Selective Inhibitor Of Nuclear Export Research Articles

Phase 2 March Study: ATG-010 Plus Low Dose Dexamethasone in Chinese Relapsed/Refractory Multiple Myeloma (RRMM) Patients Previously Treated with an Immunomodulatory Agent (IMiD) and a Proteasome Inhibitor (PI)

Background:ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM based on the STORM study. MARCH is a single arm, Phase 2, registrational study to assess efficacy and safety of Sd in Chinese pts with RRMM.Methods:Enrolled Chinese pts were previously refractory to PI, IMiD, and last line of therapy. ATG-010 (80mg) plus dexamethasone (20mg) was administered twice weekly. The primary endpoint was overall response rate (ORR) per independent review committee. The planned 82 pts would provide ~80% power to test against null hypothesis (H 0) of 15% ORR at one-sided α of 0.025 at the primary analysis, which is presented here.Results:As of 6 th May 2021, 9 (11%) of the 82 pts were still on treatment. Median follow-up was 10.6 months (mo) (range: 2.3-19.6).Median age was 60 years (39% ≥ 65yrs). Median duration from MM initial diagnosis was 3.2 years. A total of 61 pts (74.4%) had cytogenetic abnormalities (del(17p): 22.0%), 18 (22.0%) with baseline plasmacytoma, and 18 (22.0%) with creatinine clearance < 60ml/min. Median number of prior regimens were 5 (range 1-16); 23 pts (28.0%) had received daratumumab (triple-class exposure), 20 pts were triple-class refractory (TCR), and10 pts (12.2%) had undergone CAR-T therapy.ORR was 29.3% (95% CI: 19.7, 40.4), rejecting H 0, including 4 VGPR (very good partial response). Median duration of response (DOR) was 4.7 mo, median progression free survival (PFS) was 3.7 mo, and median overall survival (OS) was 13.2 mo.Among 20 TCR pts, ORR was 25.0% (95% CI:8.7, 49.1), mDOR 10.2 mo, mPFS 2.9 mo, and mOS 11.9 mo.Efficacy was evident in elderly pts (≥ 65yrs), with ORR 25% (95% CI: 11.5, 43.4) and mPFS 2.8 mo. Median OS and DOR were not reached.Sd also demonstrated a similar response rate in pts with high-risk cytogenetic abnormalities, with an ORR of 24.6% (95% CI: 14.5, 37.3). Efficacy of Sd was generally consistent across cytogenetic risk subgroups, including del (17p) pts with ORR 22.2% (95% CI: 6.4, 47.6), mDOR 3.8mo, and mPFS 2.9 mo.The most common non-hematologic treatment-emergent adverse events (TEAEs) of any grade included nausea (78%), hyponatremia (67.1%), weight loss (65.9%), decreased appetite (62.2%), asthenia (59.8%)/fatigue (15.9%), and vomiting (50.0%). The most common grade≥3 non-hematologic TEAE were hyponatremia (29.3%), pneumonia (26.8%), hypokalemia (12.2%) and asthenia (9.8%)/fatigue (2.4%). The most common grade≥3 hematologic TEAEs were anemia (57.3%), lymphopenia (76.8%), thrombocytopenia (51.2%), and neutropenia (40.2%). TESAE occurred in 54.9% of pts, with the most common being thrombocytopenia and pneumonia (14.6% each). TEAE led to death in 7 pts (8.5%). Elderly pts had no significantly increased risk of adverse events, however, given their limited physical state, drug exposure was shorter in the elderly subgroup (12.6 vs 16.1 weeks), suggesting more active supportive care is required.Conclusions:MM refractory to both IMiD and PI remains a high unmet medical need, especially in China. The MARCH study demonstrates statistically significant and clinically meaningful ORR with Sd in Chinese RRMM pts, and efficacy was consistent across subgroups, including the elderly and pts with high-risk cytogenetics. Adverse events were as expected and manageable with appropriate supportive care and dose modification. These data are compatible with the STORM study and offers a new, oral therapeutic option for MM patients. DisclosuresYu: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Yang: Antengene Therapeutics Ltd.: Current Employment. Yu: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

Single Cell RNA Sequencing in Patients Enrolled in a Selinexor Clinical Trial Reveals Overexpression of Alternative Nuclear Export Pathways Associated with Resistance to Selinexor in Refractory Multiple Myeloma

