PO QD Research Articles

Abstract B003: Advancing biomarker discovery using a novel window of opportunity (WOO) trial for pancreatic ductal adenocarcinoma: Trial updates

Abstract Background: There are a growing number of targeted agents that have the potential to greatly improve the clinical outcomes of patients with PDAC beyond current standard of care chemotherapy. However, there is a lack in our understanding of which patients and intrinsic PDAC tumor types will best respond to a given targeted agent(s). In order to optimizing their clinical utility, it is crucial that we a deep understanding of the biological impact that these targeted agents (alone or combination) have within the human system. As such, we designed and implemented the WOO trial to provide a highly adaptable discovery platform for the preliminary assessment of biological activity of one or more targeted agents in patients with PDAC. Utilizing paired, pre- and on-treatment biopsies, along with a robust multiomics pipeline, the WOO trial enables independent assessment of the biological impact of targeted agent(s) on key signaling pathways that can be used to explore novel therapeutic strategies. Methods: WOO is a multi-arm early phase I trial platform designed to assess the pharmacodynamic (PD) effects of one or more study agent(s) alone or in combination in patients with PDAC. A Master Protocol is used to describe overarching design and logistics, and sub-protocols separately describe each study arm comprising the different investigational agent(s). Each participants undergoes a baseline tumor biopsy, then receives their assigned study agent(s) for a specified timeframe (not exceeding 30 days), before undergoing a repeated tumor biopsy, after which they continue to receive therapy per standard of care or clinical trials. Spatially-resolved, single cell multiplex assays are used to compare the effects of the study agent(s) on tumor cell state and heterogeneity between the paired samples. The primary study objective is to independently assess the PD feasibility of detecting a measurable change in tumor biology at post-treatment from baseline for participants within a study arm. The WOO trial uses a 2-stage Bayesian efficacy monitoring approach with a futility-stopping rule for each study arm. In stage 1 of each study arm, if 6 or more of the first 10 participants have a detectable change in tumor biology measurements (i.e., pre vs. post-treatment), then the study arm may continue to enroll an additional 10 participants. To date, 4 study arms are being evaluated: 1) poly (ADP-ribose) polymerase inhibitor (PARPi), olaparib (300 mg PO BID for 10 days), 2) MEK inhibitor (MEKi), cobimetinib (60 mg PO QD for 10 days), 3) ERK inhibitor, LY3214996 (400 mg PO QD for 10 days), and 4) PLK1 inhibitor, onvansertib (12 mg/m2 PO QD for 10 days). To date, a total of 34 participants have been enrolled and treated: n = 14 cobimetinib, n= 15 olaparib, n=2 onvansertib. Future arms to be added. Trial ID: NCT04005690. Citation Format: Charles D. Lopez, Adel Kardosh, Emerson Chen, Guillame Pegna, Alexander Guimaraes, Bryan Foster, Brian Brinkerhoff, Shaun M. Goodyear, Erin Taber, Brindha Rajagopalan, Johnson Vo, Kiara Siex, Brett Johnson, Danielle Galipeau, Dove Keith, Brett Sheppard, Brody Jonathan, Rosalie Sears, Gordon Mills. Advancing biomarker discovery using a novel window of opportunity (WOO) trial for pancreatic ductal adenocarcinoma: Trial updates [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 B003.

Abstract LB_C06: Utilizing a novel HDAC inhibitor bocodepsin (OKI-179) to overcome doxorubicin resistance in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic treatment options and a high rate of metastatic recurrence. TNBC is defined by lack of estrogen and progesterone receptor expression with non-amplified HER2, and accounts for 10-15% of all breast cancer cases. While pembrolizumab, sacituzumab govitecan and PARP inhibitors are beneficial for a subset of TNBC patients, chemotherapy including doxorubicin continues to be the primary treatment. Bocodepsin is a novel, orally bioavailable clinical stage Class 1-targeting HDAC inhibitor with activity in preclinical models of TNBC. The purpose of this study was to investigate OKI-005 (in vitro) and bocodepsin (in vivo) in combination with doxorubicin (DOX) to overcome resistance. Procedures: TNBC cell lines were exposed to a no drug, DOX, OKI-005 or combination for 72 hours and cell viability was assessed via CellTiter-Glo. Synergy scores were calculated from three independent replicates using Synergy Finder+. Apoptosis was assessed following 48 hours of drug exposure by flow cytometry. Immunoblots were performed following 24 hours of drug treatment to evaluate mechanism of action. In vitro senescence-associated beta-galactosidase was performed after 6 days drug treatment. For in vivo studies, 5 million MDA-MB-231 cells were injected subcutaneously in athymic nude mice. Mice were treated with either no drug, 1.5 mg/kg DOX IP QW, 80 mg/kg bocodepsin PO QD, or the combination. Results: Bliss scores calculated from Synergy Finder+ using the CellTiter-Glo data showed synergy for the combination of OKI-005 and DOX in all TNBC cell lines. The combination resulted in statistically significant increased apoptosis measured by Annexin V compared to single agent drug treatment in CAL-51, MDA-MB-231 and CAL-120 cell lines. Immunoblot analysis demonstrated an increase in the pro-apoptotic protein BIM and decrease in anti-apoptotic protein BCL-XL with the combination. The cyclin dependent kinase inhibitor p21 was increased by OKI-005 independently of p53 and doxorubicin for the cell lines MDA-MB-231, Hs 578T, and CAL-120. The combination resulted in increased cleaved caspase-3 for all cell lines evaluated. Senescence-associated beta-galactosidase showed an increase in senescent cells for both DOX and OKI-005, which was eradicated in combination. DOX and bocodepsin were further tested in vivo, where significant tumor growth inhibition was observed in combination compared to DOX (p=0.0016) and bocodepsin (p=0.0068). Conclusion: The addition of OKI-005 or bocodepsin to doxorubicin resulted in improved anti-proliferative and anti-cancer activity with evidence of increased apoptosis and decreased senescence. As a result, bocodepsin is a promising combination partner for doxorubicin to overcome doxorubicin resistance and promote apoptosis in TNBC. Bocodepsin has a favorable toxicity profile compared to other HDAC inhibitors and this work supports the potential clinical investigation of doxorubicin and bocodepsin in patients with metastatic TNBC. Citation Format: Stephen G Smoots, Anna R Schreiber, Marilyn M Jackson, Evan D Dus, Stacey M Bagby, Adrian T A. Dominguez, Cameron A Binns, Jennifer R Diamond, Todd M Pitts. Utilizing a novel HDAC inhibitor bocodepsin (OKI-179) to overcome doxorubicin resistance in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C06.

