bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.
Authors: Bewersdorf Jan Philipp , Verstovsek Srdan , Derkach Andriy , Masarova Lucia , Pemmaraju Naveen , Stein Eytan M. , Mauro Michael J. , Rampal Raajit , Bose Prithviraj
Published: June 2023

TPS7086

Background: Patients (pts) with myelofibrosis (MF) have a reduced life-expectancy compared to age-matched controls. Several oral Janus Kinase (JAK) inhibitors such as ruxolitinib (RUX) have been approved by the US FDA based on improvements in symptom burden and spleen volume reduction compared to physician’s choice of best available therapy. However, duration of response to these agents is generally time-limited and treatment with JAK inhibitors is not considered to have disease-modifying potential. Additionally, median overall survival after RUX discontinuation is only 11-14 months. Thus, novel mechanism-based therapies for pts with disease progression on RUX are needed. JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A, which is also upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D have also been implicated in MF pathogenesis. Finally, we and others have shown that combination of the CDK4/6 inhibitors and RUX had synergistic effects in murine models of MF (Rampal et al., CCR 2021) providing the preclinical rationale for this trial. Methods: This multicenter, phase I dose-escalation trial (NCT05714072) evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. Among the currently FDA-approved CDK4/6 inhibitors, abemaciclib was chosen for combination therapy due to less myelosuppressive effects compared with other CDK4/6 inhibitors. Inadequate response to RUX is defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms, as defined by the presence of one symptom score ≥5 or two symptom scores ≥3 using the screening MPN-SAF TSS. Following a conventional “3+3” dose-escalation design, pts will be treated with increasing doses of abemaciclib and stable doses of RUX (10mg or 15mg BID). The primary endpoint is to determine the maximum tolerated dose of RUX + abemaciclib. Secondary endpoints include measures of efficacy. Exploratory endpoints include changes in allele fraction of driver mutations, gene expression profiling, and clonal architecture to identify biomarkers of response, mechanisms of resistance, and to assess for any disease-modifying effects of the combination therapy. This trial is open to enrollment at Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center. Clinical trial information: NCT05714072 .
waveLINE-006: A phase 2 study of the safety and efficacy of zilovertamab vedotin as monotherapy or in combination in patients (pts) with aggressive and indolent B-cell malignancies.
Authors: Zinzani Pier Luigi , Mayer Jiri , Benjamini Ohad , Berkovits Alejandro , Glimelius Ingrid , Stevens Don A. , Chaudhry Arvind , Muzaffer Demir Ahmet , Garcia Sanz Ramón , Seog Kim Won , Li Fei , Halka Janusz , Marin-Niebla Ana , Ozcan Muhit , Paszkiewicz-Kozik Ewa , Santoro Armando , Ren Yixin , Ogbu Uzor , Marinello Patricia , Jurczak Wojciech
Published: June 2023

TPS7595

Background: ROR1 is a transmembrane protein expressed in hematologic malignancies. Zilovertamab vedotin (ZV) is an antibody-drug conjugate comprising a humanized IgG1 monoclonal anti-ROR1, a proteolytically cleavable linker, and the antimicrotubule agent monomethyl auristatin E. Nemtabrutinib is a reversible inhibitor of Brutons tyrosine kinase (BTK). The combination of ZV and a BTKi has the potential for improved responses in B-cell malignancies. The waveLINE-006 study (NCT05458297) is designed to investigate safety and efficacy of ZV as monotherapy or in combination with nemtabrutinib in pts with B-cell malignancies. Methods: Eligible pts are ≥18 years old with biopsy-proven and/or histologically confirmed mantle cell lymphoma (MCL), Richters transformation (RT), chronic lymphocytic leukemia (CLL), or follicular lymphoma (FL), relapsed or refractory (R/R) disease, ECOG performance status of 0 to 2, and adequate organ function (table). Approximately 275 pts will be enrolled in 6 cohorts (A-F; see table). In cohorts A and B, patients will receive ZV 2.5 mg/kg IV Q3W. In cohort C, 30 patients will be enrolled in a safety run-in phase of ZV in combination with nemtabrutinib, then an additional 15 patients will receive the RP2D of the combination. Patients in cohort D (schedule optimization) will be randomized 1:1 to receive ZV 2.5 mg/kg IV Q3W (arm 1) or ZV 2.0 mg/kg IV Q2/3W (arm 2). Patients in cohorts E and F (efficacy expansion) will receive the dose and schedule of ZV determined during schedule optimization. Each recipient of ZV or nemtabrutinib will receive the assigned intervention until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Tumor scans will be performed at baseline, then Q12W up to week 108, then Q24W thereafter. Adverse events (AEs) will be monitored and will be graded per NCI CTCAE version 5. The primary end points are the safety and tolerability of ZV alone (cohort D) and in combination with nemtabrutinib (cohort C), and the objective response rate of ZV alone (cohorts A, B, D, E, and F) and in combination with nemtabrutinib (cohort C). The secondary end points are the duration of response of ZV alone (cohorts A, B, D, E, and F) and in combination with nemtabrutinib (cohort C) and the safety and tolerability of ZV alone (cohorts A, B, E, and F). Clinical trial information: NCT05458297 . [Table: see text]
MagnetisMM-6: An open-label, multicenter, randomized phase 3 study of elranatamab + daratumumab + lenalidomide (EDR) versus daratumumab + lenalidomide + dexamethasone (DRd) in transplant ineligible (TI) patients with newly diagnosed multiple myeloma (NDMM).
Authors: Grosicki Sebastian , Yeh Su-Peng , Huang Jeffrey S.Y. , Byun Ja Min , DiRienzo Christine , Viqueira Andrea
Published: June 2023