Selinexor is a novel, first-in-class oral selective inhibitor of nuclear export which blocks Exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing apoptosis in cancer cells. Selinexor has been approved for the treatment of patients with penta-refractory multiple myeloma (MM) who have received at least 4 prior therapies. We previously reported the discovery of a novel transcriptional signature and therapeutic targets for therapy resistant MM by comprehensive single cell RNA-seq analysis (scRNA-seq) of plasma cells (PCs) in patients with primary refractory MM (PRMM) enrolled in the KYDAR clinical trial (NCT04065789, carfilzomib Lenalidomide dexamethasone daratumumab for PRMM [Cohen YC, Nature Med, 2021]).Here we report scRNA-seq analysis of PCs from patients with advanced refractory MM (aRRMM) (n=21) enrolled in an ancillary sub-study of a prospective clinical trial (XPORT-MM-028, NCT04414475), treated with selinexor combined with dexamethasone (Xd, in penta-refractory MM n=7), or with bortezomib, dexamethasone (XVd, in triple-class refractory [TCR] MM n=9), 5 patients participated in the ancillary study only. Median age was 75 years (range: 60-87), 50% were male, median time since active MM diagnosis was 4.8 years (range: 1.3-11.1). All treated patients (N=16) had TCR MM and 7/16 treated patients had penta-refractory MM. Single cell clustering analysis showed a unique molecular signature for each myeloma patient's PCs (Fig 1A), while patient-level analyses revealed a distinct transcriptional signature in aRRMM compared with PRMM (Fig 1B). aRRMM was characterized by upregulation of several pathways, including heparin growth factor (HDGF), Rho-GTPases activator (ARHGEF2), H3.3 histone variant and Prothymosin Alpha (PTMA) (Fig 1C-D). PPIA expression, which we previously identified as a biomarker and synergistic target for carfilzomib resistance, was low among healthy donors' PCs, progressively increased along with malignant evolution of plasma cell dyscrasia, from newly diagnosed MM, through PRMM, and was the highest in aRRMM (Fig 1C). We observed strong down-regulation of CD38 likely a consequence of daratumumab treatment and relapse in earlier lines.Finally, we discovered differential expression of several genes between patients with MM refractory to versus non-refractory (achieving at least partial response by IMWG criteria or a progression free survival greater than 4 months) to a selinexor-regimen (Fig 1E), including up-regulation of XPOT, a tRNA exportin, and KPNB1 a nucleocytoplasmic transporter (Fig 1F-G). Protein-protein interaction enrichment analyses revealed mRNA splicing and capping as well as nucleocytoplasmic transport as up-regulated modules in the refractory patients potentially serving as a resistance mechanism for blockade of XPO1 mediated nuclear export by selinexor.In summary, our study defines a roadmap for combining single cell RNA-seq profiling with clinical trials to stratify patients according to their level of anti-MM drug resistance, to define new biomarkers for drug resistance that may support personalized therapeutic decisions and reveal potential novel targets. [Display omitted] DisclosuresCohen: Karyopharm: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stemer: AbbVie: Consultancy. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Amit: Neogene therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; CELLINK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Maruho Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck KGaA: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Immunology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karophram: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

XPO1 Inhibitor (ATG-010) Plus Chemotherapy per Investigator's Choice for Heavily Pretreated Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Extranodal NK/T-Cell Lymphoma (ENKTL)：Preliminary Results from a Multicenter, Single-Arm, Phase Ib Study (TOUCH Trial)

BackgroundThe prognosis of R/R PTCL and ENKTL remains poor. Current therapeutic options are limited, highlighting the need for novel approaches. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. It has demonstrated clinical activity in different hematological malignancies. Preclinical synergistic anti-tumor effects are confirmed when combined with gemcitabine, cisplatin, or etoposide.MethodThe aim of this study was to evaluate safety and efficacy of ATG-010 plus GemOx or ICE regimen followed by ATG-010 maintenance in patients (pts) with R/R PTCL or ENKTL in China. The study planned to enroll 30 pts with PTCL-NOS, AITL, ALCL, PTCL-TFH, FTL and ENKTL. Pts must have had prior exposure to an anthracycline-based regimen for PTCL or an asparaginase-based regimen for ENKTL, and were relapsed or refractory from the last therapy. ATG-010 was administered orally (60 mg day 1, 8) plus standard-dose of either ICE or GemOx regimen every 3 weeks as per investigator's choice. If response was achieved after initial 2-6 cycles, pts continued to receive ATG-010 maintenance at the dose of 60 mg weekly until disease progression, intolerability or withdrawal of consent. Primary endpoints included safety according to the NCI CTCAE 5.0 and overall response rate (ORR) evaluated by investigators according to the Lugano criteria (2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). This trial was registered at ClinicalTrials.gov (NCT04425070).ResultsFrom Aug 18, 2020 to June 25, 2021, 24 pts (20 in GemOx cohort, 4 in ICE cohort) were enrolled and received at least one cycle of treatment. In this abstract, we report results of the GemOx cohort with 9 (45%) PTCL-NOS, 6 (30%) ENKTL, 4 (20%) AITL, and 1 (5%) ALCL ALK-. At study entry, median age was 55 years (range 35-69); 17 (85%) had stage III/IV disease. Five (36%) pts with PTCL had IPI score ≥3, and 5 (83%) ENKTL pts with had PINK-E score ≥2. Median number of prior regimens was 3.5 (range 1-7) with 5.5 for ENKTL and 2 for PTCL. All pts were refractory from last therapy; 11 (55%) pts had received gemcitabine-based regimens. Median time from last-line therapy to this trial was 1.5 months (range 1.0-16.7).The most common treatment-emergent adverse events (TEAEs) were hematological toxicities. All grade hematological TEAEs were neutropenia (90%), thrombocytopenia (90%) and anemia (85%). Grade≥3 hematological TEAEs included neutropenia (85%), thrombocytopenia (80%) and anemia (40.0%). The most common (>30%) non-hematological TEAEs were nausea (70%), diarrhea (65%), decreased appetite (65%), asthenia/fatigue (60%), vomiting (50%), pyrexia (40%), and hyponatremia (35%). Grade≥3 non-hematological TEAEs (≥10%) were diarrhea (15%) and pyrexia (10%). Serious TEAEs occurred in 7 (35%) pts with the most common being thrombocytopenia (20%). Three (15%) pts discontinued treatment due to TEAEs. TEAEs with a fatal outcome occurred in 1(5%) patient, who experienced rapid disease progression before death. The majority of adverse events were manageable by dose modification and supportive care.Of 17 efficacy evaluable pts, ORR was 52.9% (9/17), and CR rate was 35.3% (6/17). ORR of PTCL-NOS, ENKTL, AITL, ALCL were 62.5% (5/8), 60% (3/5), 0 (0/3), 100% (1/1); CR rate were 37.5%, 40%, 0, 100%, respectively. At a median follow-up of 6.1months, median PFS, DOR and OS of the whole cohort was 2.9, 3.1 months, and not reached (6-month OS rate 68.9%), respectively. Patients with ENKTL enjoyed a relatively longer median PFS (4.7 months).ConclusionsATG-010 plus GemOx regimen showed a manageable safety profile, and favorable activity with impressive CR rate in refractory pts, potentially offering a new therapeutic option for heavily pretreated pts with refractory PTCL or ENKTL. DisclosuresLou: Antengene Therapeutics Ltd.: Current Employment. Fei: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