Abstract LB_C07: Utilizing a BCL-2 inhibitor (venetoclax) to overcome doxorubicin resistance in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of the progesterone receptor, estrogen receptor, and human epidermal growth factor-2 over-expression. TNBC comprises 10-15% of all breast cancer cases and compared to other subtypes of breast cancer, TNBC is associated with a higher risk for metastatic recurrence and the chemotherapy agent doxorubicin (dox) remains a mainstay of treatment. Senescence is a cellular phenomenon where cells are committed to an arrested state, however, senescent cells can secrete pro-tumorigenic factors which can help to promote tumor progression and invasion. Senescence is one potential mechanism of resistance to doxorubicin in breast cancer. Avoiding senescence-mediated resistance and promoting apoptosis is one strategy to improve response to dox in TNBC. Venetoclax is an orally bioavailable FDA approved BCL-2 inhibitor with activity in preclinical models of TNBC. The purpose of this study was to investigate venetoclax in combination with dox to overcome senescence-mediated resistance and induce apoptosis. Experimental Procedures: TNBC cell lines were exposed to a no drug, dox, venetoclax or combination at increasing doses for 72 hours and cell viability was assessed via CellTiter-Glo. Synergy scores were calculated from three independent replicates using Synergy Finder+. Apoptosis at 48 hours was analyzed by flow cytometry using Annexin V on cells treated in combination and with single agents. In vitro cell survival following drug treatment for 24 hours was assessed via clonogenic assay. In vitro senescence-associated β-gal was performed after 6 days drug treatment. Athymic nude mice were subcutaneously injected with 5 million MDA-MB-231 cells for in vivo studies. Mice were treated with either no drug, 60 mg/kg venetoclax PO QD, 1.5 mg/kg dox IP QW, or the combination. Results: The combination of venetoclax and dox resulted in synergy based on CellTiter-Glo data, which was used to calculate Bliss scores using Synergy Finder+ in CAL-51, MDA-MB-231, and CAL-120 TNBC cell lines. The dox and venetoclax combination caused a statistically significant increase in apoptosis measured by Annexin V staining when compared to single agents and control in all cell lines. The combination resulted in a decrease in cellular survival in all cell lines tested as measured by the clonogenic assay. Senescence-associated beta-galactosidase showed an increase in senescent cells for both dox and venetoclax treated cells, which was eradicated in combination. Dox and venetoclax were further tested in vivo, where significant tumor growth inhibition was observed in combination compared to doxorubicin (p = 0.0031) and venetoclax alone (p = 0.0038) after 48 days of treatment. Conclusion: The addition of venetoclax to doxorubicin resulted in decreased cellular proliferation, increased apoptosis, and decreased senescence. As a result, venetoclax is a promising combination partner for doxorubicin to overcome doxorubicin resistance and promote apoptosis in TNBC. Citation Format: Evan D Dus, Stephen G Smoots, Anna R Schreiber, Marilyn M Jackson, Stacey M Bagby, Adrian T A Dominguez, Cameron A Binns, Todd M Pitts, Jennifer R Diamond. Utilizing a BCL-2 inhibitor (venetoclax) to overcome doxorubicin resistance in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C07.

A Dual-Specific Inhibitor of Rock/Aurk, RR-1752, for Primary Myelofibrosis

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized by driver mutations in JAK2, CALR, and MPL resulting in constitutive activation of JAK-STAT signaling. Abnormalities in megakaryocyte (MK) numbers and morphology are a common feature of MF where abnormal MKs are associated with bone marrow fibrosis and pro-inflammatory cytokine release. Therapies that target constitutive JAK-STAT signaling and atypical megakaryocytes could provide clinical benefit for patients with MF. ROCK and Aurora kinase (AURK) are overexpressed in MPN and linked to dysregulated MKs of patients with MPN. We therefore tested the activity of RR-1752, a dual-specific inhibitor of ROCK and AURK, in preclinical models of MF. RR-1752 acted as an inhibitor of pSTAT3 in IL-2 stimulated human PBMC 1h post stimulation and significantly inhibited phosphorylated myosin light chain 2 (pMLC2) in two human MPN cell lines, HEL-92.1.7 and UKE-1, confirming an on-target action. RR-1752 inhibited colony formation by HEL-92.1.7 and UKE-1, (IC 50 = 25.2 nM and 54.6 nM respectively). RR-1752 also induced cell cycle arrest in HEL-92.1.7 and UKE-1 specifically at the G2/M checkpoint. RR-1752 was also tested in a hematopoietic colony formation assays of MF patient derived CD34 + cells. RR-1752 led to concentration specific inhibition of MF patient derived CD34 + cell colony formation between 100-190 nM demonstrating relevant activity against patient-derived MF samples (51% inhibition at 190 nM as compared to vehicle control). These data were in line with flow cytometrically determined cell viability data of MF CD34 + cells cultured in the presence of varying concentrations of RR-1752 in liquid culture. The in vivo activity of RR-1752, was examined using the human HEL- 92.1.7 cell line, homozygous for both JAK2 V617F and p53 M133K in a mouse xenograft model. The effects of RR-1752 alone and in combination with ruxolitinib were compared to single agent ruxolitinib. The administration of RR-1752, 25 mg/kg PO daily resulted in a significant (p<0.01) improvement in median survival (31 days) compared to ruxolitinib alone, 45 mg/kg PO daily (21 days). RR-1752 5.0 mg/kg PO QD plus ruxolitinib 45 mg/kg PO QD also resulted in a significant improvement in survival (p<0.05) compared to single agent ruxolitinib but was inferior to single agent RR-1752 at 25mg/kg. The demonstrated activity in MF patient derived CD34 + cells combined with the significant improvement in survival compared to the approved drug ruxolitinib in an aggressive, JAK2/p53 mutant MF xenograft model provides a compelling case for its evaluation as a therapeutic modality in MF patients. Dose optimization of RR-1752 alone and in combination with ruxolitinib in the HEL-92.1.7 IV dissemination model as well as testing in the hMPL-W515L-evoked myelofibrosis model is ongoing. Conventional treatments for MF have largely focused on symptom management but RR-1752 treatment could result not only in beneficial symptom improvement but also important disease modifying potential by inhibiting JAK-STAT signaling, cell cycle progression and targeting dysregulated MKs.

Bellwave-010: Phase 3, Open-Label, Randomized Study of Nemtabrutinib Plus Venetoclax Versus Venetoclax Plus Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least One Prior Therapy

Background: Venetoclax + rituximab (VR) is a standard therapy among patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have relapsed after at least 1 line of prior therapy. However, there is an unmet need for more effective treatments. Bruton's tyrosine kinase (BTK) is a critical signaling molecule in the pathogenesis of CLL, and inhibitors of BTK have resulted in significant improvements in survival for patients with CLL. Nemtabrutinib is a noncovalent, reversible, competitive inhibitor of BTK that does not require the C481 residue of BTK for binding and inhibition of kinase activity. As a result, nemtabrutinib can target both wild-type and C481-mutant forms of BTK. Results from the ongoing BELLWAVE-001 study have demonstrated manageable safety and durable antitumor activity of nemtabrutinib in patients with CLL/SLL with and without C481 mutations. The randomized, active-controlled, open-label, phase 3 BELLWAVE-010 study (NCT05947851) is designed to investigate the efficacy and safety of nemtabrutinib + venetoclax versus VR as second-line (2L) or later treatment for patients with relapsed/refractory (R/R) CLL/SLL. Study Design and Methods: Patients aged ≥18 years with active CLL/SLL that is relapsed/refractory to at least 1 prior therapy per the iwCLL 2018 criteria, an ECOG performance status of 0-2, and adequate organ function are eligible. Patients with Richter transformation, active central nervous system involvement, or severe bleeding disorder are excluded. Approximately 720 patients will be enrolled in 2 parts: an open-label, nonrandomized dose escalation and confirmation phase (part 1) to evaluate safety and determine the optimal dose of nemtabrutinib in combination with venetoclax and an open-label, parallel-group, randomized phase (part 2) comparing the efficacy and safety of nemtabrutinib + venetoclax with VR. In part 1, 30 patients will be enrolled to establish the dose of nemtabrutinib using a modified toxicity probability interval design. Patients will receive nemtabrutinib at 2 dose levels (45 mg PO QD starting dose, escalating to 65 mg PO QD) for 28 days followed by the combination of nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks). In part 2, approximately 690 patients will be randomly assigned 1:1 to receive either nemtabrutinib at the recommended dose for 28 days followed by the combination of nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks) or venetoclax (20-400 mg PO QD ramp up over 4 weeks) + rituximab (or rituximab biosimilar; 375 mg/m 2 at week 6 followed by 500 mg/m 2 Q4W starting at week 10 until week 26 [total 6 doses]). Patients will receive study treatment for ~2 years or until unacceptable toxicity, disease progression, or other discontinuation criteria are met. Randomization will be stratified by BTK-C481 mutation status (detected vs not detected; determined by droplet digital PCR with a limit of detection of approximately 0.01%-0.1%), geographic region (US/Canada vs Europe vs rest of world) and risk (high risk [del(17p) and/or TP53-mutated and/or IGHV-unmutated] vs low risk [absence of high-risk factors]). Response will be assessed (including imaging, physical examination, constitutional symptoms, hematological evaluations, and bone marrow biopsy as required) every 12 weeks up to week 97 and every 24 weeks thereafter or more frequently if clinically indicated. Adverse events will be monitored up to 30 days after treatment cessation (90 days for serious adverse events) and will be graded per NCI CTCAE, version 5.0. Hematologic toxicities will be evaluated according to iwCLL 2018 criteria. Patient-reported outcomes will be assessed using the EORTC QLQ-C30, EORTC QLQ-CLL17, and EQ-5D-5L questionnaires. The primary end points for part 1 are safety and tolerability, including dose-limiting toxicities, and to establish the recommended dose of nemtabrutinib in combination with venetoclax. The primary end point for part 2 is PFS as assessed per iwCLL 2018 criteria by blinded independent central review (BICR). Secondary end points for part 2 include undetectable minimal residual disease in bone marrow at month 14 as assessed by central laboratory, ORR, and DOR per iwCLL 2018 criteria by BICR, OS, and safety. Exploratory end points include ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life.