TPS8065

Background: Elranatamab, a humanized bispecific antibody targeting B cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, has shown promising efficacy and acceptable safety in clinical studies, as monotherapy (MagnetisMM-3, NCT04649359) and in combination with daratumumab (MagnetisMM-5, NCT05020236), in the treatment of patients with relapsed/refractory multiple myeloma (RRMM). Despite recent advances in the treatment of NDMM, MM remains incurable and more effective treatment options are needed. The aim of the MagnetisMM-6 study (NCT05623020) is to evaluate EDR versus DRd for TI patients with NDMM. Methods: MagnetisMM-6 is an ongoing, open-label, 2-arm, multicenter, randomized phase 3 study estimated to enroll ~646 patients. There are 2 parts: Part 1 evaluates the safety and recommended phase 3 dose (RP3D) of EDR: Part 2 evaluates the efficacy and safety of EDR at RP3D vs DRd in TI patients with NDMM. TI is defined as age ≥65 or age < 65 with comorbidities impacting the possibility of transplant. The primary endpoints of Part 2 are minimal residual disease (MRD) at 12 mo and progression-free survival. Secondary endpoints include overall and sustained MRD negativity rates, duration of MRD negativity, objective response rate, complete response (CR) rate, time to response, duration of response, duration of CR, overall survival, safety, quality of life, immunogenicity, and pharmacokinetics. Part 1 includes TI patients with NDMM as well as patients with RRMM who have received 1−2 prior lines of therapy including ≥1 immunomodulatory drug and ≥1 proteasome inhibitor. Part 2 includes only TI patients with NDMM. Key inclusion criteria are: ≥18 y; a diagnosis of MM (according to International Myeloma Working Group [IMWG] criteria); an ECOG performance status ≤2; and measurable disease based on IMWG criteria (serum M-protein ≥0.5 g/dL, urinary M-protein excretion ≥200 mg/24 hr, or involved serum free light chain [FLC] ≥100 mg/L and abnormal serum immunoglobulin κ:λ FLC ratio [ < 0.26 or > 1.65]). Key exclusion criteria are: smoldering MM; monoclonal gammopathy; Waldenström’s macroglobulinemia; plasma cell leukemia; active, uncontrolled bacterial, fungal, or viral infections; previous systemic treatment for MM (NDMM patients only); previous treatment with a BMCA-directed therapy or anti-CD38-directed therapy ≤6 mo of the first dose of study treatment (RRMM patients only); or stem cell transplant ≤3 mo of the first dose of study treatment or active graft versus host disease (RRMM patients only). As of February 2023, the study is open and enrolling at 9 sites in 5 countries. Clinical trial information: NCT05623020 .
MagnetisMM-7: An open-label, multicenter, randomized phase 3 study of elranatamab versus lenalidomide in post-transplant patients with newly diagnosed multiple myeloma.
Authors: Mateos Manteca Maria Victoria , Grosicki Sebastian , Kim Kihyun , Negre Eric , Vandendries Erik
Published: June 2023

TPS8066

Background: Elranatamab is a humanized bispecific antibody targeting B cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells. Elranatamab has shown promising efficacy and acceptable safety in pts with relapsed and/or refractory multiple myeloma (MM). The aim of the MagnetisMM-7 study is to evaluate elranatamab monotherapy vs lenalidomide monotherapy in pts with newly diagnosed MM (NDMM) after undergoing autologous stem cell transplant (ASCT). Methods: MagnetisMM-7 is an ongoing, open-label, 2-arm, multicenter, randomized phase 3 study estimated to enroll ~700 pts. ClinicalTrials.gov ID: NCT05317416. Pts are randomized to receive either subcutaneous elranatamab or oral lenalidomide once daily. After initial step-up dosing, two alternative dosing regimens of elranatamab are examined. The primary endpoint is progression-free survival (PFS) assessed by blinded independent review per International Myeloma Working Group (IMWG) criteria (up to ~5 y). Secondary endpoints include overall survival, minimal residual disease (MRD) negativity rate at 12 mo after randomization per IMWG criteria as assessed via next-generation sequencing (NGS), sustained MRD negativity rate at 24 mo after randomization as assessed via NGS, PFS by investigator, duration of MRD negativity, complete response (CR) rate, duration of CR, safety, quality of life, immunogenicity, and pharmacokinetics. Key inclusion criteria are: ≥18 y; a diagnosis of MM with measurable disease according to IMWG criteria; history of induction therapy for NDMM, followed by high dose therapy and ASCT with or without consolidation; partial response or better according to IMWG criteria; identification of the dominant malignant clone; and Eastern Cooperative Oncology Group performance status ≤1. Randomization must occur ≤120 d from ASCT; for pts who receive consolidation therapy after ASCT, randomization must occur ≤60 d of consolidation and ≤7 mo of ASCT. Key exclusion criteria are: plasma cell leukemia; amyloidosis; Waldenström's macroglobulinemia; POEMS syndrome; known active CNS involvement or clinical signs of myelomatous meningeal involvement; previous MM maintenance treatment; prior treatment with BCMA-targeted therapy; any other active malignancy ≤3 y of enrollment; active, uncontrolled bacterial, fungal, or viral infection; and previous administration of an investigational drug or vaccine ≤30 d or 5 half-lives preceding the first dose of study treatment. As of February 2023, the study is open and enrolling at 29 sites in 13 countries. Clinical trial information: NCT05317416 .
Neoadjuvant immunotherapy in sarcomatoid mesothelioma (Alliance A082101).
Authors: Mansfield Aaron Scott , Wang Xiaofei F. , Wigle Dennis A. , Watt Colleen , Masters Gregory A. , Kelley Kathryn , Kozono David E. , Stinchcombe Tom
Published: June 2023