ATG-010 Plus Low-Dose Dexamethasone (Sd) in Chinese Relapsed/Refractory Multiple Myeloma (RRMM) Patients Previously Received Chimeric Antigen Receptor T-Cell (CAR-T)

Background:There are limited treatment options for multiple myeloma (MM) patients who have a disease progression after CAR-T therapy. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, inhibiting exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM. MARCH study, a single arm, Phase 2, registrational study evaluating Sd in Chinese RRMM pts, achieved an overall response rate (ORR) of 29.3% (95% CI: 19.7, 40.4), rejecting the null hypothesis of the study. Given its unique and novel mechanism of action, Sd preserves anti-tumor activity regardless of specific prior therapies. In the MARCH study, encouraging activity was demonstrated in a small group of Chinese RRMM pts previously exposed to CAR-T therapy.Methods:The study enrolled 82 pts previously exposed and refractory to a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and last line of therapy. Among them, 10 had received lymphodepleting conditioning followed by CAR-T cell therapy before study screening. ATG-010 (80mg) plus dexamethasone (20mg) was administered orally twice weekly. Response was assessed by an independent review committee.Results:Among 10 pts, 8 were male and 2 were female. Median age was 58.5 years. Median duration from MM initial diagnosis was 5.2 years. A total of 6 pts (60.0%) had high-risk cytogenetic abnormalities, including 4 pts (40.0%) with del (17p). Three pts had baseline plasmacytoma. Five pts (50%) experienced very rapid disease progression as indicated by a median of 46.2% increase of tumor burden from screening to Cycle 1 Day 1. Patients were heavily pre-treated with a median of 9.5 prior regimens (range: 5-12), with 8 receiving more than 6 regimens. Four pts were exposed to daratumumab (triple-class exposure). ORR was 50% including 1 very good partial response and 4 partial responses. Disease control rate defined as SD and above was 70%. Median duration of response was 1.4 months (mo) (95% CI: 0.96, NE). Median progression free survival was 1.9 mo (95% CI: 0.93, 3.74). xx pts (xx%) pts died; median overall survival was not reached, and estimated 12-mo OS rate was 68.6%.Adverse events were consistent with those events previously reported with Sd regimen in RRMM patients. The most common grade≥3 treatment emergent adverse events (TEAEs) included anemia, thrombocytopenia, neutropenia and nausea. Most events were manageable with appropriate supportive care or dose modification. Four pts (40%) experienced TESAEs, including anemia, pneumonia, neutropenia, and upper gastrointestinal hemorrhage. There were no TEAEs leading to treatment discontinuation or death.Conclusions:Sd was able to induce an encouraging response with a manageable safety profile for a group of Chinese RRMM patients desperately needing treatment after failing CAR-T therapy. With the small sample size, further investigation is warranted, including using ATG-010 in combination with other anti-MM therapies to potentially enhance and prolong therapeutic benefit. DisclosuresYu: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Yu: Antengene Therapeutics Ltd.: Current Employment. Yang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

Nuclear-localized human respiratory syncytial virus NS1 protein modulates host gene transcription.

SUMMARYHuman respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in the pediatric, elderly, and immunocompromised individuals. RSV non-structural protein NS1 is a known cytosolic immune antagonist, but how NS1 modulates host responses remains poorly defined. Here, we observe NS1 partitioning into the nucleus of RSV-infected cells, including the human airway epithelium. Nuclear NS1 coimmunoprecipitates with Mediator complex and is chromatin associated. Chromatin-immunoprecipitation demonstrates enrichment of NS1 that overlaps Mediator and transcription factor binding within the promoters and enhancers of differentially expressed genes during RSV infection. Mutation of the NS1 C-terminal helix reduces NS1 impact on host gene expression. These data suggest that nuclear NS1 alters host responses to RSV infection by binding at regulatory elements of immune response genes and modulating host gene transcription. Our study identifies another layer of regulation by virally encoded proteins that shapes host response and impacts immunity to RSV.