A Phase I Study of Venetoclax Combined with Homoharringtonine, Cytarabine, and G-CSF for the Treatment of Pediatric De Novo Acute Myeloid Leukemia

Introduction: B-cell lymphoma factor 2 (BCL-2) family, as an important factor regulating apoptosis, is abnormally expressed in most hematological malignancies. Clinical trials of venetoclax(VEN) combined with conventional chemotherapy for pediatric AML are ongoing. Previous research has shown that the combination of HHT and VEN can synergistically promote cell apoptosis. Therefore, a phase I study utilizing HAG combined with VEN, in patients with de novo AML pediatric was undertaken to evaluate the safety and feasibility. Methods: This ongoing single center Phase I trial combining 11 days of VEN, 10 days of Ara-c plus G-CSF with increasing doses of HHT, namely HAGV. VEN was given as a ramp-up over 1 day, followed by a fixed dose of 240 mg/m 2 PO QD over a total period of 10 days, Ara-c 10 mg/m 2/q12h IVGTT fixed dose over 10 days and G-CSF 5ug/kg IH fixed dose over 10 days. Three dose levels of HHT, 1mg/m 2(dose level 1 group), 2/m 2(dose level 1 group) and 3mg/m 2(dose level 3 group) daily were studied in a 3 × 3 dose-escalation design to define maximum tolerated dose (MTD). The primary objective was to determine safety and tolerability. Adverse events (AE) and dose-limited toxicities (DLT) were monitored throughout treatment. The secondary objective was to evaluate preliminary efficacy. The trial is registered under ChiCTR2200064901. Results: Between October 2022 and June 2023, 14 patients [50% female, median age 100 months (range 39-153)] were enrolled in the dose level 1(n=3)、dose level 2(n=5) and dose level3(n=6) portions of the study (Figure 1). Four (28.6%) had normal cytogenetics. The most common fusion gene was RUNX1::RUNX1T1(n=5, 35.7%), followed by MLL-r (n=2, 14.3%, 1 case with MLL-AF6 and 1 case with MLL-AF10), CBFβ-MYH11(n=1, 7.1%) and NUP98-NSD1(n=1, 7.1%). The most common mutations identified were NRAS (n=4, 28.6%), CEBPA-dm (n=3, 21.5%), KIT (n=3, 21.5%), CEBPA-sm (n=2, 14.3%) and KRAS (n=2, 14.3%). All patients completed one cycle of HAGV as Induction I. One patient in dose level 1 group achieved NR after Induction I and then withdraw from the trail. Eventually, total 13 patients received two cycles of HAGV as Induction II. No DLTs were observed. There were no deaths in the first 30 days from treatment initiation. During Induction I, the most common non-hematological toxicity regardless of grade and attribution included febrile neutropenia(n=13, 92.9%), nausea or vomiting (n=7, 50.0%), lung infection(n=6, 42.9%), ECG T-wave changes (n=4, 28.6%) and sinus tachycardic (n=3, 21.4%) (Table 1). All the 14 patients experienced at least one grade 3 AE, with thrombocytopenia (n=14, 100%), neutropenia (n=14, 100%), and febrile neutropenia (n=13, 92.9%) most common. The median time of neutropenia and platelet recovery time were 22 days(range 14-38）and 16 days(range 10-28) in Induction I, respectively. During Induction II, 4 of the 13 patients are still in the recovery period and has not reached the evaluation point. Among the remaining 9 patients, the most common non-hematological toxicity included febrile neutropenia(n=7, 77.8%), nausea or vomiting (n=4, 44.4%), ECG T-wave changes (n=3, 33.3%), sinus tachycardic (n=3, 33.3%) and lung infection(n=2, 22.2%). The median time of neutropenia and platelet recovery time were 18 days(range 7-34）and 15 days(range 0-29) in Induction II, respectively. Serious AEs of grade 4-5 were not observed during Induction therapies. Remission assessment showed CR in 11/14(78.6%) patients after Induction I and 8/9(88.9%) patients after Induction II. Conclusions: We have determined that the combination of VEN plus HAG is safety and HHT at doses of 1, 2 and 3mg/m 2 was well tolerated. No DLTs were observed, and the most common Grade 3 non-hematological toxicity were febrile neutropenia.

Preliminary Results of a Phase Ⅱ Study of Lenalidomide Combined with Immunochemotherapy in Patients with Primary Central Nervous System Lymphoma

Conclusion Introduction：PCNSL is a diffuse large B cell lymphoma (DLBCL) occurring exclusively in the brain, spinal cord, cranial nerves, leptomeninges and/or eyes. Pathophysiology is incompletely understood, although a central role seems to comprise immunoglobulins binding to self-proteins expressed in the central nervous system (CNS) and alterations of genes involved in B cell receptor, Toll-like receptor and NF-κB signalling. Standard of care includes methotrexate-based polychemotherapy followed by age-tailored thiotepa-based conditioned autologous stem cell transplantation, whole-brain radiotherapy or singledrug maintenance。Lenalidomide, an immunomodulatory agent that penetrates the CNS, has shown promise in relapsed/refractory (R/R) aggressive NHL, with well-demonstrated singleagent activity and tolerability. We hypothesized that lenalidomide combined with immunochemotherapy(MTX-based regimen)might be a favorable option for PCNSL pts. Here, we present preliminary data from the phase 2 trial of lenalidomide combined with immunochemotherapy in PCNSL pts (NCT04737889). To investigate the efficacy of lenalidomide combined with immunochemotherapy in untreated PCNSL.The primary objective is 2-year progression free survival(PFS). The secondary objectives are objective response rate (ORR), incidence of grade 3/4 adverse event (AE), and overall survival (OS). aged 18-75 years untreated PCNSL and adequate organ function are being enrolled.Lenalidomide(25mg qd po,totally 10 days/cycle) plus R-MT(Rituximab-Methotrexate+Temozolomide) was administered in TN PCNSL. A totally of 6 cycles of treatment was planned for pts. Completed responders(CR) undergo autologous stem cell transplantation (ASCT) 、reduced dose whole brain radiotherapy or lenalidomide maintenance for 24 months, based on the patient's fitness and preference. RESULTS：From March 2019 to 18 April 2023, 24 pts have been enrolled . Their baseline characteristics are displayed in Table 1. By 30 May 2025, all pts had been evaluated for response. There were 19 CRs (79.2%), 3 PRs (12.5%) and 2 PDs(8.3%) . The median follow-up time was10 (1.2 - 51.4) months . One pt withdrew informed consent due to grade 3 renal toxicity , One died from non-tumor-related disease. Two year progression-free survival (PFS) and overall survival was 62% and 67%，respectively,the median PFS and OS not achieved. The most common adverse events were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% pts were neutropenia, leukopenia .Grade 3/4 non-hematologic AEs occurred in ≥20% pts was hepatic injury. Lenalidomide combined with immunochemotherapy showed encouraging activity and acceptable tolerance in pts with TN PCNSL.The study is still ongoing and it is worth looking forward to updating the long-term survival data.