TPS8602

Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS). For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Clinical trial information: NCT05647265 .
NeoCOAST-2: A phase 2 study of neoadjuvant durvalumab plus novel immunotherapies (IO) and chemotherapy (CT) or MEDI5752 (volrustomig) plus CT, followed by surgery and adjuvant durvalumab plus novel IO or volrustomig alone in patients with resectable non-small-cell lung cancer (NSCLC).
Authors: Guisier Florian , Bennouna Jaafar , Spira Alexander I. , Kim Dong-Wan , Shim Byoung Yong , Abdul Sater Houssein , Grenga Italia , Parmar Swapnil S , Bielska Agata A. , Yohannes Alula , Mager Raymond , Hamid Oday , McGrath Lara , He Yun , Soo-Hoo Yee , Kumar Rakesh , Spicer Jonathan , Forde Patrick M. , Cascone Tina
Published: June 2023

TPS8604

Background: Neoadjuvant platinum-based CT plus IO prolongs event-free survival (EFS) and increases pathological complete response (pCR) rate in patients with resectable NSCLC vs CT alone (Forde et al. N Engl J Med 2022). IO+IO+CT combinations have the potential to further improve pCR and survival outcomes. The phase 2 NeoCOAST-2 study (NCT05061550) is evaluating multiple neoadjuvant IO+IO+CT combinations in patients with resectable, early stage NSCLC. Novel IO molecules being evaluated include the anti-CD73 monoclonal antibody (mAb), oleclumab; the anti-NKG2A mAb, monalizumab; and the PD-1/CTLA-4 bispecific mAb, volrustomig. The latter recently demonstrated durable responses vs a PD-1 inhibitor plus CT as first-line treatment for patients with metastatic NSCLC (ESMO 2022; LBA56). Here we describe the NeoCOAST-2 study design. Methods: This randomized, open-label, multicenter study will enrol approximately 210 patients with previously untreated, histologically/cytologically confirmed, resectable Stage IIA–IIIB (AJCC 8th edition) NSCLC. Patients will be stratified by PD-L1 expression ( < 1% vs ≥1%) and receive treatment with durvalumab + oleclumab + CT, durvalumab + monalizumab + CT, or volrustomig + CT every 3 weeks for 4 cycles prior to surgery, followed by adjuvant durvalumab + oleclumab, durvalumab + monalizumab, or volrustomig for up to 1 year or until disease progression per RECIST v1.1. Surgery should occur within 40 days after the last dose of neoadjuvant therapy and adjuvant therapy should commence within 10 weeks after surgery. The primary endpoints are pCR rate (per blinded independent pathologist review) and safety and tolerability. Secondary endpoints include investigator-assessed EFS, disease-free survival and overall survival, feasibility to surgery, major pathological response rate, objective response rate following neoadjuvant therapy, pharmacokinetics, immunogenicity, and changes in circulating tumor DNA. The study is currently recruiting patients across the US, Europe, Canada, and Asia. Clinical trial information: NCT05061550 .
Phase 3 study of durvalumab combined with oleclumab or monalizumab in patients with unresectable stage III NSCLC (PACIFIC-9).
Authors: Barlesi Fabrice , Goldberg Sarah B. , Mann Helen , Gopinathan Aarthi , Newton Michael David , Aggarwal Charu
Published: June 2023

TPS8610

Background: Based on the findings of the phase 3 PACIFIC trial, durvalumab as consolidation therapy is the standard of care for patients with unresectable Stage III NSCLC and no disease progression following chemoradiotherapy (CRT; the PACIFIC regimen). However, further improvements in outcomes are needed for this population and, to build upon the backbone of PD-L1 inhibition with durvalumab, immunotherapy combinations including anti-TIGIT, anti-CD73, and anti-NKG2a monoclonal antibodies (mAbs) are now being explored. Two potential candidates, oleclumab and monalizumab, have demonstrated encouraging clinical activity in a randomized, phase 2 trial when combined with durvalumab in this setting. Oleclumab (MEDI9447) is a human IgG1λ mAb that inhibits the function of CD73, to reduce extracellular adenosine production and thus promote antitumor immunity. Monalizumab (IPH2201) is a first-in-class, humanized, IgG4 mAb that prevents NKG2A from binding to HLA-E, which reduces inhibition of natural killer and CD8+ T cells. The combination of each of these molecules with durvalumab consolidation therapy was evaluated in the phase 2 COAST study (NCT03822351). In COAST (n = 189), patients receiving combination therapy reported numerically higher objective response rates (durvalumab plus oleclumab: 30.0%; durvalumab plus monalizumab: 35.5%; durvalumab monotherapy: 17.9%) and prolonged progression-free survival versus durvalumab alone, with no new/significant safety signals (Herbst, et al. 2022). Thus, the combination of oleclumab or monalizumab with consolidative durvalumab warrants further evaluation in a phase 3 trial. Methods: PACIFIC-9 (NCT05221840) is a phase 3, double-blind, placebo-controlled, randomized, international trial. Eligible patients (age ≥18 years) must have EGFR/ALK wild-type unresectable Stage III NSCLC, a WHO performance status of 0/1, documented PD-L1 status, and must not have progressed following ≥2 cycles of definitive, platinum-based concurrent CRT. Approximately 999 patients will be randomized (1:1:1) to receive up to 12 months of treatment (in 28-day cycles) with durvalumab plus either oleclumab (Arm A); monalizumab (Arm B); or placebo (Arm C). The primary endpoint is progression-free survival (RECIST v1.1) by blinded independent central review (BICR). Overall survival is a key secondary endpoint. Other secondary endpoints include objective response rate and duration of response (RECIST v1.1; BICR), patient-reported outcomes, PD-L1 expression on tumor cells relative to efficacy outcomes, and safety/tolerability (CTCAE v5.0). Trial enrollment is ongoing. Previously presented at the World Conference on Lung Cancer (WCLC) 2022, FPN (Final Publication Number): P1.10-01, Fabrice Barlesi et al. Clinical trial information: NCT05221840 .
Prophylactic cerebral irradiation or active brain magnetic resonance imaging surveillance in small-cell lung cancer patients (EORTC-1901: PRIMALung).
Authors: Levy Antonin , Berghmans Thierry , Andratschke Nicolaus , Leonetti Giulia , Koller Michael , Faivre-Finn Corinne ,   EORTC Lung Cancer Group
Published: June 2023