P-211: Phase 2 MARCH study: ATG-010 plus Dexamethasone in Chinese relapsed/refractory Multiple Myeloma (RRMM) patients previously treated with an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI)

<h3>Background</h3> ATG-010 (selinexor), a novel, oral selective inhibitor of nuclear export, inhibits exportin1. In preclinical and clinical studies, ATG-010 has demonstrated activity against multiple myeloma (MM). ATG-010 (80 mg biweekly) plus dexamethasone (20 mg biweekly) (Sd) has been approved by US FDA for treatment of patients (pts) with penta-refractory MM based on the STORM study. MARCH is a single arm, Phase 2 study to assess efficacy and safety of Sd in Chinese pts with RRMM. <h3>Methods</h3> Enrolled Chinese pts were previously treated with and refractory to PI, IMiD, and the last line of therapy. Sd was administered in 4-week cycles. The primary endpoint was overall response rate (ORR) per independent review committee. The total planned 82 pts provide -80% power to test against H0 of 15% ORR at one-sided α of 0.025. This abstract includes data from the first 60 treated pts. <h3>Results</h3> As of 13 Oct 2020, 18 (30%) of the 60 pts were on treatment. Median follow-up was 9.5 months (mo) (range: 1.9-12.8). Median age was 61 years (range 43-82; 42% > 65). Pts had received a median of 5 (range 1-16) prior MM regimens, with the following baseline risk factors: 72% R-ISS II/III, 70% cytogenetic abnormalities, 22% del (17p13),20% renal impairment, 15% prior CAR-T therapy, and 25% pre-treated with daratumumab (considered ‘triple-class exposed'). ORR was 26.7% (95% CI: 16.1, 39.7). Median duration of response (DOR) was 4.6 mo (95% CI: 1.42, NE). Median progression free survival was 3.7 mo (95% CI: 1.92, 4.66). Median overall survival (OS) was not reached; 9-mo OS rate was 68.5%. ORR was 33.3% in triple-class-exposed pts. Nine pts had prior CAR-T therapy with a median of 9 prior regimens (range 5-12). Among them, ORR was 44.4%, and median DOR was 3 mo (95% CI; 0.96, 4.63). Common treatment emergent adverse events (TEAEs) of any grade included: thrombocytopenia (87%), nausea (87%), leukopenia (85%), anemia (85%), lymphopenia (78%), neutropenia (73%), weight loss (72%), hyponatremia (65%), decreased appetite (63%), asthenia (62%)/fatigue (17%), hyperglycemia (53%), vomiting (52%), hypocalcemia (38%), hypokalemia (30%), diarrhea (30%), and pneumonia (27%). Common TEAEs of Grade ≥ 3 included: anemia (60%), thrombocytopenia (55%), leukopenia (42%), lymphopenia (42%), neutropenia (38%), hyponatremia (28%), and pneumonia (23%). Thirty pts (50%) had TESAEs, including (>3%): thrombocytopenia (15%), pneumonia (15%), anemia (6.7%), and hyponatremia (3.3%). Eight pts (13.3%) had TEAEs leading to treatment discontinuation, including (>2%): thrombocytopenia (5%) and pneumonia (3%). There were three fatal TEAEs: pneumonia, intracranial hemorrhage, and sudden death (1 each). <h3>Conclusions</h3> MM pts refractory to both IMiD and PI remain a high unmet medical need. The MARCH study confirms the efficacy of Sd in Chinese patients with a manageable safety profile. These data are consistent with the STORM trial and offer a new, oral therapeutic option for MM patients.

Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication

Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M) protein is a major RSV structural protein with a key role in virus assembly. Interestingly, M is localised to the nucleus early in infection and its export into the cytoplasm by the nuclear exporter, exportin-1 (XPO1) is essential for RSV assembly. We have shown previously that chemical inhibition of XPO1 function results in reduced RSV replication. In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185. Our data shows that therapeutic administration of the SINE compounds results in reduced RSV titre in human respiratory epithelial cell culture. Within 24 h of treatment, RSV replication and XPO1 expression was reduced, M protein was partially retained in the nucleus, and cell cycle progression was delayed. Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter.

Selinexor and the Selective Inhibition of Nuclear Export: A New Perspective on the Treatment of Sarcomas and Other Solid and Non-Solid Tumors.

Nucleocytoplasmic transport has been found dysregulated in many types of cancer and is often described as a poor prognostic factor. Specifically, Exportin-1 (XPO1) has been found overexpressed in many tumors and has become an attractive target in molecular oncology and therapeutics development. The selective inhibitor of nuclear export, Selinexor, is one of the most scientifically interesting drugs that targets XPO1 in clinical development. In this review, we summarized the most relevant preclinical and clinical results achieved for non-solid tumors, sarcomas, and other kind of solid tumors.

Quality of life analyses in patients with multiple myeloma: results from the Selinexor (KPT-330) Treatment of Refractory Myeloma (STORM) phase 2b study

BackgroundSelinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy – Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM.MethodsFACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders.ResultsEighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores.ConclusionThe majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach.Trial registrationThis trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.

1331P Open-label phase I/II study evaluating the tolerability and anti-tumor activity of selinexor (SEL) and docetaxel (DTX) in non-small cell lung cancer (NSCLC)

Patients (pts) with NSCLC have few treatment options beyond 3 lines. RAS mutations (mut), found in 25% of NSCLC adenocarcinomas, are associated with poor response to conventional chemotherapy and poor clinical outcomes. SEL, an oral selective inhibitor of nuclear export (SINE), has shown synergy with taxane-based therapy in mouse models of prostate, breast and ovarian cancer. Preliminary clinical data (NCT03095612) have shown anti-tumor activity of SEL with DTX in pts with NSCLC with RAS mut treated with at least 1 prior regimen containing a checkpoint inhibitor.

Selinexor, a selective inhibitor of nuclear export, enhances the anti-tumor activity of olaparib in triple negative breast cancer regardless of BRCA1 mutation status.

