECISTv1.1 by BICR and OS. Secondary endpoints are ORR, DCR, and DOR per RECISTv1.1 by BICR; PFS per RECISTv1.1 by investigator review; PFS2; safety; and PROs. Enrollment is ongoing.ResultsTrial in progress: there are no available results at the time of submission.ConclusionsTrial in progress: there are no available conclusions at the time of submission.

The in vitro antineoplastic activity of the combination of 5-fluorouracil (5-FU) and interferon-alfa (IFN) has been attributed to multiple mechanisms including enhanced thymidylate synthase inhibition (Elias) and increased susceptibility to interferon-stimulated natural killer cells (Imai). Our group has previously examined weekly dosing schedules of 5-FU and IFN (Quan). Monthly bolus 5-FU + interferon-alfa-2b has not undergone formal phase II testing. In our current study, 18 patients with metastatic cancer who had experienced disease progression on at least 2 prior lines of systemic therapy, have been treated with 5-FU 500 mg/M2 intravenously over 3-5 minutes followed immediately by IFN-2b 3 million IU subcutaneously daily for 3 days monthly on an outpatient basis. Patient characteristics: 12 males/6 females, median age-57 (range: 35-69), median ECOG performance status-1; most common tumor types: colon (6), adenocarcinoma of the lung (4), rectum (3), pancreas (3); common metastatic sites: liver (11), lymph nodes (10), lungs (9). Median number of prior chemotherapy regimens: 3 (range: 2-8). Most common toxicities: rigors, nausea/emesis, fever, and fatigue. Median number of cycles received: 2 (1-11). Sixteen patients are evaluable for response (2 are too early). Two ongoing partial responses have been seen: One patient with adenocarcinoma of the lung (lung + lymph node metastases) at 8.9+ months and one with colon (liver and lymph node metastases at 1.25+ months. Thymidylate synthase levels are being analyzed. Monthly bolus 5-FU followed by subcutaneous IFN-2b is well-tolerated in previously-treated metastatic cancer and shows some evidence of activity in adenocarcinoma of the lung and colon cancer.