TPS8614

Background: PRIMALung is an EORTC-sponsored study. Primary objective is to show that overall survival with brain MRI surveillance alone is non-inferior to brain MRI surveillance combined with PCI in patients with SCLC. PCI is currently SOC in most institutions, but can be associated with neurocognitive toxicity and impact quality of life. 600 patients will be recruited from 50 EORTC centres in 10 countries. This study is currently recruiting and will play an important role in clarifying whether MRI surveillance is a viable strategy in SCLC. Furthermore, it will answer important questions about the role of PCI in the era of immunotherapy, particularly in ES-SCLC. Methods: Key eligibility: ECOG performance status ≤ 2 patients with SCLC (Limited or Extensive-Stage, stage I-IV) who did not progress after (≤ 16 weeks from day 1 of last cycle of chemotherapy to randomisation) completed standard therapy. Absence of progression, brain metastases or leptomeningeal disease after completing therapy. Trial Interventions: Patients will be randomised 1:1 to receive brain MRI surveillance with or without PCI (25Gy in 10 fractions). Primary objective - to show that overall survival with brain MRI surveillance alone is non-inferior to brain MRI surveillance combined with PCI. Secondary objectives - cognitive failure-free survival, quality of life and acute/late toxicities according to CTCAE v5.0. The trial was open to recruitment on 27/10/2022. Three countries open to date (Belgium, Switzerland, UK). Further sites in France, Poland and Austria will be open to recruitment Q1 2023. The first patient has been randomized on the 4th of January 2023. Further information: https://clinicaltrials.gov/ct2/show/NCT04790253 contact: 1901@EORTC.org. Clinical trial information: NCT04790253 .
STAR-121: A phase 3, randomized study of domvanalimab (DOM) and zimberelimab (ZIM) in combination with chemotherapy vs pembrolizumab (pembro) and chemotherapy in patients with untreated metastatic non-small cell lung cancer (mNSCLC) with no actionable gene alterations.
Authors: Rodriguez-Abreu Delvys , Gray Jhanelle Elaine , Ahn Myung-Ju , Johnson Melissa Lynne , Yu Xinwei , Chen Xueying , Phuong Patrick Hoang , Kim Jongseok , Reck Martin
Published: June 2023

TPS9141

Background: Although immune checkpoint inhibitors have improved clinical outcomes in mNSCLC, the majority of patients will experience progression and shorter survival. Thus, an urgent need exists for more effective treatment options in mNSCLC. DOM is an anti-TIGIT IgG1, Fc-silent monoclonal antibody designed to inhibit the interaction between TIGIT and its ligand, CD155, thereby reducing immunosuppression of T cells and natural killer cells and promoting antitumor activity. ZIM is an anti–PD-1 IgG4 monoclonal antibody with demonstrated antitumor activity in vivo and preliminary clinical activity in multiple tumor types. Preliminary studies have shown that dual blockade of TIGIT and PD-(L)1 increases antitumor activity relative to PD-(L)1 inhibition. In ARC-7, a randomized phase 2 study in PD-L1–high, first-line NSCLC, DOM and ZIM in combination recently demonstrated a higher objective response rate (ORR) and longer median progression-free survival (PFS) than ZIM monotherapy. We hypothesize that DOM and ZIM in combination with chemotherapy will improve clinical outcomes in patients with untreated mNSCLC without EGFR or ALK aberrations regardless of PD-L1 expression. Methods: STAR-121 is a phase 3, global, open-label, randomized study to evaluate the safety and efficacy of DOM and ZIM plus chemotherapy vs pembro plus chemotherapy as first-line therapy for patients with mNSCLC with no EGFR or ALK aberrations or other known actionable gene alterations. Approximately 720 patients will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 tumor proportion score ( < 50% vs ≥50%), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Eligible patients are aged ≥18 with untreated mNSCLC with no EGFR or ALK aberrations. Group A will receive DOM 1200 mg + ZIM 360 mg + platinum-doublet chemotherapy (PT), group B will receive pembro 200 mg + PT, and group C will receive ZIM 360 mg + PT. DOM, ZIM, and pembro will be administered until disease progression (PD) as assessed by blinded independent central review (BICR) per RECIST 1.1 or intolerable toxicity or for up to 35 doses. Study treatment will be administered IV every 3 weeks. PT will be chosen by investigators based on tumor histology and administered for the first 4 cycles, after which, pemetrexed can be continued for patients with nonsquamous histology until PD or intolerable toxicities. The primary endpoints are PFS by BICR and overall survival. Key secondary endpoints are ORR and duration of response by BICR, safety, and quality of life. This study is currently enrolling globally. Clinical trial information: NCT05502237 .
ARC-10: A phase 3 study to evaluate zimberelimab + domvanalimab versus pembrolizumab in front-line, PD-L1-high, locally advanced or metastatic non–small-cell lung cancer.
Authors: Chouaid Christos , Ho Gwo Fuang , Runglodvatana Yotsawaj , He Xian , Ahlers Christoph Matthias , Pomponio Debbie , Todd Trever , Dang Thao , Naidoo Jarushka
Published: June 2023

