Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma

Research Article For reprint orders, please contact: [email protected] Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma Mrinal Gounder*,1, Albiruni R Abdul Razak2, Adrienne M Gilligan3, Hoyee Leong3, Xiwen Ma3, Neeta Somaiah4, Sant P Chawla5, Javier Martin-Broto6, Giovanni Grignani7,Scott M Schuetze8, Bruno Vincenzi9, Andrew J Wagner10, Bartosz Chmielowski11, Robin L Jones12, Jatin Shah3, Sharon Shacham3, Michael Kauffman3, Richard F Riedel13 &StevenAttia 14 1Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, NY 10021, USA 2Toronto Sarcoma Program, Princess Margaret Cancer Centre, Toronto, ON, M5G 2C1, Canada 3Karyopharm Therapeutics, Newton, MA 02459, USA 4Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 5Sarcoma Oncology Center, Santa Monica, CA 90403, USA 6Institute of Biomedicine Research (IBIS)/CSIC/Universidad de Sevilla, Virgen del Rocio University Hospital, Calle Antonio Maura Montaner, 41013, Sevilla, Spain 7Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo (TO), Italy 8Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109, USA 9Policlinico Universitario Campus, Bio-Medico, Via ´ Alvaro del Portillo, 200, 00128, Roma, Italy 10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA 11Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90024, USA 12The Royal Marsden NHS Foundation Trust & The Institute of Cancer Research, London, SM2 5PT, UK 13Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA 14Department of Internal Medicine, Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL 32224, USA *Author for correspondence: Tel.: +1 646 888 4167; [email protected] Objective: Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma. Materials & methods: HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size). Results: Pain scores worsened for placebo versus selinexor across all postbaseline visits, although differences in HRQoL at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms deteriorated over time. Conclusion: Patients treated with selinexor reported lower rates and slower worsening of pain compared with patients who received placebo. Lay abstract: The goal of this study was to compare the health-related quality of life (HRQoL) of patients with advanced unresectable dedifferentiated liposarcoma treated with selinexor compared with those treated with placebo. HRQoL was measured prior to treatment initiation and at the first day of each cycle of their treatment using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Pain scores worsened for placebo compared with selinexor across all visits after treatment, but differences at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms worsened over time reflecting the progressive disease burden in this patient population. As pain is one of the most devastating symptoms associated with advanced and progressing cancers, the significant reduction in pain in the selinexor arm, according to patient perception, represent a relevant added value of this drug in dedifferentiated liposarcoma. First draft submitted: 5 March 2021; Accepted for publication: 31 March 2021; Published online: 15 April 2021 Keywords: advanced liposarcoma •pain •patient-reported outcomes •progression-free survival •quality of life •selective inhibitor of nuclear export •selinexor Future Oncol. (2021) 17(22), 2923–2939 ISSN 1479-6694 292310.2217/fon-2021-0284 C 2021 Karyopharm Therapeutics Research Article Gounder, Razak, Gilligan et al. As one of the most common soft-tissue sarcomas (STS) in adults, liposarcomas represent 24 and 45% of extremity and retroperitoneal sarcomas, respectively [1]. Among liposarcomas, the well-differentiated liposarcoma (WDLS)/dedifferentiated liposarcoma (DDLPS) subgroup is the most common, with an incidence of approximately 1000 new cases per year in the USA [2]. It was originally believed that DDLPS was a higher-grade tumor progression from WDLS; however, DDLPS has more recently been understood to have evolved from a common precursor to WDLS, harboring 12q amplification [3]. Localized STS is treated with surgery; however, recurrence is common and systemic treatment options are limited [4,5]. For advanced STS, anthracyclines are considered the standard front-line therapy, with doxorubicin being the most commonly prescribed. While response rates exceeding 20% with doxorubicin alone or in combination with ifosfamide have been reported, median survival in patients with metastatic STS has not improved beyond 20.5 months [6,7]. Subsequent lines of therapy for advanced/metastatic disease include eribulin and trabectedin with median progression-free survival (PFS) of 2.0 and 2.2 months, respectively [8–10]. Thus, current treatment options for DDLPS are limited to parenteral, cytotoxic chemotherapeutic agents, and off-label CDK-4 and -6 inhibitors, presenting an unmet clinical need for more therapeutic options [11,12]. The impact of STS and its treatment on health-related quality of life (HRQoL) can be substantial. Patients receiving treatment commonly report issues with pain, role and social functioning, fatigue, insomnia, loss of appetite, anxiety and depression [13]. A study evaluating the impact of preradiation and postradiation and surgery outcomes among patients with localized extremity STS reported that the magnitude of surgery-related impairment explained 54% of the decline in HRQoL while the ability to participate in activities with friends and family explained 61% of the variation in HRQoL [14]. Another study in the metastatic setting, using the European Organization for Research and Treatment of Cancer 30-item core quality of life (QoL) questionnaire (EORTC QLQ-C30) indicated that disease progression was associated with a 30-point decline in Global Health Status [15]. Understanding patient reported outcomes (PROs) and HRQoL in this population of patients with advanced, incurable disease is critical and has become an increasingly important end point in clinical trials as they provide information on the impact of a disease and its treatment from the perspective of the patient [5,16]. Additionally, the US FDA recognizes HRQoL as a meaningful primary outcome in cancer clinical trials [17]. This study focuses on the HRQoL impact of selinexor, a selective inhibitor of the nuclear export protein exportin 1 in the treatment of advanced and metastatic DDLPS in patients who have experienced disease progression while on at least two prior lines of systemic therapy. Exportin 1 (XPO1 and CRM1) is one of seven encoders of nuclear export receptors responsible for the transport of many proteins and RNA species; overexpression or mutation of XPO1 has been shown to function as an oncogenic driver [18]. The majority of tumor suppressor proteins are exported from the nucleus solely by XPO1; this results in functional inactivation of their anticancer regulatory functions [19–22]. Selinexor is a potent, oral, first-in-class selective inhibitor of nuclear export (SINE) compound that enhances nuclear sequestration of tumor suppressor proteins, growth regulators and messenger RNAs of oncogenic proteins by blocking XPO1 [23–25]. Currently approved in previously treated multiple myeloma and diffuse large B-cell lymphoma [23,26,27], selinexor is being investigated across a broad range of solid tumors. In a Phase I clinical study, oral selinexor demonstrated antitumor activity in patients with DDLPS, reducing target lesion size in 40% of patients, with 47% of patients experiencing stable disease for 4 months or longer. Activity in heavily pretreated leiomyosarcoma and other STS was also observed [28]. The Selinexor In Advanced Liposarcoma (SEAL) trial (ClinicalTrials.gov: NCT02606461) is a Phase II/III, multicenter, randomized, double-blinded, placebo-controlled study initiated to assess the efficacy, safety and HRQoL of patients with advanced unresectable DDLPS treated with either selinexor or placebo. Patients with advanced and metastatic DDLPS that experienced disease progression after at least two prior lines of systemic therapy were enrolled in May 2017 through September 2020 at 70 sites in North America, Europe and Israel. In the Phase III portion of the study, the focus of this manuscript, eligible patients were randomly assigned in a 2:1 ratio to treatment with selinexor or placebo. Patients with other subtypes of liposarcoma or with known CNS metastases were excluded. Patients were administered selinexor (60 mg) or matching placebo in a blinded fashion twice weekly in 6-week cycles. Patients were stratified by prior eribulin or trabectedin use, and the number of prior system therapies (2 vs ≥3). Treatment was administered until disease progression, discontinuation or unacceptable toxic effects. Following objectively confirmed progression, crossover from the placebo arm to open label selinexor was permitted [29]. 