Triple negative breast cancer (TNBC) is a deadly disease with limited treatment options. Selinexor is a selective inhibitor of nuclear export that binds covalently to exportin 1 thereby reactivating tumor suppressor proteins and downregulating expression of oncogenes and DNA damage repair (DDR) proteins. Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor approved for the treatment of patients with breast cancer harboring BRCA mutations. We examined the effects of co-treatment with selinexor and olaparib in TNBC cell lines. BRCA1 wildtype (BRCA1-wt) and BRCA1 mutant (BRCA1-mut) TNBC cell lines were treated with selinexor and/or olaparib and effects on cell viability and cell cycle were evaluated. The effects of treatment were also evaluated in mouse xenograft models generated with BRCA1-wt and BRCA1-mut TNBC cell lines. Treatment with selinexor inhibited cell proliferation and survival of all TNBC cell lines tested in vitro. This effect was enhanced following treatment of the cells with the combination of selinexor and olaparib, which showed synergistic effects on tumor growth inhibition in MDA-MB-468-derived (BRCA1-wt) and MDA-MB-436-derived (BRCA1-mut) xenografts. As co-treatment with selinexor and olaparib exhibits anti-tumor activity regardless of BRCA1 mutation status, the clinical implications of the combination warrant further investigation.

A 2:1 randomized, open-label, phase II study of selinexor vs. physician’s choice in older patients with relapsed or refractory acute myeloid leukemia

Selinexor, a selective inhibitor of nuclear export, has demonstrated promising activity in patients with acute myeloid leukemia (AML). This randomized, phase II study evaluated selinexor 60 mg twice weekly (n = 118) vs. physician’s choice (PC) treatment (n = 57) in patients aged ≥60 years with relapsed/refractory (R/R) AML. The primary outcome was overall survival (OS). Median OS did not differ significantly for selinexor vs. PC (3.2 vs. 5.6 months; HR = 1.18 [95% CI: 0.79–1.75]; p = 0.422). Complete remission (CR) plus CR with incomplete hematologic recovery trending in favor of selinexor occurred in a minority of patients. Selinexor treated patients had an increased incidence of adverse events. The most common grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anemia, hyponatremia. Despite well-balanced baseline characteristics, there were numerically higher rates of TP53 mutations, prior myelodysplastic syndrome, and lower absolute neutrophil counts in the selinexor group; warranting further investigation of selinexor in more carefully stratified R/R AML patients. Registered trial: NCT02088541.

Selinexor for the treatment of patients with previously treated multiple myeloma

ABSTRACT Introduction Multiple myeloma (MM) is an increasingly treatable but still incurable hematologic malignancy. Prognosis has improved significantly over recent years, although further advances remain urgently needed, especially for patients with heavily pre-treated and resistant disease for whom there are limited options. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export (SINE) compound that triggers apoptosis in malignant cells by inducing nuclear retention of oncogene messenger RNAs (mRNAs) and reactivation of tumor suppressor proteins (TSPs). In clinical studies of patients with relapsed and/or refractory MM, selinexor has demonstrated both manageable toxicity and encouraging efficacy. Areas covered This review will provide an overview of the mechanism of action of selinexor as well as the efficacy and safety data from clinical studies using selinexor for the treatment of multiple myeloma. Expert opinion Long-term outcomes for patients with MM will continue to improve due to numerous recent and imminent therapeutic advances, although critical areas of unmet need remain. Oral selinexor is likely to contribute to the meeting of these needs and the further advancement of MM therapy in a meaningful way.

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes

BackgroundThe SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor. Patients and MethodsData from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate. ResultsORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels ≥ 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups. ConclusionsOverall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin.

Abstract 2383: Mir-7974: An oncogenic miRNA that perpetuates gastric cancer

Abstract The global incidence of gastric cancer exceeds 1 million people per year and has a 5-year survival rate of 31%. Current chemotherapies are not effective because of genetic and epigenetic heterogeneity and late stage detection. Previously, we showed that exportin 1 (XPO1) is a therapeutic target in gastric cancer, as it facilitates the nuclear export of various cancer related tumor suppressor proteins (TSPs) through direct interaction with their nuclear export sequences (NES). XPO1 is upregulated in a variety of tumors including gastric cancer, leading to increased cytoplasmic localization of TSPs supporting malignant transformation and cancer cell proliferation, Knockdown of XPO1 leads to anti-tumor effects and pharmacologic targeting of XPO1 is achievable with selective inhibitors of nuclear export (SINE) compounds. In 2019 and 2020, the first generation XPO1 inhibitor KPT-330 was FDA approved for the use in penta-refractory multiple myeloma and non-Hodgkin's Lymphoma. Besides protein, mRNA and non-coding RNAs are also transported across the nuclear membrane. Non-coding RNA transport is generally attributed to another nuclear export protein, exportin 5 (XPO5), which plays a critical role in microRNA (miRNA) biogenesis. Nevertheless, there is emerging evidence supporting the role of XPO1 in non-coding RNA transport. In order to elucidate the role of XPO1 in non-coding RNA biology, we performed small RNA sequencing on gastric cancer cell lines treated with the XPO1 inhibitor selinexor. Our results revealed statistically significant changes in miR-7974 and miR-129-1-3p. These two miRs are recognized to influence protein modifications and cell survival. Administration of a miR-7974 mimic and a miR-129-1-3p inhibitor reduced proliferation of gastric cancer cells. Next, we evaluated the miR target genes of interest. At the mRNA level, we found upregulation of RasGEF Domain Family Member 1a (RASGEF1A), downregulation of DNA damage-regulated autophagy modulator 1 (DRAM1), downregulation of TIMP2 and downregulation of Cyclin G2 protein encoding gene CCNG2. Western Blots confirmed inhibition of AKT, RAS and Wnt signaling. Our results also showed that miR-7974 overexpression correlated with cellular XPO1 levels through the enhancement of XPO1 and its cargoes RCC1 and RANBP2. Finally inhibition of XPO1 by SINE compounds reversed the observed oncogenic phenotypes caused by these microRNAs. Our results unveil a novel interaction network between XPO1 and small non-coding RNAs and show that XPO1 induced small-noncoding microRNAs influence gastric cancer proliferation, and can be reversed by SINE compounds. This implies that modulation of microRNAs might be explored as a biomarker for XPO1 inhibitor therapy and warrants further investigation. Citation Format: Rachel E. Sexton, Mohammad Najeeb Al-Hallak, Bayan Al-Share, Yiwei Li, Amro Aboukameel, Yosef Landesman, Trinayan Kashyap, Steve Kim, Ramzi M. Mohammad, Philip A. Philip, Asfar S. Azmi. Mir-7974: An oncogenic miRNA that perpetuates gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2383.