TPS9148

Background: Despite improvements in the management of locally advanced or metastatic non–small cell lung cancer (NSCLC) from programmed cell death/ligand protein 1 (PD-[L]1) inhibition, there remains an unmet need for improved treatment options. PD-L1 expression is a known biomarker of response to anti–PD-L1 therapies in metastatic NSCLC. The combination of PD-1 inhibition with inhibition of the immunosuppressive T cell Immunoglobulin and ITIM domain (TIGIT) pathway is associated with improved response and prolonged progression-free survival in patients with advanced NSCLC. Domvanalimab (dom) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks TIGIT, thereby reducing immunosuppression of T/natural killer (NK) cells and promoting antitumor activity. Zimberelimab (zim) is an mAb that binds to PD-1 on T/NK cells, preventing PD-L1-mediated immunosuppressive effects and resulting in tumor cell death. This phase 3 study will investigate the efficacy and safety of combination therapy with dom + zim compared with pembrolizumab monotherapy in patients with PD-L1-high NSCLC. Methods: ARC-10 (NCT04736173) is a global, phase 3, randomized, multicenter, open-label study. Eligible patients are adults with histologically confirmed, treatment-naive, locally advanced or metastatic, squamous or non-squamous NSCLC with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, high expression of PD-L1 (tumor cells [TC] ≥50%), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients must not have genomic tumor aberrations for which targeted therapies are approved and available (eg, EGFR, ALK, ROS, BRAF, NTRK). Approximately 600 patients will be randomized 1:1 to receive combination therapy with dom + zim (dom 1200 mg intravenous [IV] once every 3 weeks [Q3W] + zim 360 mg IV Q3W) or pembrolizumab monotherapy (200 mg IV Q3W) for 21-day cycles until disease progression, intolerance, or a maximum of 35 cycles. Randomization will be stratified by ECOG performance status (0 vs 1), geographical region (Asia vs non-Asia), and histology (squamous vs non-squamous). The primary efficacy endpoint is overall survival. Secondary efficacy endpoints include blinded independent central review of progression-free survival and confirmed overall response rate according to RECIST v1.1. Safety endpoints include the presence of treatment-emergent adverse events and laboratory parameters. Health-related quality of life will be assessed by measuring the time to first symptom deterioration in the NSCLC-Symptom Assessment Questionnaire total score. Study recruitment is planned in Asia, North and South America, Africa, and Europe. Clinical trial information: NCT04736173 .
A first-in-human, open-label, dose escalation and expansion study of orally administered NX-019 in patients with advanced EGFR mutant cancer.
Authors: Spira Alexander I. , Kim Dong-Wan , Ahn Myung-Ju , Kim Sang-We , Hong Min Hee , Dusek Rachel , Gammon Guy M. , Wilson Keith , Yang James Chih-Hsin , Massarelli Erminia
Published: June 2023

TPS9159

Background: CNS involvement, brain metastases and/or leptomeningeal disease, is common in patients with EGFR mutant NSCLC and occurs in 25-50% of patient’s journeys. Despite the activity and increased CNS penetration of later generation EGFR inhibitors, management of CNS disease remains a clinical challenge. NX-019 is a broad-spectrum EGFR inhibitor targeting both common and rare mutations including EGFR ex20ins, G719S, and L861Q. NX-019 exhibits selective activity towards mutant vs. wt. EGFR in preclinical studies. Substantial CNS exposure has been demonstrated in animal models, as well as potent anti-tumor activity toward intracranial xenografts with prolonged inhibition of EGFR signaling. Similar drug levels compared to plasma were measured in the brains of rats and mice. NX-019 was readily detectable in the CSF of cynomolgus monkeys, dogs and rats at concentrations similar to the estimated plasma free fraction. Methods: NT019-101 is a first-in-human, international, open-label study designed to evaluate single-agent NX-019 in patients with EGFR-mutant, locally advanced or metastatic NSCLC that has progressed following prior treatment. Patients with ECOG performance status 0–2 and EGFR mutant cancers including stable, asymptomatic brain metastases are eligible for Dose Escalation. Patients with known EGFR C797S mutations and secondary drivers, e.g., MET amplification and RET fusions, are excluded. Primary endpoints are to determine recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), safety and tolerability (part 1), and to evaluate antitumor activity at the RP2D by RECIST v1.1 and RANO-BM (part 2). Secondary endpoints are to evaluate pharmacokinetics (PK) and antitumor activity by RECIST v1.1 (part 1) and PK, safety, tolerability, and CNS antitumor activity (part 2). Dose escalation will utilize a 3+3 design with up to 6 patients per cohort in part 1. Part 2 will enroll patients in 5 cohorts (n = 10 or 29 each), including patients with NSCLC who have (1) new or progressing CNS metastases including leptomeningeal disease after treatment with osimertinib, (2) active CNS disease and ex20ins mutations, (3) ex20ins mutations without CNS disease and (4) other rare mutations, based on a Simon 2-stage design. First patient was treated in October 2022 and enrollment is ongoing. The study is planned for approximately 35 centers in North America and Asia-Pacific region. Clinical trial information: NCT05514496 .
Phase 1 study of SGN-BB228, an investigational CD228 x 4-1BB costimulatory antibody anticalin bispecific, in patients with advanced melanoma and other solid tumors (SGNBB228-001).
Authors: Henry Jason Timothy , Mehnert Janice M. , Rudnicki Erika , Pinelli Juan , Daud Adil
Published: June 2023