2924 Future Oncol. (2021) 17(22) future science group Health-related quality of life & pain with selinexor in patients with advanced dedifferentiated liposarcoma Research Article The primary objective of the SEAL trial was to compare PFS based on the Independent Review Committee’s disease outcome assessments in patients randomized to the selinexor arm versus the placebo arm. The selinexor regimen conferred a 30% increase in median PFS (hazard ratio [HR]: 0.70; median 2.83 vs 2.07; p = 0.0228) [29].Thistrial was one of the largest global Phase III trials in patients with relapsed DDLPS and showed a significantly improved PFS with twice-weekly oral selinexor at 60 mg. The most common side effects, primarily nausea, anorexia and fatigue, were reversible and could be mitigated with standard supportive care; cytopenia was uncommon [30].In this study, the secondary end point of HRQoL outcomes, as measured by the EORTC QLQ-C30, were compared between patients randomized with the selinexor arm versus the placebo arm. Materials & methods Patient population The patient-reported outcome population (PRP) was a subset of the per-protocol population of the Phase III portion of the trial (NCT02606461) and included those who completed the EORTC QLQ-C30 at baseline. All analyses were based on the PRP. PRO assessments At baseline and day 1 of each cycle, the EORTC QLQ-C30 questionnaire was assessed. The EORTC QLQC30 contains 30 questions and includes five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, nausea/vomiting and pain), a Global Health Status/QoL scale and six single-item symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). Scores range from 0 to 100 and higher scores on the functional scales indicate better functioning, while higher scores on the symptom scales indicate more severe symptoms [31]. For this study, prespecified analyses focused on physical functioning, role functioning, pain and global health/QoL. Statistical analyses Quality of completion of each PRO assessment measure was described at each visit by treatment arm. For PRO assessments collected at the visits, the number and percentage of patients who completed all questions were reported. The denominator of the percentage was the number of patients who remained in the study at each assessment. Due to attrition loss, results were reported from change in baseline through day 169 for selinexor versus placebo. By day 211, there was an 85% drop and less than 30 patients in the selinexor arm and a 93% drop and less than ten patients in the placebo arm that completed a PRO questionnaire. Therefore, statistical analyses were unable to be performed past day 169 due to inadequate sample size. Mixed-effect model repeated measures Mixed effects models for repeated measures (MMRM) were fit to the longitudinal data to estimate differences in change from baseline on the respective PRO domains in both adjusted and unadjusted models. Likelihood-based mixed-effect models are a principled approach for handling missing at random data, using all available observations and yielding unbiased estimates by assuming missing data follow the same distribution as the observed data, conditional on observed data [32]. The adjusted MMRM model included treatment, visit, baseline PRO score and a randomization stratification variable. All mixed models included a fixed-effect interaction term between visit and treatment arm and a random effect for patient. Restricted Maximum Likelihood estimation was applied as the primary method. Responder analysis Using literature-based meaningful change thresholds (MCTs) for the EORTC QLQ-C30 domains, at each postbaseline visit, results were reported