REM-422, a Potent, Selective, Oral Small Molecule mRNA Degrader of the MYB Oncogene, Demonstrates Anti-Tumor Activity in Mouse Xenograft Models of AML

The c-MYB (MYB) oncogenic transcription factor is a key regulator of hematopoietic cell differentiation and proliferation. Recurrent genetic lesions or dysregulation of MYB have been identified in a variety of cancers, including adenoid cystic carcinoma (ACC), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), pediatric low-grade glioma (pLGG), and others. AML is characterized by multiple oncogenic abnormalities and high MYB mRNA expression. Evidence from in vitro and in vivo animal studies suggests that MYB may be a key downstream effector of these oncogenic abnormalities through the direct regulation of genes such as BCL2, MYC and FLT3. Functional genomics studies reveal MYB dependencies in human leukemia cell lines and mouse models of leukemia. Together, these data suggest that MYB is an attractive therapeutic target for AML and other hematological malignancies. Therapeutic agents that directly target MYB have yet to be developed, presumably due to the challenges of targeting this intrinsically disordered transcription factor, which lacks tractable ligand binding pockets. Here, we describe the mechanism of action and biological activity of REM-422, a potent, selective, oral small molecule messenger RNA (mRNA) degrader of MYB. REM-422 was identified through screening and medicinal chemistry efforts directed towards identifying small molecules that induce the inclusion of a normally unused ‘poison exon’ (PE), which contains a premature termination codon, into the MYB pre-mRNA transcript. Poison exon inclusion activates the nonsense-mediated decay pathway and promotes the degradation of MYB mRNA. We demonstrate in a cell-free assay that REM-422 acts by selectively facilitating the binding of the U1 snRNP spliceosome complex, which governs exon usage by recognizing 5‘ splice sites, to oligonucleotides containing the MYB PE 5‘ splice site sequence. REM-422 treatment of human leukemia cell lines promotes poison exon inclusion, leading to degradation of MYB mRNA and subsequent reduction in MYB protein levels (Figure 1A). In a panel of AML cell lines, REM-422 demonstrated preferential anti-proliferative activity in cell lines with high MYB expression, and in those shown to be MYB-dependent through functional genomics studies. To understand the pharmacokinetic (PK) and pharmacodynamic (PD) effects of MYB in vivo, Kasumi-1 AML cells were implanted subcutaneously in CB17 scid immunocompromised mice and REM-422 was dosed by oral gavage after the formation of established tumors. QD PO administration of REM-422 demonstrated dose-dependent effects in tumors on MYB mRNA levels, with induction of the MYB poison exon leading to reductions of MYB functional mRNA. In a 21-day study, REM-422 demonstrated significant anti-tumor activity, including tumor regressions at well tolerated dose levels (Figure 1 left). To further investigate the activity of REM-422, AML patient cells were injected into NOG immunocompromised mice and allowed to engraft. After successful engraftment, mice were dosed by oral gavage once daily with REM-422 at 10 mg/kg or vehicle for 24 days. Flow cytometry analysis of bone marrow and peripheral blood samples demonstrated that REM-422 led to the eradication of human leukemia cells from both compartments (Figure 1 right). Together, these data demonstrate that REM-422 treatment leads to degradation of MYB mRNA in preclinical models of AML and supports the therapeutic potential for REM-422 in AML patients.

Immune Profiling and Responses of Smoldering Multiple Myeloma Patients Treated in a Phase Ib Study of Pvx-410 Vaccine Targeting XBP1/CD138/CS1 Antigens, and Citarinostat, a Histone Deacetylase Inhibitor (HDACi) with and without Lenalidomide

BACKGROUND AND SIGNIFICANCE Immunoparesis plays an important role in the progression of smoldering multiple myeloma (SMM). Therapies that augment the immune response may prevent or slow the progression to symptomatic multiple myeloma. We have previously shown that PVX-410, a multi-peptide cancer vaccine (OncoPep., Inc.) targeting XBP1/CD138/CS1, is immunogenic in SMM, as a single therapy and in combination with lenalidomide. Here, we investigated whether co-administration of PVX-410 with an oral HDAC inhibitor, citarinostat, +/- lenalidomide enhances vaccine specific immune response in patients with SMM. STUDY DESIGN AND METHODS This 2-cohort phase 1b multicenter study accrued 16 adults (≥18 years) with HLA-A2 + SMM and high risk of progression to active MM. Patients received citarinostat in combination with PVX-410 (double combination cohort) and with PVX-410 and lenalidomide (triple combination cohort). PVX-410 was given as six doses of 0.8 mg biweekly (weeks 0, 2, 4, 6, 8, and 10) via subcutaneous injection followed by a single dose of PVX-410 during follow-up visits at month 1, 2, 3, 6, and 9; 3 cycles of citarinostat (180 mg QD PO for 21 days every 28 days) and lenalidomide (25 mg on Days 1-21 every 28 days) were given to patients in the double and triple combination cohorts respectively in conjunction with the initial 6 doses of PVX-410. Patients were followed post-treatment for 12 months. Peripheral blood (PB) and bone marrow (BM) samples at baseline and month one after treatment were analyzed by single-cell RNA sequencing. T-cell receptor and B-cell receptor sequencing were also performed to investigate T cell and B-cell clonal expansion before and after treatment. Flow cytometric analyses of anti-MM functionality of the XBP1/CD138/CS1-specific CD8 + cytotoxic T lymphocytes (CTL) was performed at various timepoints from baseline up to 12-month post-treatment. The development of antigen-specific memory CD8 + CTL through upregulation of 41BB and production of Th1-type of cytokines (IFN-g, IL-2, TNF-a) were evaluated by flow cytometry. Deep whole genome sequencing was performed on subsets of CD138 + cells from BM isolates to corroborate our findings. RESULTS We screened 16 SMM patients; 15 (94%) received treatment (7 with the double and 8 with the triple combination). By the end of the 12-month post-treatment follow-up period no patients progressed to symptomatic myeloma in the double combination cohort; one patient in the triple combination cohort withdrew by month 3 for disease progression. Most patients receiving the double combination had stable disease (SD) as their best clinical response (n=5), one had partial response (PR) and one minimal response (MR). Triple combination therapy resulted in better clinical response including PR (n=2), MR (n=4) and SD (n=2). Single-cell transcriptomic analyses of 21 PB samples from 13 patients and 15 BM samples from 11 patients at baseline and month one after treatment is in progress. Immune monitoring studies on 125 samples from 15 different patients at various timepoints from baseline up to 12-month post-treatment are ongoing. Fourteen patients (100%) had at least one treatment-related adverse event (trAEs), mostly grade 1-2 in severity. The most common trAEs among patients receiving double vs triple combination were fatigue (71% vs 63%), injection site reactions (43% vs 50%), neutropenia (57% vs 38%), anemia (29% vs 38%), and diarrhea (0% vs 50%). There was one grade 3 trAE: specifically, a thromboembolic event in one patient who was receiving lenalidomide and despite aspirin prophylaxis, but who fully recovered. DISCUSSION The combination of PVX-410 with citarinostat, with and without lenalidomide is generally safe in this patient population. The objective clinical response was relatively modest given the short duration of therapy: longer follow up is needed to assess the impact on progression to active myeloma. PB and marrow transcriptome profiling along with the immunogenicity studies are in progress and will be presented. We will evaluate whether PB mononuclear cells have the potential to replace BM as a surrogate for genetic and immunological surveillance in SMM, as we anticipate that further understanding of the immune alterations among patients with SMM and the response to immunomodulatory therapy may provide insight on early intervention and prevention of progression to symptomatic disease.