TPS9597

Background: SGN-BB228 is an investigational costimulatory Antibody Anticalin bispecific (Mabcalin) molecule directed to CD228 and 4-1BB. CD228 is a tumor-associated antigen selectively expressed by multiple tumor types including melanoma, mesothelioma, pancreatic, colorectal, and lung cancers with minimal expression in normal tissue. 4-1BB is an inducible costimulatory receptor expressed on activated T cells and other immune cell populations. The clinical development of 4-1BB agonist antibodies has been hampered by limited efficacy and/or poor tolerability at active doses (Segal et al 2017, Segal et al 2018). SGN-BB228 is designed to deliver a potent costimulatory bridge between tumor-specific T cells and tumor cells, potentially localizing antitumor activity to the tumor microenvironment and expanding the therapeutic window for 4-1BB agonism. In vitro, SGN-BB228 shows potent CD228-conditional 4-1BB stimulation and cytotoxic T cell activation (Updegraff et al 2022) providing rationale for evaluating SGN-BB228 in patients (pts) with melanoma or other solid tumors. Methods: SGNBB228-001 (NCT05571839) is a phase 1, open label, multicenter study designed to evaluate the safety, tolerability, PK, and antitumor activity of SGN-BB228 in adults ≥18 years of age with advanced melanoma or other solid tumors. The study includes dose escalation (Part A), dose and schedule optimization (Part B; optional), and dose expansion in disease-specific cohorts (Part C). Parts A and B will enroll pts with histologically or cytologically confirmed metastatic or unresectable cutaneous melanoma, and Part C will enroll pts with cutaneous melanoma, mesothelioma, pancreatic, colorectal, or non-small cell lung cancer. Pts must have disease that is relapsed, refractory, or intolerant to standard of care therapies, ECOG PS 0-1, and adequate organ function. Pts with known active CNS metastases or prior use of agents targeting CD228 or 4-1BB are excluded. Pts with cutaneous melanoma must have received anti PD(L)-1 agent as monotherapy or in combination. Pts with a targetable BRAF mutation must have received, been intolerant to, or declined treatment with BRAF/MEK targeted therapy prior to study entry. Primary endpoints include rate of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints are PK, ORR, DOR, PFS, OS, and incidence of antidrug antibodies. Safety and antitumor activity endpoints will be assessed by dose, schedule, and tumor type using descriptive statistics. The ORR and its 95% CI will be estimated. DOR, PFS, and OS will be estimated using Kaplan-Meier method. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT05571839 .
A phase 3 trial of fianlimab (anti–LAG-3) plus cemiplimab (anti–PD-1) versus pembrolizumab in patients with previously untreated unresectable locally advanced or metastatic melanoma.
Authors: Baramidze Ana , Gogishvili Miranda , Makharadze Tamta , Zhvania Mariam , Vacharadze Khatuna , Crown John , Melkadze Tamar , Hamid Omid , Long Georgina V. , Robert Caroline , Sznol Mario , Martinez-Said Hector , Mani Jayakumar , Chaudhry Usman , Salvati Mark , Lowy Israel , Fury Matthew G. , Gullo Giuseppe
Published: June 2023

TPS9602

Background: Fianlimab (anti-lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti- programmed cell death-1 [PD-1]) are both high-affinity, fully human, IgG4 monoclonal antibodies (Abs). Concurrent blockade of anti-LAG-3 and anti-PD-1 has shown enhanced efficacy (increase in progression free survival [PFS]) in advanced melanoma (Mel). We previously presented data from a phase 1 study showing a 63.8% objective response rate (ORR) across two separate cohorts of advanced PD-(L)1 naïve metastatic Mel patients (pts) treated with fianlimab plus cemiplimab with an acceptable risk-benefit profile. Methods: This is a randomized, double-blind, phase 3 study to evaluate fianlimab plus cemiplimab compared to pembrolizumab in pts with previously untreated unresectable locally advanced or metastatic Mel (NCT05352672). This study will be conducted globally, at approximately 200 sites. Key inclusion criteria are: (1) ≥12 years of age; (2) histologically confirmed unresectable Stage III and Stage IV (metastatic) Mel (3) no prior systemic therapy for advanced unresectable disease, prior (neo)adjuvant therapies are allowed with treatment/disease-free interval of 6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) valid LAG-3 results; (6) Eastern Cooperative Oncology Group performance status (PS) of 0 or 1 (for adult pts), Karnofsky PS ≥70 (pts ≥16 years) or Lansky PS ≥70 (pts < 16 years); and (7) anticipated life expectancy of at least 3 months. There are 4 arms to the study: (1) Arm A: fianlimab (1600 mg) + cemiplimab (350 mg) every 3 weeks (Q3W), intravenously (IV); (2) Arm A1: fianlimab (400 mg) + cemiplimab (350 mg) Q3W, IV; (3) Arm B: pembrolizumab (200 mg Q3W, IV) + saline/dextrose placebo (placebo); (4) Arm C: cemiplimab (350 mg Q3W, IV) + placebo. The trial is expected to enroll approximately 1590 pts. The primary endpoint is progression-free survival. The key secondary endpoints are overall survival and objective response rate. The additional secondary endpoints include disease control rate, duration of response, safety, pharmacokinetics of cemiplimab and fianlimab, and immunogenicity (incidence and titer of anti-drug Abs and neutralizing Abs). The study is currently open for enrollment. Clinical trial information: NCT05352672 .
A pilot, open study to assess efficacy and safety of ON-01910 (rigosertib) in patients with recessive dystrophic epidermolysis bullosa associated locally advanced/metastatic squamous cell carcinoma.
Authors: Banner Lauren , Hosler Linda , Parris Matthew , Gelder Mark Stephen , Laimer Martin , Bauer Johann , South Andrew , Nikbakht Neda
Published: June 2023