Abstract 994: Investigating inhibition of nuclear export in breast cancer cells

Abstract XPO1 (Exportin aka CRM1) is a mediator of nuclear export that is known to be dysregulated in cancers. Selective inhibitors of nuclear export (SINEs) have shown some promise in cancer treatment, but the mechanism is poorly understood in cancer specific subtypes. Here, we investigated XPO1 inhibition in breast cancer by treating a panel of breast cancer cell lines with a SINE (Selinexor) and saw a bimodal response, with most triple-negative cell lines showing sensitivity and some ER+ cell lines showing resistance to the therapy. Changes in the expression of BIRC5 (Survivin) have been previously implicated in XPO1 inhibitor response. Using RT-qPCR experiments we were able to show that after 24 hours of selinexor treatment, the expression of BIRC5 does change in two sensitive cell lines MDA-MB-231 and MCF7, but is not necessarily changed at earlier time points. To more holistically explore the mechanism of XPO1 inhibition induced cell death, we performed RNA-Seq and differential gene expression analysis on these two cell lines at 2, 8, and 24 hours post treatment with Selinexor (compared to vehicle). Our results indicate that several breast cancer and cell cycle associated genes show expression changes as early as 2 hours post-treatment and showed-consistent changes across the time-points. Overall, our analysis sheds light on the mechanism by which XPO1 inhibition induces cell death in breast cancer, which may help elucidate potential biomarkers as well as to nominate rationale combinations to explore with XPO1 inhibition. Citation Format: Robert F. Gruener, Geoffrey L. Greene, R. Stephanie Huang. Investigating inhibition of nuclear export in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 994.

Abstract 1049: Optimizing the treatment schedule of selinexor in combination with decitabine in AML

Abstract Background: Decitabine (DEC) is a hypomethylating agent approved to treat acute myeloid leukemia (AML) that can reactivate tumor suppressor genes that are epigenetically silenced by DNA methylation. Selinexor (SEL) is a selective inhibitor of nuclear export that inhibits exportin 1 (XPO1/CRM1) from shuttling cargoes, including tumor suppressor proteins and oncogene mRNAs bound to eIF4e, from the nucleus to the cytoplasm. DEC priming has been previously found to increase the antileukemic effects of SEL in AML in vitro and in vivo, through DEC-mediated upregulation of tumor suppressor proteins such as CDKN1A (p21) and FOXO3A, which are XPO1 cargos localized in the nucleus after SEL treatment. The goal of this study was to determine the optimal dosing schedule for combination treatment of SEL and DEC in AML. Methods: The efficacy of concomitant and sequential drug treatment using DEC and SEL was evaluated in the subcutaneous implanted MV4-11 xenograft models of AML in NOD-SCID mice. Tumor bearing mice were treated with vehicle, SEL once weekly at 15 mg/kg, DEC at 0.4 mg/kg (M-F, week 1 only) and combinations of DEC with SEL 15 mg/kg on Mondays only (DEC + SEL M, concomitant) or Fridays only (DEC + SEL F, sequential) starting from week 1. In the follow up experiment mice were treated similarly except for revised combination group schedules, SEL was administered once weekly starting either from Friday of week 1 (sequential A) or Monday of week 2 (sequential B). Tumor volume and body weight of mice were monitored for five weeks of treatment, and tumors were collected at the end of the study for immunohistochemistry (IHC) analysis. Results: DEC and SEL effectively inhibited tumor growth as single agents. Concomitant administration of SEL and DEC did not enhance the anti-tumor effect, with no significant difference among the tumor growth inhibition (TGI) rate for mice treated with SEL alone (62.7%), DEC alone (60.0%) and the concomitant combination (DEC + SEL M, 62.6%) (p&amp;gt;0.05). Whereas sequential administration of SEL after DEC priming (DEC + SEL F) enhanced the anti-tumor effects, as TGI (81.7%) was significantly higher than each single agent alone (p&amp;lt;0.05). In the follow up experiment, TGI for the two sequential DEC and SEL combination groups was similar (86.19% for sequential schedule A and 86.17% for sequential schedule B, p&amp;gt;0.05). Conclusions: The introduction of SEL post priming with DEC showed greater TGI than when SEL and DEC were dosed concomitantly. A delay of 4-7 days between the first dose of SEL after DEC priming demonstrated better antileukemic effect than concomitant dosing. This is relevant to potential future clinical trials because separation of dosing DEC and SEL has the potential to increase tolerability of the combination without affecting antileukemic activity. Citation Format: Leah F. Henegar, Hua Chang, Christopher J. Walker, Trinayan Kashyap, Nicholas Fredette, Kathleen Martyn, Sharon Shacham, Yosef Landesman. Optimizing the treatment schedule of selinexor in combination with decitabine in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1049.