Methotrexate in Combination with Orelabrutinib, Thiotepa, and Rituximab (R-MTO) Followed By Autologous Stem-Cell Transplant for Primary Central Nervous System Lymphoma Treatment

Background: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive B-cell malignancy. Despite the possibility of a cure, the prognosis remains poor. The standard treatment includes high-dose methotrexate and rituximab, followed by consolidation with either whole-brain radiation therapy or autologous stem cell transplantation (ASCT). However, there is still no clear consensus on the best treatment approach. To improve outcomes, we incorporated thiotepa chemotherapy, which has shown promising activity in inhibiting tumor growth by disrupting DNA bonds, into the regimen. Additionally, we introduced orelabrutinib, a novel and potent BTK inhibitor with high cerebrospinal fluid concentrations, which has demonstrated efficacy in treating PCNSL. In light of these findings, we conducted a clinical study to evaluate the efficacy and safety of a combination regimen of thiotepa, orelabrutinib, and methotrexate with rituximab (R-MTO) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with PCNSL. Methods: This is an ongoing, single-center, single-arm, open-label study conducted between April 2022 and July 2023. The study enrolled patients aged 18-80 years diagnosed with PCNSL. The patients received 5-8 cycles of R-MTO regimen as induction therapy, consisting of rituximab 375 mg/m 2 iv on day 0, MTX 3.5 g/m 2 iv on day1, thiotepa, 30-40 mg/m 2 on day 4 and orelabrutinib 150 mg qd po for 3 weeks per cycle). After completing the R-MTO therapy, patients were proposed to receive orelabrutinib monotherapy as maintenance treatment for up to 2 years. The efficacy was assessed by MRI/PET per the International PCNSL Collaborative Group (IPCG) criteria. Patients who did not experience disease progression subsequently underwent consolidation treatment with high-dose chemotherapy (HCT) plus ASCT. The HCT regimen involved busulfan 3.2 mg/kg on days -5, -4, thiotepa 250 mg/m 2 on days -7 and -6, cytarabine 2g/m 2 q12h on days -3 and -2, followed by reinfusion of stem cells on day 0. The primary endpoint of the study was progression-free survival (PFS) at 2 years, evaluated by intention-to-treat (ITT). Secondary endpoints included complete response (CR) rate, overall response rate (ORR), overall survival (OS) and toxicities. Results: Between April 2022 and July 2023, a total of 19 patients with PCNSL were enrolled in our study, including 16 who were newly diagnosed and had not received any prior treatment. The median age of the patients was 62 years, ranging from 31 to 72, with 9 out of 19 (47.37%) being male. By the data cutoff, all the patients had completed 4 cycles of treatment. Additionally, 8 out of 19 (42.11%) patients had completed six cycles of treatment, and 2 out of 19 (10.52%) patients had completed 7 to 8 cycles of treatment. The ORR was 94.73% (18/19), and the CR rate was 89.47% (17/19) after 4 cycles of treatment. However, one patient with a P53 mutation progressed after 2 cycles of treatment and unfortunately died 3.8 months after diagnosis. Among the six patients who underwent autologous HSCT, all of them (100%) remained in CR. One patient died due to a COVID-19 infection after 6 cycles of R-MTO and ASCT. The most common hematological adverse events associated with the R-MTO regimen were mild to moderate (grade 1-2) decreases in neutrophil count, which typically resolved within a few days. Conclusions: The R-MTO induction treatment has demonstrated notable efficacy in achieving higher response rates among patients with PCNSL, and the associated adverse events are manageable.

Venetoclax Plus High-Dose Cytarabine and Mitoxantrone (HAM-Ven) As Salvage Treatment for Relapsed/Refractory AML: Updated Results of the Phase-I/II SAL Relax Trial

Background Primary refractory disease and relapse remain the main obstacles for cure in AML. In fit patients, several salvage cytostatic options based on higher doses of cytarabine have been published, with complete remission (CR) rates ranging from 40-55%. The BCL2 inhibitor venetoclax has demonstrated impressive antileukemic activity when combined with hypomethylating agents or low-dose cytarabine in newly diagnosed unfit AML patients. In the phase-I part of the RELAX trial of the Study Alliance Leukemia (SAL), we demonstrated the feasibility of combining venetoclax with higher-dose cytarabine plus mitoxantrone (HAM) in relapsed AML, resulting in a CR/CRi rate of 92%. Here, we report the updated results from the phase-I and additional patients from the phase-II dose expansion in relapsed or refractory (r/r) AML patients. Methods Patients with r/r AML fit for intensive salvage treatment were eligible. Based on the safety results from the phase-I part, patients were treated with the recommended phase-II dose combination of 400 mg venetoclax PO QD (d1-14) including a 2-day ramp-up, followed by cytarabine 1000 mg/m 2 IV BID (d3-5) in combination with mitoxantrone 10 mg/m 2 IV QD (d5-7). Concomitant CYP3A inhibitors were allowed with the appropriate dose adjustments, patients did not receive G-CSF. Patients achieving a CR could enter a maintenance phase with 400 mg venetoclax PO QD over twelve 28-day cycles. This research was supported by a grant from AbbVie Inc. The trial is registered under NCT04330820. Results Between April 2020 and June 2023, 12 patients were enrolled in the dose-escalation part and 40 patients in the expansion part, of whom 38 were evaluable for response by the time of writing. Median follow-up was 6.7 months. Among the 12 patients in the dose-escalation part, 3 received 200 mg/m 2 cytarabine QD over seven days, 3 received 500 mg/m 2 BID over three days and 3 received 1000 mg/m 2 BID over three days, each with identical doses of venetoclax (400 mg PO QD d1-14) and mitoxantrone (10 mg/m 2 IV QD d5-7). Of all 38 evaluable patients, 17 (44.7%) had adverse genetic risk according to ELN2022, and 1 (2.6%) had progressed from antecedent MDS. Median age was 56 years (range, 26-74 years). All patients experienced CTCAE grade ≥3 cytopenias. A median number of two non-hematologic grade 3 and 4 adverse events (AEs) in 32 patients with sufficient data were recorded. Grade 3 and 4 AEs occurring in ≥ 10% of patients included febrile neutropenia, pneumonia, sepsis and gastrointestinal disorders. The 30- and 60-day mortality was 2.6% and 5.2%. Remission assessment showed CR/CRi in 31/38 patients (81.6%). Among the seven patients with no CR/CRi, six showed refractory disease and one died in aplasia before response assessment. CR/CRi rate was 100% (8/8), 81,8% (9/11) and 70.6% (12/17) in patients with favorable, intermediate, and adverse risk, respectively. Utilizing LAIP-based DFN MRD approach, 7/32 (21.9%) evaluable patients were classified as MRD negative (CR/CRi MRD-). In 7/25 (28%) CR/CRi MRD+ patients, the MRD burden was below 0.1% CD45 + events. Of all 31 CR/CRi patients, 26 are in ongoing CR/CRi, 16 received allogeneic HCT as postremission treatment. Three patients died in CR from infectious complications after allogeneic HCT or post-remission treatment and two relapsed and succumbed to progressive disease. Six patients commenced maintenance treatment, of whom four are in ongoing remission. Discussion The combination of venetoclax with higher doses of cytarabine and mitoxantrone (HAM-Ven) is a well-tolerated and very efficacious treatment option leading to complete remissions in 81.6% of patients with r/r AML studied in the RELAX trial. Safety and efficacy compare favorably with published results from the FLAG-Ida-Ven regimen, thereby providing a less dose-intense, fludarabin-free approach for the treatment of fit r/r AML patients. Enrollment into the RELAX trial is currently ongoing. Updated results will be presented at the meeting.