TPS9604

Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is an extremely rare, severe blistering disease driven by mutations in collagen seven (COL7A1). Besides the skin and mucosal blistering, this genodermatosis is also characterized by aggressive cutaneous squamous cell carcinomas (cSCCs) arising from patients’ chronic wounds. The cumulative risk of death from these cSCCs is 70% by age 45. There are limited effective treatment options for advanced (unresectable/metastatic) RDEB-associated cSCCs. While the standard of care for any advanced cSCC is immune checkpoint inhibitors, only half of the treated patients had responses in clinical trials. Their use for RDEB-associated SCCs been limited to case reports, and our own experience has not been positive. Conventional chemotherapy in RDEB-associated cSCC is another proposed treatment strategy, however, case reports demonstrated limited response rates without lasting effects. Currently it is recommended palliatively, although there are concerns about adverse effects. Other existing options are tyrosine kinase inhibitors, resulting in mixed responses to treatment for advanced cSCCs of any type, and epidermal growth factor receptor inhibitors, demonstrating limited effectiveness in a small number of case reports on RDEB-associated cSCCs. More effective therapeutic modalities for advanced/metastatic RDEB-associated cSCCs are needed. We previously demonstrated that RDEB SCC keratinocytes are specifically affected by polo-like kinase-1 (PLK-1) siRNA. Eight PLK-1 inhibitors were screened for cytotoxicity. Of the 8 candidates, ON-01910 was superior as it demonstrated the largest therapeutic window for distinguishing between tumor versus normal cells. The ON-01910 clinical trial is in progress in patients with RDEB with advanced/metastatic cSCCs. Methods: ON-01910 is being evaluated in both oral and intravenous formulations in an open-label, non-randomized phase 2 study in RDEB patients with advanced, treatment resistant cSCC. The trial explores the anti-tumor activity of ON-01910 and evaluates its safety and tolerability. Secondary objectives are to assess the impact on quality of life and to perform biomarker analysis on patient tissue. This study began in August 2021 and is ongoing. One patient is currently enrolled in the oral arm at Thomas Jefferson University in the USA. Safety is assessed according to the CTCAE v5. Tumor response in lymph nodes is determined per the RECIST 1.1 and in skin via clinical examination with serial tumor measurements. Key eligibility criteria include 1) diagnosis of RDEB and associated measurable, advanced cSCC confirmed histologically 2) failure to respond to standard of care including excision for localized disease 3) no concomitant cancer therapies. Clinical trial information: NCT04177498 .
KEYVIBE-010: Adjuvant coformulated vibostolimab with pembrolizumab versus adjuvant pembrolizumab in patients with high-risk stage II-IV melanoma.
Authors: Long Georgina V. , Eggermont Alexander M. , Gershenwald Jeffrey E. , Schadendorf Dirk , Ascierto Paolo Antonio , Dummer Reinhard , Hauschild Axel , Carlino Matteo S. , Ribas Antoni , Robert Caroline , Scolyer Richard A. , Sondak Vernon K. , Cohen Jonathan E , Zhang Jinchun , Grebennik Dmitri O. , Krepler Clemens , Luke Jason J.
Published: June 2023