for the overall population and by treatment arm [33–36]. Meaningful change status for each scale of interest in the direction of the PRO end point were defined as follows: if the score improved from baseline by at least one MCT, the patient was categorized at this cycle as ‘improved’; if the change from baseline was within ±1 MCT, the patient was categorized at this cycle as ‘stable’; and if the score worsened from baseline by at least one MCT, the patient was categorized at this cycle as ‘worsened’. For the EORTC QLQ-C30, Osoba et al. estimated important differences in patients with breast and small-cell lung cancer as 5–10 points for a small effect and 10–20 points for a moderate effect [33]. Kemmler et al. recommended a threshold of 20 points for classifying individual patient change based on findings that thresholds of 5–10 points future science group www.futuremedicine.com 2925 Research Article Gounder, Razak, Gilligan et al. are too low when focusing on the individual patient [34]. A recent evaluation of quality of life in patients with STS used a threshold of 10 points for MCT [35]. Based on this range of recommendations, an intermediate value of 10 points was selected as the MCT for all EORTC QLQ-C30 scales for the following analyses [36]. Chi-squared tests were performed to test for differences between the treatment arms at postbaseline visits. Time to definitive deterioration Time to definitive deterioration (TDD) was defined as the time from randomization to the first occurrence of meaningful deterioration (worsened by at least one MCT) that was not followed by subsequent improvement during the blinded treatment. For patients without a meaningful deterioration, TDD was censored at the time of the last PRO assessment. For patients without a postbaseline PRO assessment, TDD was censored at randomization. Median TDD and its 95% CI were summarized using the Kaplan–Meier method for each treatment arm. Cox proportional hazard models compared the hazard rates between arms adjusted for the stratification variable as the covariate. Post hoc exploratory analysis Analyses to examine the association between baseline HRQoL scores and PFS and overall survival (OS) were performed using Kaplan–Meier techniques and Cox proportional hazards regression. The exploratory analyses were stratified by treatment arm. Results Quality of completion A total of 277 patients were enrolled in the Phase III portion of the trial; 255 (92.1%) completed a baseline QLQ-C30 assessment and were included in these analyses: 168 (65.6%) patients in the selinexor arm and 88 (34.4%) patients in the placebo arm. Overall, completion rates for all items for the EORTC QLQ-C30 in the PRP were generally greater than 95% across most time points in both treatment arms (Table 1). Specifically, at baseline, day 43, day 85, day 127, day 169, day 211 and day 253, the percentage of patients who completed select domains for the EORTC-QLQ-C30 (pain, physical function, role function and Global Health/QoL) ranged from 95.0 to 100.0% in the selinexor arm and 83.3 to 100.0% in the placebo arm. Baseline patient characteristics Age, sex, race and ethnicity was balanced between the two arms (Table 2). The median age was 65 years (range: 33–84). Overall, a higher percentage of males versus females (total: 62.1 vs 37.9%, respectively) were enrolled. Most patients were White (77.7%) and 4.7% were Hispanic or Latino. The majority of patients reported received at least one concomitant pain or steroid medication (75.4%) at any point during the study period. The proportion of patients treated with a concomitant steroid medication was higher in the selinexor arm versus placebo (43.5 vs 19.3%, respectively). Among the 43.5% in the selinexor arm that received a concomitant steroid medication, 71.2% consisted of low dose (2–4 mg) dexamethasone. Approximately 60.5% of patients had an Eastern Cooperative Oncology Group score of 1. At baseline, pain scores were significantly higher in the selinexor arm compared with the placebo arm (28.27 vs 20.27; p = 0.0264) (Table 3). Median baseline tumor burden (defined as the sum of the longest diameter among target lesions per RECIST v1.1) [37] was 