Recombinant Human Thrombopoietin Combined with Thrombopoietin Receptor Agonists Can Facilitate the Recovery of Platelet after Allogeneic HSCT

Introduction:Thrombocytopenia is a common complication after hematopoietic stem cell transplantation (HSCT) and is strongly associated with transplant-related morbidity and mortality. According to the statistics, the incidence of post-HSCT thrombocytopenia is about 5%-37%. So far, there is no standard treatment regimen for thrombocytopenia after HSCT. Recombinant human thrombopoietin (rhTPO) can act on megakaryocytes alone and has been wildly used in clinical practice. Thrombopoietin receptor agonists (TPO-RAs), another type of drugs that can increase platelet count, has been available since 2008. It can bind to the TPO receptor and cause the conformational change of the receptor, and then activate the JAK2/STATE5 pathway to increase the proliferation of megakaryocyte progenitors and platelet production. There have been many prospective or retrospective studies discussing the efficacy and safety of rhTPO and TPO-RAs monotherapy in patients with thrombocytopenia. In clinical practice, it is very meaningful to clarify whether the combination of two types of drugs has a synergistic effect when one type of drug has poor efficacy. M ethods This study is a retrospective study in total 12 patients from 2022 to 2023. We selected a total of 6 patients who underwent HSCT in our center during the past year, and used rhTPO combined with avatrombopag to help platelet recovery as observation group. Then, 6 patients treated with rhTPO alone with no statistical difference at baseline were selected as the control group. The basic characteristics of these patients are shown in the table1. All the patients were informed and consented to use rhTPO+TPO-RA (avatrombopag) or rhTPO alone. If platelet count <20×10 9/L during treatment，which will be treated with platelet infusion. All the patients were treated with a modified BUCY regimen as the conditioning regimen and ATG+MMF+cyclosporine+short-range MTX were used to prevent graft vs host disease (GVHD). In observation group, the patients were treated with rhTPO 15000U qd i.m and avatrombopag 40mg qd po, while in control group the patients were treated with rhTPO 15000U qd i.m alone. We recorded the platelet counts of the two groups at day0,7,14,21. Based on this data, the percentage increase and growth rate of platelets were calculated. (the percentage increase: difference in platelet count before and after medication/platelet count before medication ×100%; the growth rate: difference in platelet count before and after medication/duration of medication.) The above two values were used to evaluated the efficacy of two treatment protocols. Adverse events occurred during treatment including fever, weakness, liver damage, joint pain, bleeding and thrombosis would be recorded to evaluate the safety. Results In observation group, patients' platelet counts increased by an average was 54×10 9/L (range 40 to 69). In control group, the average and median increase in their platelet counts was 22 (range -2 to 49). P=0.025 (P<0.05). In terms of the percentage increase in platelet count, the average increase was 452% in observation group VS. 110% in control group. p=0.022(P<0.05). Refer to Figure1a. The average growth rates of platelet counts in observation group were 2.03×10 9/L per day. The averagerate of increase in control group were 1.07×109/L per day. P=0.041(P<0.05). The mean platelet count of the two groups at various time points were shown in Figure1b. None of the patients had any adverse events occurred. No patient developed clinical meaningful abnormality of liver function and discontinued avatrombopag or TPO treatment due to intolerability and adverse effects. Conclusion Our data shows that the treatment protocol of avatrombopag combined with rhTPO may have a greater effect on platelet growth and boost a faster platelet growth rate. Importantly, no additional adverse effects occurred when the addition of avatrombopag.

Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426.

LBA4501 Background: At the first interim analysis of the randomized, open-label, phase 3 KEYNOTE-426 (NCT02853331) study, 1L pembro + axi showed statistically significant OS, PFS, and ORR over sun for advanced ccRCC. We report results with 5-y minimum follow-up. Methods: Adults with confirmed locally advanced or metastatic ccRCC with or without sarcomatoid features, no previous systemic therapy for metastatic ccRCC, KPS ≥70%, and ≥1 lesion measurable per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for 35 doses (~2 y) + axi 5 mg PO BID or sun 50 mg PO QD on a 4-wk-on/2-wk-off schedule. Dual primary end points were OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included ORR and DOR per RECIST v1.1 by BICR, and safety. A post hoc analysis adjusting for the effect of subsequent therapy on OS using a 2-stage adjustment model was conducted. Results: Of 861 enrolled patients (pts), 432 were assigned to pembro + axi and 429 to sun. Median study follow-up was 67.2 mo (range, 60.0-75.0). Efficacy for the ITT population and IMDC risk subgroups are shown in table. For pembro + axi vs sun, the 60-mo OS rates were 41.9% vs 37.1%, and the 60-mo PFS rates were 18.3% vs 7.3%. Median DOR (range) was 23.6 mo (1.4+ to 68.6+) for pembro + axi and 15.3 mo (2.3-68.3) for sun. In pts who discontinued treatment, 237/381 pts (62.2%) in the pembro + axi arm and 300/406 pts (73.9%) in the sun arm received subsequent anticancer treatment. The HR for OS when adjusted for subsequent therapy was 0.67 (95% CI, 0.52-0.84). Clinical data on pts who completed 2 y of pembro will be presented. No new safety signals were observed. Conclusions: After 5 y of follow-up, pembro + axi had sustained OS, PFS, and ORR benefits over sun in advanced ccRCC. These results are the longest follow-up to date of an anti–PD-1/L1 inhibitor + VEGFR TKI in this pt population and continue to support the use of pembro + axi as a 1L standard of care for advanced ccRCC. Clinical trial information: NCT02853331 .

Effect of CBM588 in combination with cabozantinib plus nivolumab for patients (pts) with metastatic renal cell carcinoma (mRCC): A randomized clinical trial.

LBA104 Background: We have previously demonstrated that the live bacterial product CBM588 may augment clinical outcomes in pts with mRCC receiving 1st-line (1L) therapy with dual immune checkpoint inhibitors (ICIs; Dizman et al Nature Medicine 2022). As tyrosine kinase inhibitors (TKIs) in combination with ICIs also represent a 1L standard of care in mRCC, we sought to determine if CBM588 would augment clinical outcome with the TKI cabozantinib (cabo) with nivo. Methods: Eligible pts were ≥18 yrs old (Karnofsky performance status ≥70%) with histologically verified (clear-cell, papillary or sarcomatoid component) mRCC and no prior systemic therapy for metastatic disease. Patients were randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg PO QD and 480mg IV monthly, respectively) alone or with CBM588 dosed at 80mg PO BID. The primary endpoint was the relative abundance of Bifidobacterium spp. in stool specimens at baseline and after 12 weeks of treatment. Secondary endpoints included assessment of response rate, overall survival, progression-free survival (PFS), systemic immunomodulation, and toxicity. A two-group t-test with a one-sided type I error of 0.05 was used to assess the study's primary endpoint, hypothesizing an increase in Bifidobacterium spp. with CBM588 therapy. Results: A total of 30 (20:10 M:F) pts were recruited; median age was 65 (36-84) and 5 pts (17%) had sarcomatoid features and 2 pts (7%) had predominant papillary histology. 12 (40%), 12 (40%) and 6 pts (20%) had good, intermediate and poor risk, respectively. Metagenomic sequencing of paired stool specimens showed a significant decrease in diversity from baseline to week 12 in patients receiving cabo/nivo (P=0.02); no significant difference was observed in those treated with cabo/nivo+CBM588. No significant change in Bifidobacterium spp. was observed. RR was 63% in pts receiving cabo/nivo+CBM588 vs 33% in pts receiving cabo/nivo alone. Median PFS was not reached in pts receiving CBM588 vs 5.8 mos in pts receiving cabo/nivo along (P=0.03). Grade 3/4 toxicities were observed in 44% and 42% of patients on control and experimental arms, respectively. Conclusions: In the second prospective trial assessing the addition of CBM588 to ICI-based therapy in mRCC, a consistent result with improved PFS and RR was observed. Further translational efforts are underway to characterize the mechanism through which CBM588 augments clinical activity. Clinical trial information: NCT05122546 .

Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC).