TPS9611

Background: Pembrolizumab is an anti−PD-1 monoclonal antibody that has been shown to significantly improve recurrence-free survival and distant metastasis-free survival when used as adjuvant therapy in patients with high-risk resected melanoma (Long GV, et al. Lancet Oncol. 2022;23:1378-88; Eggermont AMM, et al. Lancet Oncol. 2021;22:643-54). Combining pembrolizumab with other therapies may further improve outcomes in this setting. Vibostolimab is an anti-TIGIT monoclonal antibody that showed antitumor activity and manageable safety when used in combination with pembrolizumab in patients with advanced solid tumors in the phase 1 KEYVIBE-001 study (Niu J, et al. Ann Oncol. 2022;33:169-80). The randomized, double-blind, phase 3 KEYVIBE-010 study (NCT05665595) is designed to evaluate the efficacy and safety of adjuvant coformulated vibostolimab and pembrolizumab (MK-7684A) versus pembrolizumab alone in patients with resected high-risk stage IIB-IV melanoma. Methods: Eligible patients are ≥12 years of age (weighing ≥40 kg if < 18 years), with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th edition guidelines, and an Eastern Cooperative Oncology Group performance status of 0 or 1 (Lansky play-performance scale ≥70 if < 16 years; Karnofsky performance status ≥70 if ≥16 to < 18 years). Patients must not have received any prior systemic therapy beyond complete resection and no more than 12 weeks can have elapsed between final surgical resection and randomization. Patients with ocular, mucosal, or conjunctival melanoma, and prior allogeneic tissue/solid organ transplant are excluded. Patients will be stratified by risk. Approximately 1560 patients will be randomly assigned 1:1 to receive intravenous coformulated vibostolimab 200 mg with pembrolizumab 200 mg or pembrolizumab 200 mg (2 mg/kg up to a maximum of 200 mg for adolescents) every 3 weeks. Treatment will continue for 17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. The primary end point is recurrence-free survival by investigator review. Secondary end points are distant metastasis-free survival by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% confidence intervals will be estimated using a stratified Cox regression model with the Efron method of handling ties, with treatment as a covariate. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05665595 .
NADOM trial: Neoadjuvant/adjuvant trial of darovasertib in ocular melanoma (OM).
Authors: O'day Roderick , Conway Max , Lim Li-Anne , McKenzie John , Atkinson Victoria , Glasson William , McGrath Lindsay , Cherepanoff Svetlana , Gray Elin , Maurer Matthew A. , O'Quigley Michael , Shackleton Mark J. , Joshua Anthony M.
Published: June 2023

TPS9612

Background: Darovasertib (Daro) is a novel inhibitor of PKC, that has pre-clinical activity in GNAQ/GNA11 tumours including ocular melanoma. A recently completed clinical trial of Daro monotherapy in metastatic OM with a response rate of 11%, and DCR of 78% with only mild manageable toxicity, suggesting utility in localized disease and in the adjuvant setting. Methods: NADOM is an investigator-initiated window-of-opportunity phase 2 clinical trial open in 3 centers across Australia. Eligible patients include patients planned for enucleation, ECOG 0-1 with adequate organ function. The primary objective is the feasibility and safety of neoadjuvant Daro in a pilot cohort of 12 patients. Secondary objectives include the effect of Daro on circulating biomarkers (including CTCs and ctDNA), imaging assessments (MRI, FDG-PET and ocular ultrasound), pharmacokinetic and pharmacodynamic correlates and radiographic PFS in the adjuvant setting. Treatment comprises a neo-adjuvant period of treatment of up to 6 months at ophthalmologist discretion with Daro (300mg bid) before definitive management. Patients who demonstrated radiological, biomarker or clinical response are then offered an adjuvant period of treatment for up to 6 months following integrated consensus at multi-disciplinary ocular oncology meetings. DSMB meetings are scheduled to ensure clinical and peri-operative safety regularly. Enrolment commenced in November 2022 and accrual is ongoing in the 6 month neo-adjuvant cohort. Results: To date, an initial safety cohort of 1 month of neo-adjuvant treatment has been cleared following DSMB review. Conclusions: Recruitment is ongoing and expected to complete in late 2023. Clinical trial information: NCT05187884 .
CemiplimAb-rwlc survivorship and epidemiology (CASE): A prospective study of safety and efficacy of cemiplimab in patients with advanced basal cell carcinoma in a real-world setting.
Authors: Park Soo J , Ellison David , Weight Ryan Michael , Homsi Jade , Rabinowits Guilherme , Ruiz Emily S. , Strasswimmer John , Simmons Josh David , Panella Timothy J. , Quek Ruben GW , Ursino Gregory , Pouliot Jean-Francois , Khushalani Nikhil I.
Published: June 2023

TPS9614

Background: Basal cell carcinoma (BCC) is the most common form of non-melanoma skin cancer in the United States. Surgical excision is the standard treatment, with < 1% of cases progressing to locally advanced or metastatic disease. Hedgehog pathway inhibitors (HHIs) are the first-line therapy for advanced BCC (aBCC); the US Food and Drug Administration and European Medicines Agency have approved the use of cemiplimab (a programmed cell death-1 inhibitor) in advanced BCC (aBCC) patients previously treated with (or are inappropriate for) HHI. Limited real-world data exist on the clinical characteristics, disease management and progression, and survivorship of patients with aBCC. The ongoing C.A.S.E. study aims to evaluate the efficacy, safety, disease evolution, survivorship, and patient reported outcomes (PRO) in patients treated with cemiplimab in the real-world setting. Methods: This trial in progress (NCT03836105) aims to describe the effectiveness and safety of cemiplimab 350 mg administered every 3 weeks for treatment of patients with aBCC in real-world clinical settings. Up to 100 adult patients with aBCC who are prescribed commercially available cemiplimab from ~65 study sites in the United States will be included. The duration of follow-up will be 24 months. Endpoints for this study relate to real-world efficacy, including overall survival; progression-free survival; objective response rate, (partial or complete response); and disease control rate, defined as the percentage who do not progress for ≥ 6 months; Time to response, duration of response, time to treatment failure, and disease-specific death will also be assessed. Real-world safety outcomes will also be captured, including immune-related adverse events, infusion-related reactions, and serious adverse events. Patient selection criteria and treatment patterns will be analyzed using descriptive statistics. This study also aims to describe the patient experience of real-world treatment with cemiplimab. PROs including global quality of life, functioning, and symptoms will be captured at baseline and follow-up visits via the EORTC QLQ-C30 and the Skin Care Index. Recruitment for this trial is ongoing. Clinical trial information: NCT03836105 .