156.2 mm in diameter (range: 20.7–486.7) with no significant difference between treatment arms. MMRM analysis Overall, pain scores worsened in the placebo arm compared with the selinexor arm across all postbaseline visits, though some visits (day 43 and 85) were not statistically significant (Table 3 and Figure 1). By day 127, average pain scores significantly worsened by a mean 16.16 points in the placebo arm compared with 3.98 points in the selinexor arm, where a mean -12.18 difference was observed, in favor of the selinexor arm (95% CI: -23.31 to -1.06; p = 0.0320). By day 169, pain scores significantly worsened in the placebo arm compared with the selinexor arm, where a mean -14.24 difference was observed, in favor of the selinexor arm (95% CI: -27.15 to -1.32; p = 0.0308). At day 43, physical function (-6.25; 95% CI: -11.40 to -1.09; p = 0.0177), role function (-9.12; 95% CI: -16.47 to -1.77; p = 0.0152) and Global Health/QoL (-5.53; 95% CI: -11.05 to -0.01; p = 0.0495) significantly worsened for selinexor compared with placebo. This significant trend was observed at day 85 for physical function in favor of placebo (-7.83; 95% CI: -14.38 to -1.29; p = 0.0192). While scores gradually deteriorated across both groups, 2926 Future Oncol. (2021) 17(22) future science group Health-related quality of life & pain with selinexor in patients with advanced dedifferentiated liposarcoma Research Article 43 144 71 94 33 53 17 40 11 26 20 17 11112 12 7 4 288426 85 127 169 211 253 295 337 Study visit (days) Change from baseline Pain subscale 379 421 463 505 547 589 -20 -10 0 10 20 30 40 50 60 70 80 +Selinexor arm Placebo arm 43 143 70 93 33 52 17 39 11 26 20 17 11112 12 7 4 288426 85 127 169 211 253 295 337 Study visit (days) Change from baseline Physical functioning subscale 379 421 463 505 547 589 -40 -30 -20 -10 0 10 20 30 +Selinexor arm Placebo arm ++ ++ + + + +++ ++ + ++ + ++++ 43 143 71 93 33 52 17 39 11 26 20 17 11112 12 7 4 288426 85 127 169 211 253 295 337 Study visit (days) Change from baseline Role functioning subscale 379 421 463 505 547 589 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 +Selinexor arm Placebo arm 43 144 71 94 33 53 17 40 11 26 20 17 11112 12 7 4 288426 85 127 169 211 253 295 337 Study visit (days) Change from baseline Global health status/QoL subscale 379 421 463 505 547 589 -40 -30 -20 -10 0 10 20 30 + Selinexor arm Placebo arm +++++ + ++ ++ + +++ ++ ++ ++ Figure 1. Model-based change from baseline on European Organization for Research and Treatment of Cancer quality of life-30 item questionnaire. QoL: Quality of life. future science group www.futuremedicine.com 2927 Research Article Gounder, Razak, Gilligan et al. Table 1. Quality of completion of the European Organization for Research and Treatment of Cancer quality of life-30 item questionnaire. Time point Domain Completed all items n (%) n Selinexor (n = 168) n Placebo (n = 88) Baseline Pain 168 167 (99.4%) 88 88 (100.0%) Physical function 168 166 (98.8%) 88 87 (98.9%) Role function 168 167 (99.4%) 88 88 (100.0%) Global Health/QoL 168 168 (100.0%) 88 88 (100.0%) Day 43 Pain 144 142 (98.6%) 71 69 (97.2%) Physical function 144 142 (98.6%) 71 70 (98.6%) Role function 144 144 (100.0%) 71 70 (98.6%) Global Health/QoL 144 140 (97.25) 71 71 (100.0%) Day 85 Pain 94 94 (100.0%) 33 33 (100.0%) Physical function 94 92 (97.9%) 33 32 (97.0%) Role function 94 94 (100.0%) 33 33 (100.0%) Global Health/QoL 94 94 (100.0%) 33 33 (100.0%) Day 127 Pain 53 53 (100.0%) 17 17 (100.0%) Physical function 53 52 (98.1%) 17 17 (100.0%) Role function 53 53 (100.0%) 17 17 (100.0%) Global Health/QoL 53 53 (100.0%) 17 17 (100.0%) Day 169 Pain 40 40 (100.0%) 11 11 (100.0%) Physical function 40 39 (97.5%) 11 11 (100.0%) Role function 40 40 (100.0%) 11 11 (100.0%) Global Health/QoL 40 40 (100.0%) 11 11 (100.0%) Day 211 Pain 26 26 (100.0%) 6 6 (100.0%) Physical function 26 25 (96.2%) 6 6 (100.0%) Role function 26 26 (100.0%) 6 6 (100.0%) Global Health/QoL 26 26 (100.0%) 6 5 (83.3%) Day 253 Pain 20 20 (100.0%) 4 4 (100.0%) Physical function 20 19 (95.0%) 4 4 (100.0%) Role function 20 20 (100.0%) 4 4 (100.0%) Global Health/QoL 20 20 (100.0%) 4 4 (100.0%) EORTC QLQ-C30: European Organization for research and treatment of cancer quality of life cancer-30 item questionnaire; QoL: Quality of life. no significant differences were observed across treatment arms beginning at day 127 for physical function, day 85 for role function and day 85 for Global Health/QoL. Responder analysis For the pain domain, the percentage of selinexor patients who experienced worsening of pain was lower compared with the placebo arm (27.1 vs 40.8%, respectively) and the percentage of selinexor patients who experienced an improvement in pain was higher than in the placebo arm (28.5 vs 15.5%, respectively) at day 43 (p = 0.0458) (Table 4). These trends were observed for day 85, 127 and 169, although they were not statistically significant. The percentage of selinexor patients who experienced worsening of symptoms was higher than in the placebo arm for physical function at day 43 (36.4 vs 15.7%; p = 0.0070). However, results became nonsignificant after day 85 (p = 0.0532 and 0.0587 for pain and physical functioning, respectively). Although not considered significant, the percentage of patients who did not experience a deterioration in pain (stable or improved) was higher in the selinexor arm compared with the placebo arm for pain (75.0 vs 63.6%, respectively; p = 0.4835), role function (61.6 vs 36.4%, respectively; p = 0.1508) and Global Health/QoL (67.5 vs 63.6%, respectively; p = 0.8759) but lower for physical function (69.2 vs 81.8%, respectively; p = 0.6453) at day 169. 2928 Future Oncol. (2021) 17(22) future science group Health-related quality of life & pain with selinexor in patients with advanced dedifferentiated liposarcoma Research Article Table 2. Baseline patient characteristics (patient-reported outcome population). Selinexor arm (n = 168) Placebo arm (n = 88) Total (n = 256) Age (years)† n168 88 256 Median 64.5 65.0 65.0 Min, Max 33, 84 31, 85 31, 85 Age category n (%)† 18–50 17 (10.1) 11 (12.5) 28 (10.9) 51–64 67 (39.9) 32 (36.4) 99 (38.7) 65–74 62 (36.9) 36 (40.9) 98 (38.3) ≥75 22 (13.1) 9 (10.2) 31 (12.1) Sex n (%) Male 102 (60.7) 57 (64.8) 159 (62.1) Female 66 (39.3) 31 (35.2) 97 (37.9) Race n (%) Asian 8 (4.8) 2 (2.3) 10 (3.9) Black or African–American 3 (1.8) 1 (1.1) 4 (1.6) Native Hawaiian or other Pacific islander 2 (1.2) 0 2 (0.8) White 126 (75.0) 73 (83.0) 199 (77.7) Other 28 (16.7) 12 (13.6) 40 (15.6) Missing 1 (0.6) 0 1 (0.4) Ethnicity n (%) Hispanic or Latino 6 (3.6) 6 (6.8) 12 (4.7) Not Hispanic or Latino 136 (81.0) 71 (80.7) 207 (80.9) Not reported 21 (12.5) 8 (9.1) 29 (11.3) Unknown 5 (3.0) 3 (3.4) 8 (3.1) Geographic region n (%) North America 86 (51.2) 51 (58.0) 137 (53.5) Europe and Israel 82 (48.8) 37 (42.0) 119 (46.5) Patients with at least one concomitant pain or steroid medication, n (%) 128 (76.2%) 65 (73.9%) 193 (75.4%) Pain 112 (66.7%) 61 (69.2%) 173 (67.6%) Steroid 73 (43.5%) 17 (19.3%) 90 (35.2%) Baseline tumor burden (mm) n161 84 245 Median 153.8 160.8 155.2 Min, Max 20.7, 486.7 30.7, 473.6 20.7, 486.7 ECOG performance status, n (%)‡ 0 64 (38.1%) 37 (42.0%) 101 (39.5%) 1 104 (61.9%) 51 (58.0%) 155 (60.5%) †Age is the age at date of randomization. ‡ECOG performance-status scores range from 0 to 5, with higher scores reflecting greater disability. ECOG: Eastern Cooperative Oncology Group; Max: Maximum; min: Minimum. Time to definitive deterioration The number of patients with definitive deterioration in QLQ-C30 pain scores was greater in the placebo arm (38 patients, 43.2%) compared with the selinexor arm (58 patients, 34.5%) (Table 5). The median TDD was 5.5 months longer in the selinexor arm compared with the placebo arm (8.4 vs 2.9 months). The adjusted HR comparing time with deterioration in pain scores between selinexor and placebo was 0.50 (95% CI: 0.32–0.77; p = 0.0016) in favor of selinexor (Figure 2). There were no significant differences in the TDD for physical function, role function or Global Health/QoL scores. future science group www.futuremedicine.com 2929 Research Article Gounder, Razak, Gilligan et al. Table 3. Model-based change from baseline on European Organization for Research and Treatment of Cancer quality of life-30 item questionnaire.