4502 Background: In the phase 3 CLEAR trial, L+P showed clinically meaningful and statistically significant benefits in PFS (primary endpoint) and OS, and improved ORR compared with S in 1L aRCC (Motzer NEJM 2021). Here, we report 4-yr follow-up results from the final prespecified OS analysis of CLEAR (data cutoff: 31 Jul 2022). Methods: Treatment-naïve pts (n=1069) who had aRCC with a clear-cell component were randomized (1:1:1) to receive: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors were geographic region and MSKCC prognostic risk group. This final prespecified OS analysis was triggered by ~304 death events in 2 arms. OS, PFS, ORR, duration of response (DOR), and PFS on next-line therapy (PFS2) were assessed for L+P and S. PFS, ORR and DOR were assessed per independent review using RECIST v1.1. Nominal P-values are shown. Results: At a median follow-up (IQR) of 49.8 mos (41.4–53.1) for L+P and 49.4 mos (41.6–52.8) for S, 149 and 159 deaths had occurred, respectively. OS benefit with L+P vs S was maintained (HR, 95% CI; 0.79, 0.63–0.99). OS favored L+P vs S across MSKCC risk groups (HR, 95% CI; favorable [fav]: 0.89, 0.53–1.50; intermediate [int]: 0.81, 0.62–1.06; poor: 0.59, 0.31–1.12). PFS benefit of L+P vs S was maintained (HR, 95% CI; 0.47, 0.38–0.57). PFS favored L+P vs S across MSKCC risk groups (HR, 95% CI; fav: 0.46, 0.32–0.67; int: 0.51, 0.40–0.65; poor: 0.18, 0.08–0.42). ORR was greater with L+P (71.3%; complete response [CR], 18.3%) vs S (36.7%; CR, 4.8%) (relative risk, 95% CI; 1.94, 1.67–2.26). Less pts in the L+P arm (181/355, 51.0%) received subsequent anticancer therapies compared with the S arm (246/357, 68.9%); 56 (15.8%) and 195 (54.6%) received PD-1/PD-L1 checkpoint inhibitors, respectively. Analysis of OS adjusted for subsequent therapies will be presented. PFS2 was longer with L+P vs S (43.3 vs 25.9 mos; HR, 95% CI; 0.63, 0.51–0.77). Grade ≥3 treatment-related adverse events occurred in 74.1% and 60.3% pts in the L+P and S arms, respectively. Conclusions: L+P continues to demonstrate clinically meaningful benefit vs S in OS, PFS, ORR, and CR in the 1L treatment of pts with aRCC at 4-yr follow-up, thus supporting the robustness of the primary analysis data from CLEAR. Clinical trial information: NCT02811861 .[Table: see text]

INAVO121: Phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2–) PIK3CA-mutated (mut) locally advanced or metastatic breast cancer (LA/mBC).

TPS1123 Background: Standard-of-care (SoC) endocrine therapy (ET) for pts with HR+, HER2– LA/mBC was transformed by combinations with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is); a CDK4/6i-based combination is approved in high-risk early BC. However, in most pts, mechanisms of resistance that emerge during or after treatment with a CDK4/6i and ET combination lead to relapse/disease progression. Dysregulating mutations in PIK3CA, occurring in ~40% of HR+, HER2– BCs, represent a common mechanism of resistance to CDK4/6is and ET combinations. ALP (a selective PI3Kα inhibitor; PI3Kαi) + FUL is approved for pts with HR+, HER2–, PIK3CAmut LA/mBC, but its widespread implementation in clinical practice has been challenging. As such, there is a significant need to develop PI3Kαis with a better therapeutic index. INAVO is a highly potent and selective PI3Kαi that also facilitates the degradation of mutated PI3Kα isoform. INAVO has demonstrated manageable safety/tolerability, alone and in combination with SoC treatments in HR+, HER2–, PIK3CAmut LA/mBC. Moreover, an ongoing Phase I trial showed that INAVO + FUL elicited encouraging preliminary antitumor activity in heavily pretreated pts, including a CDK4/6i-based regimen. Methods: INAVO121 (NCT05646862) is a Phase III, randomized, open-label study evaluating INAVO + FUL vs. ALP + FUL in pts with HR+, HER2–, PIK3CAmut LA/mBC (confirmed by circulating-tumor DNA or tumor tissue), who progressed during or after a CDK4/6i-based regimen with adequate hematologic and organ function. Up to two prior lines of systemic therapy in LA/mBC, including one line of chemotherapy are allowed. Pts are randomized 1:1 to receive INAVO (9 mg oral daily; PO QD) + FUL (500 mg intramuscularly on Days [D] 1 and 15 of Cycle [C] 1, then D1 of subsequent cycles), or ALP (300 mg PO QD) + FUL. Randomization is stratified by visceral disease (yes vs. no) and prior CDK4/6i therapy (adjuvant vs. metastatic setting). Pts will receive treatment until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival, BICR-objective response rate, BICR-best overall response, BICR-duration of response, BICR-clinical benefit rate, safety, tolerability, pt-reported outcomes, and pharmacokinetics. The study is open for enrollment, targeting 400 pts at ~200 sites globally. A stratified log-rank test at an overall 0.05 significance level (two-sided) will be used for the primary endpoint analysis. Median PFS will be estimated using Kaplan–Meier methodology. An independent data monitoring committee will be in place for safety and efficacy. Clinical trial information: NCT05646862 .

Neoadjuvant giredestrant + palbociclib (P) vs. anastrozole (A) + P in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+, HER2– eBC): Patient (pt)-reported outcomes (PROs) in the randomized, open-label, international phase II coopERA BC study.

591 Background: Endocrine therapies (ETs) are the therapeutic mainstay for ER+ BC but persistent adverse events (AEs; eg joint pain, especially with aromatase inhibitors) negatively impact quality of life, and resistance impacts efficacy. Giredestrant, a highly potent, nonsteroidal, oral selective ER antagonist and degrader (PO SERD), may help address these issues. coopERA BC (NCT04436744) evaluated giredestrant in eBC and met its primary endpoint, demonstrating a greater reduction of Ki67 with giredestrant vs. A after 2 weeks. Giredestrant was well tolerated as a single agent and with P. We report exploratory PRO analyses. Methods: Pts with cT1c-cT4a-c (≥ 1.5 cm within cT1c) ER+, HER2– untreated eBC and baseline Ki67 score ≥ 5% were randomized 1:1 to 30 mg PO daily (QD) giredestrant or 1 mg PO QD A on days (D)1–14 of a window-of-opportunity phase. A 16-week neoadjuvant phase added 125 mg PO QD P on D1–21 of four 28-D cycles. Presence/frequency/severity/interference of relevant symptomatic AEs were assessed at Cycles 1–4 via NCI PRO-CTCAE library items; overall burden due to AEs, via FACT-G item GP5. Results: PRO completion rates were > 80% at all time points. PRO-CTCAE postbaseline frequency scores were comparable between arms and mostly 0/1 (never/rare; reported for: Diarrhea > 80% of pts; hot flash > 60%; joint pain > 65%; nausea > 90%; vomiting > 90%). No rash was reported by > 90% of pts; fatigue at 0/1 severity (none/mild) by > 75% and at 0/1 interference (none at all/a little bit) by 80%. Hot flash frequency scores of 2–4 (occasionally/frequently/almost constantly) were reported by 30% of pts in the giredestrant + P arm and 37% in the A + P arm; joint pain frequency scores of 2–4, by 25% and 35%. Worst postbaseline scores of 3–4 are shown in the table. FACT-G GP5 showed greater proportions of “improved/no change” responses in the giredestrant + P than the A + P arm at Cycles 2–4 (Cycle 2 75%; Cycle 3 71%; Cycle 4 68% vs. 62%; 66%; 53%), and smaller proportions of “worsened” responses (25%; 29%; 32% vs. 38%; 34%; 47%). Conclusions: This is the first analysis to our knowledge of PROs with a PO SERD in eBC; it showed that most pts reported minimal symptomatic AEs at frequency and severity levels that were generally numerically lower in the giredestrant + P than the A + P arm (particularly joint pain). Furthermore, there were numeric trends towards greater stability and improvement and less worsening of treatment burden in the giredestrant + P arm. Studies to further assess giredestrant’s clinical benefit are ongoing in the adjuvant setting. Clinical trial information: NCT04436744 . [Table: see text]

STELLAR-303: A phase 3 study of XL092 in combination with atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer.