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Refractory Multiple Myeloma

Introduction - Elevated expression of XPO1 (Exportin 1) increases the nuclear export / inactivation of tumor suppressor proteins (e.g. p53, IkB, p21, FOXO) and promotes the export / translation of eIF4E-bound oncoprotein mRNAs (e.g. c-MYC, BCL-2, Cyclin D). Selinexor, the first oral Selective Inhibitor of Nuclear Export (SINE) compound, inhibits XPO1 and has shown promising anti-cancer activity across hematological and solid tumors in Phase 1 and 2 clinical trials, including in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Considering the breadth of knowledge on selinexor ± dexamethasone (dex) in RRMM, eltanexor (KPT-8602), a second-generation oral SINE compound, was evaluated for safety and tolerability in this pt population. The primary objectives were to determine the safety, preliminary anti-MM activity, and the recommended Phase 2 dose (RP2D) of eltanexor ± dex.Methods - In this Phase 1/2 study, using a 3+3 dose escalation design, eltanexor is dosed orally (QDx5 or QoDx3 weekly) for a 28-day cycle with a starting dose of 5 mg. Pts with less than a minor response (MR) after 1 cycle or partial response (PR) after 2 cycles were permitted to add low dose dex. In some pts, dex was added from day 1. The pharmacokinetic (PK) and pharmacodynamic (XPO1 mRNA) profiles of eltanexor were evaluated.Results - As of 31-July-2017, 36 pts (23 M/13 F; median prior therapies: 7; median age: 66) with RRMM were enrolled; most with quad- or penta-refractory MM. Median duration of treatment is 76 days (range: 10 - 441). Most common drug related adverse events (AEs; >30%, any grade) are thrombocytopenia, nausea, neutropenia, anemia, leukopenia, fatigue, diarrhea, and dysgeusia. Grade ≥3 related AEs include thrombocytopenia (43%), neutropenia (26%), leukopenia (14%), and anemia (11%). Although 2 dose limiting toxicities (DLTs; >4 missed doses and Grade 4 thrombocytopenia) were observed in different cohorts, the protocol-defined maximum tolerated dose (MTD) was not reached. Further evaluation of 20 or 30 mg eltanexor QDx5 + dex is ongoing in expansion cohorts. The preliminary efficacy of eltanexor (Table 1) shows that eltanexor ± dex can induce responses and disease stabilization. A dose proportional PK profile without accumulation has been observed. Mean Cmax and AUC0-inf values for eltanexor doses of 5 - 60 mg ranged from 36.6 - 284 ng/mL and 164 - 2,581 ng*h/mL, respectively. Tmax and t½ ranged from 0.5 - 8.0 h and 4.0 - 7.1 h, respectively. For all cohorts evaluated, the fold-change maximum (Fmax) of XPO1 mRNA expression was achieved 4 - 8 h post-dose (tmax). The Fmax for XPO1 mRNA was roughly dose proportional to the Cmax of eltanexor. As expected, based on observations with other SINE compounds, the plateau for Fmax of XPO1 mRNA in treated pts was ~6 - 10-fold change and was achievable at 40 - 60 mg of eltanexor.Conclusions - Based on preliminary data, eltanexor is well tolerated and demonstrates promising activity in this heavily pre-treated RRMM population. The gastrointestinal and constitutional toxicities observed with <40 mg eltanexor QDx5 are low grade, transient, and do not limit dosing. Thrombocytopenia (with minimal clinical impact) was the most common hematologic toxicity and was expected in this population. As with selinexor, addition of low-dose dex (20 mg) twice weekly (BIW) to the eltanexor treatment regimen appeared to improve efficacy while maintaining tolerability. Of the 31 evaluable pts, 25 received dex with their eltanexor regimen. Therefore, both 20 and 30 mg eltanexor QDx5 + 20 mg dex BIW are being evaluated to clearly define the RP2D. Based on these results and anti-tumor activity previously observed with selinexor, pts with advanced colorectal cancer, castration resistant prostate cancer, and myelodysplastic syndrome are being enrolled. [Display omitted] DisclosuresRossi:Thrassos: Consultancy; Celgene: Consultancy. Baz:Sanofi: Research Funding; BMS: Research Funding; merck: Research Funding; takeda: Research Funding; celgene: Honoraria, Research Funding; karyopharm: Research Funding. Hofmeister:Roche: Research Funding; Celgene: Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding. Shustik:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Richter:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Chen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Vogl:Teva: Consultancy; Karyopharm: Consultancy; Constellation: Research Funding; GSK: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Amgen: Consultancy; Calithera: Research Funding. Baloglu:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

A Phase Ib/II Trial of Selinexor Combined with Lenalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma

Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs; IkB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. The combination of lenalidomide/dexamethasone (Rd) is an approved regimen in relapsed/refractory multiple myeloma (RRMM) with an overall response rate (ORR) of 70-76% and a low complete response rate. In combination with selinexor, the anticipated overlapping toxicities are fatigue, thrombocytopenia and neutropenia. We hypothesized that selinexor could be safely combined with Rd and improve efficacy.Methods - The objective of this phase 1b/2 dose escalation study (NCT02343042) was to determine the tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) of the combination of selinexor, lenalidomide (len) and dexamethasone (SRd) in RRMM. Patients (pts) with RRMM who received ≥ 1 prior therapy were enrolled. Selinexor was dosed escalated in two regimens once-weekly (QW) or twice weekly (BIW) with both dosing cohorts starting at 60 mg, len 25 mg PO daily and dexamethasone (dex) 20 mg BIW or 40 mg QW.Results - As of 15-Jul-2017, 18 pts (13 male / 5 female) were enrolled. The median age was 68 years and pts received a median of 1 (range, 1 - 7) prior treatment regimen. Thrombocytopenia was the most common side effect with 4 associated DLTs (2 pts each in the 60 mg BIW and 80 QW cohorts). One additional DLT of grade 3 anorexia was observed in the 60 mg BIW cohort. Common treatment-related grade 1/2 adverse events (AEs) included: nausea (67%), anorexia (44%), fatigue (28%), vomiting (28%), and constipation (28%). Grade 3/4 AEs include: thrombocytopenia (56%), neutropenia (39%), fatigue (11%) and anemia (6%). No DLTs were observed with selinexor 60 mg QW and long-term tolerability was observed. Fifteen pts were evaluable for response, of which 11 pts responded for an ORR of 73%. Among the len naïve pts (n=11), an ORR of 91% was seen, including 3 very good partial responses (VGPR), 7 partial responses (PR, 2 unconfirmed) and 1 unconfirmed minor response (MR). Of the len refractory/relapsed pts (n=4), there was 1 unconfirmed PR, 1 MR, and 2 stable disease (SD). Median PFS was 6.6 months with a median follow up of 4 months. Based on tolerability and anti-MM activity the RP2D of SRd is selinexor 60 mg QW, len 25 mg qd and dex 40 mg QW.Conclusions - The all oral combination of SRd has significant clinical activity in pts with MM. Importantly, in len naïve pts, the ORR was 91%. No new or unexpected toxicities were observed. The combination has no thrombotic, cardiac, pulmonary, liver or renal toxicity. The main DLT was thrombocytopenia. This phase 1 trial demonstrated that selinexor be can safely combined with Rd in RRMM with high ORR in len naïve pts. These results support the further studies in both newly diagnosed MM as well as in RRMM. DisclosuresBahlis:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed; Janssen, BMS, Celgene: Consultancy; Celgene: Research Funding. Sebag:Celgene, Janssen: Consultancy. Lentzsch:BMS: Consultancy; Amgen: Consultancy; Caelum Biosciences: Other: leadership position and stock. Bensinger:Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Bayer: Research Funding. Chen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment.

Selinexor in Combination with Pomalidomide and Low Dose Dexamethasone in a Relapsed / Refractory Multiple Myeloma Patient Population with Prior Proteasome Inhibitor and Lenalidomide Exposure

Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM) with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of 3.6 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD. Strategies to improve the ORR and PFS are needed. In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability. We present the results of a phase I dose escalation study of selinexor in combination with pom and dex (SPd) in RRMM.Methods - The primary objective of this phase 1b/2 study (NCT02343042) is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of SPd. Patients (pts) with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60; 80 mg) or twice-weekly (BIW, 60; 80 mg), with pomalidomide (pom) 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW.Results - As of 15-Jul-2017, 29 pts (14 male / 15 female) have been enrolled. The median age is 61 years, with a median of 4 (range, 2 - 9) prior treatment regimens. Twenty-five patients were IMiD refractory (15 len, 2 pom, 8 pom/len). Three dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (60 mg BIW, pom 3 mg) and 4 missed doses in Cycle 1 (100 mg QW, pom 4 mg). Common treatment related Grade 1/2 adverse events (AEs) include: nausea (55%), fatigue (48%), anorexia (48%) and diarrhea (24%). Grade 3/4 AEs include: neutropenia (48%), thrombocytopenia (31%), and anemia (28%). Doses of 60 mg QW and 80 mg QW are being evaluted to determine RP2D. Twenty-four pts were evaluable for response. Responses rates can be seen in Table 1. Median PFS is 11.6 months with a median follow up of 7.7 months. Eight pts are still on study, (range 1 - 16+ months).Conclusions - Once weekly selinexor can be safely combined with Pd. This all oral combination of selinexor, pom and dex (SPd) has significant clinical activity with an ORR 54% in pts with heavily pretreated MM compared to previously published data of 30% ORR. No additional toxicities over monotherapy with selinexor or the Pd combination were observed. The novel all oral combination of SPd is a well-tolerated regimen and supports further clinical development in RRMM. [Display omitted] DisclosuresChen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sebag:Celgene, Janssen: Consultancy. Bensinger:Bayer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding. Gasparetto:Celgene: Research Funding; Janssen, BMS, Celgene: Consultancy; Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed. Lentzsch:Caelum Biosciences: Other: leadership position and stock; Amgen: Consultancy; BMS: Consultancy. Schiller:Celator/Jazz: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment. Bahlis:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.