TPS3630 Background: Metastatic colorectal cancer (mCRC) is associated with poor prognosis and limited treatment options for patients who have progressed on first- and second-line chemotherapy. Regorafenib and trifluridine-tipiracil are approved in third- or later-line setting, but survival benefit is limited. Immune checkpoint inhibitor (ICI) therapy with nivolumab ± ipilimumab or single-agent pembrolizumab is approved in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC; however, MSI-H mCRC is present in only ~5% patients. Phase 1/2 studies have evaluated the tyrosine kinase inhibitor (TKI) cabozantinib in combination with the ICIs atezolizumab and durvalumab and have demonstrated encouraging clinical activity, with data suggesting greater benefit in RAS wild-type (wt) versus RAS mutant (mut) mCRC (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, et al. ASCO GI 2022:Abs 135). XL092 is a TKI that targets MET, VEGFR2, and the TAM kinases AXL and MER, which are implicated in tumor growth, metastasis, angiogenesis, and immunosuppression of the tumor microenvironment. XL092 displays immunomodulatory properties that may promote an immunopermissive tumor microenvironment and its half-life of 16–22 hours is supportive of once daily (QD) dosing. The phase 3 STELLAR-303 study (NCT05425940) is evaluating the efficacy and safety of XL092 in combination with atezolizumab versus regorafenib in patients with microsatellite stable or microsatellite instability-low mCRC who have progressed after or are intolerant to standard of care (SOC) therapy. Methods: STELLAR-303 is a global, randomized, open-label, phase 3 study. Eligible patients are aged ≥18 years with non-MSI-H/dMMR mCRC (determined by tissue-based analysis) that is measurable per RECIST v1.1 and have an ECOG performance status of 0–1 and adequate organ function. Patients must have progressed during/after or be intolerant to SOC therapies for mCRC; prior regorafenib, trifluridine-tipiracil, or anti–PD-L1/PD-1 ICIs are not allowed. Patients are randomized 1:1 to XL092 100 mg PO QD + atezolizumab 1200 mg IV Q3W or to regorafenib 160 mg PO QD (21 days/28-day cycle); randomization is stratified by geographic region (Asia, other), RAS status (wt, mut), and liver metastases (yes, no). Enrollment of 600 patients is planned (400 RASwt, 200 RASmut). The primary endpoint is duration of overall survival (OS) in the RASwt population, with other efficacy endpoints (progression-free survival, objective response rate, and duration of response per RECIST v1.1 by investigator and change in tumor markers) assessed in the RASwt population and, with OS, in the RASmut populations and in all randomized patients. Additional endpoints will assess safety, quality of life, changes in biomarkers, pharmacokinetics, immunogenicity, and healthcare utilization. Enrollment is ongoing. Clinical trial information: NCT05425940 .

Belzutifan plus lenvatinib for patients (pts) with advanced clear cell renal cell carcinoma (ccRCC) after progression on a PD-1/L1 and VEGF inhibitor: Preliminary results of arm B5 of the phase 1/2 KEYMAKER-U03B study.

4553 Background: The oral HIF-2α inhibitor belzutifan demonstrated antitumor activity with manageable safety as monotherapy in pts with heavily pretreated ccRCC and in combination with a VEGF-TKI in pts who previously received a PD-1/L1 inhibitor. KEYMAKER-U03B (NCT04626518) is phase 1/2, multicenter, multi-arm, open-label, adaptive umbrella study. We present preliminary results from arm B5 for belzutifan + lenvatinib. Methods: In all arms, adults with histologically confirmed ccRCC, KPS ≥70%, and disease progression on or after PD-1/L1 inhibitor and VEGF-TKI treatment (in sequence or in combination) were enrolled. In arm B5, pts received belzutifan 120 mg PO QD + lenvatinib 20 mg PO QD. The study comprised a safety lead-in phase to establish the recommended phase 2 dose (RP2D), followed by an efficacy phase. Primary end point for the safety lead-in phase was safety and tolerability to establish RP2D; co-primary end points of the efficacy phase were safety and ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include clinical benefit rate (CBR; CR + PR + SD ≥6 mo), DOR and PFS per RECIST v1.1 by BICR. Response will be presented in pts who had an opportunity to receive ≥2 postbaseline scans due to ongoing enrollment. PFS was evaluated in all enrolled pts and safety in all treated pts. End points will be evaluated in each arm separately; no comparisons will be made across arms. Results: As of September 29, 2022, 32 pts were enrolled and 30 received treatment. Median age was 60.5 y, 78% were male and 78% had intermediate/poor IMDC risk. 23 pts were on treatment at data cutoff date. Median follow up was 6.9 mo (range: 0.1-18.2). Safety of belzutifan 120 mg + lenvatinib 20 mg was manageable. Of 10 evaluable pts in the safety lead-in phase, only 1 experienced a dose-limiting toxicity (grade 1 dyspnea). Among pts who had opportunity for ≥2 postbaseline scans (n = 24), ORR was 50% (95% CI, 29-71; all PRs); CBR was 54% (95% CI, 33-74). Median DOR was not reached (NR; range: 1.4+ to 14.0+ mo); 74% of responders remained in response for ≥12 mo by KM estimation. For all enrolled pts, median PFS was 11.2 mo (95% CI, 4-NR); 6-mo rate was 55%. In the safety analysis, 28 pts (93%) experienced a treatment-related AE (TRAE), most commonly (≥40%) anemia (43%), fatigue (43%), and hypertension (43%). Grade 3-4 TRAEs occurred in 15 pts (50%); most commonly hypertension (27%) and anemia (17%). 1 pt experienced grade 2 hypoxia. No pt died due to a TRAE. Conclusions: Preliminary data from the belzutifan + lenvatinib combination exhibited promising antitumor activity in pts with ccRCC that progressed on PD-1/L1 inhibitors and VEGF-TKIs. Safety findings were consistent with individual profiles of each agent. The combination is being further evaluated in the phase 3 LITESPARK-011 study. Clinical trial information: NCT04626518 .

Interim analyses (IA) of the giredestrant (G), G + abemaciclib (A), and G + ribociclib (R) arms in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced/metastatic BC (ER+, HER2– LA/mBC).

1061 Background: Limitations of current approved endocrine therapies (ETs), a mainstay tx for ER+ BC, include incomplete ER signaling inhibition. Novel ETs, such as selective estrogen receptor antagonists and degraders (SERDs), may help overcome this. G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P). MORPHEUS BC (NCT04802759) is evaluating the safety and efficacy of G tx combinations in ER+, HER2– LA/mBC. We present results from the 16-week IA of G and G + CDK4/6i (A or R). Methods: Eligible pts had disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC. Pts were randomized 1:6 (planned n = 15 per arm) to receive G (30 mg PO QD; control arm), G + A (150 mg PO BID), or sequentially, G + R (600 mg PO QD) until disease progression/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate; other endpoints included progression-free survival, overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Genetic alterations were defined using baseline circulating tumor DNA. Results: As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL). As of Sept 22, 2022, 11 and 16 (of whom 14 were evaluable) pts were enrolled in the G and G + R arms, respectively; 64%/86% received one prior line of tx in the LA/mBC setting; 73%/36% received prior fulvestrant; 73%/57% had liver metastases at BL. Three pts had a partial response (PR; G + A, n = 1; G + R, n = 2); 19 had stable disease (G, n = 5; G + A, n = 7; G + R, n = 7). DCRs were 36% (G), 40% (G + A), and 50% (G + R). Safety is shown. Conclusions: G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies. G can therefore be combined with all three approved CDK4/6is. Clinical trial information: NCT04802759 . [Table: see text]