† Domain Least square adjusted mean change (standard error) Selinexor vs placebo Selinexor (n = 168) Placebo (n = 88) Difference (95% CI) p-value QLQ-C30 Baseline –n 168 88 – – – Pain 28.27 (2.13) 20.27 (2.94) 8.11 (0.99 to 15.22) 0.0264 – Physical function 75.55 (1.66) 77.01 (2.29) -1.46 (-7.01 to 4.09) 0.6070 – Role function 69.96 (2.26) 76.70 (3.11) -6.74 (-14.27 to 0.78) 0.0801 – Global Health/QoL 63.19 (1.70) 66.19 (2.35) -3.00 (-8.68 to 2.68) 0.3017 Day 43 –n 144 71 – – – Pain 1.35 (2.44) 8.05 (3.11) -6.70 (-13.69 to 0.29) 0.0603 – Physical function -8.19 (1.79) -1.94 (2.30) -6.25 (-11.40 to -1.09) 0.0177 – Role function -15.58 (2.56) -6.46 (3.25) -9.12 (-16.47 to -1.77) 0.0152 – Global Health/QoL -7.67 (1.94) -2.14 (2.46) -5.53 (-11.05 to -0.01) 0.0495 Day 85 –n 94 33 – – – Pain 3.17 (2.70) 9.44 (3.98) -6.26 (-15.10 to 2.57) 0.1641 – Physical function -11.73 (2.00) -3.90 (2.96) -7.83 (-14.38 to -1.29) 0.0192 – Role function -15.17 (2.91) -6.38 (4.37) -8.79 (-18.53 to 0.95) 0.0767 – Global Health/QoL -8.71 (2.14) -6.60 (3.15) -2.10 (-9.08 to 4.87) 0.5534 Day 127 –n 53 17 – – – Pain 3.98 (3.13) 16.16 (5.04) -12.18 (-23.31 to -1.06) 0.0320 – Physical function -14.73 (2.34) -8.61 (3.77) -6.11 (-14.42 to 2.20) 0.1490 – Role function -20.26 (3.49) -11.20 (5.75) -9.06 (-21.77 to 3.64) 0.1616 – Global Health/QoL -12.46 (2.48) -6.54 (3.99) -5.91 (-14.71 to 2.88) 0.1869 Day 169 –n 40 11 – – – Pain 6.76 (3.436) 20.99 (5.883) -14.24 (-27.15 to -1.32) 0.0308 – Physical function -11.94 (2.581) -3.92 (4.405) -8.02 (-17.70 to 1.66) 0.1039 – Role function -14.63 (3.906) -14.28 (6.821) -0.35 (-15.35 to 14.65) 0.9633 – Global Health/QoL -9.16 (2.726) -8.17 (4.652) -0.99 (-11.20 to 9.22) 0.8489 †A positive increase in pain indicates worsening of symptoms. A positive increase in function scores and global health/QoL indicate improvement of symptoms. EORTC QLQ-C30: European Organization for research and treatment of cancer quality of life cancer-30 item questionnaire; QoL: Quality of life. Exploratory analysis Patients treated with selinexor had significantly longer PFS compared with placebo across all domains despite health status (≥50 or <50 for pain and ≤50 or >50 for physical function, role function and Global Health/QoL) and no difference in tumor burden at baseline (Table 6). In the context of crossover, where many of the patients on placebo did cross over to selinexor, there was no significant differences observed for OS. Discussion Liposarcomas are rare malignancies with substantial heterogeneity and these differences are exacerbated by prior surgeries, cytotoxic chemotherapies and radiation. These factors pose profound challenges in clinical practice and confound our understanding of the patient experience. To better understand the experience of patients with advanced DDLPS, this study aimed to assess changes in HRQoL between the selinexor and placebo arms. The underlying hypothesis for this study was that first-in-class oral selinexor provides equivalent (or better) PROs in HRQoL domains when compared with placebo in the context of improving PFS and tumor shrinkage. These analyses focused on the pain, physical functioning, role function and Global Health/QoL scores from the EORTC 2930 Future Oncol. (2021) 17(22) future science group Health-related quality of life & pain with selinexor in patients with advanced dedifferentiated liposarcoma Research Article Table 4. Categorical change from baseline to day 169 by treatment arm for European Organization for Research and Treatment of Cancer quality of life-30 item questionnaire scores. Domain Status Selinexor Placebo p-value EORTC QLQ-C30 pain Day 43 n 144 71 0.0458 Worsened 39 (27.1%) 29 (40.8%) Stable 64 (44.4%) 31 (43.7%) Improved 41 (28.5%) 11 (15.5%) Day 85 n 94 33 0.0532 Worsened 28 (29.8%) 16 (48.5%) Stable 41 (43.6%) 14 (42.4%) Improved 25 (26.6%) 3 (9.1%) Day 127 n 53 17 0.2926 Worsened 17 (32.1%) 6 (35.3%) Stable 20 (37.7%) 9 (52.9%) Improved 16 (30.2%) 2 (11.8%) Day 169 n 40 11 0.4835 Worsened 10 (25.0%) 4 (36.4%) Stable 20 (50.0%) 6 (54.5%) Improved 10 (25.0%) 1 (9.1%) EORTC QLQ-C30 physical function Day 43 n 143 70 0.0070 Worsened 52 (36.4%) 11 (15.7%) Stable 77 (53.8%) 48 (68.6%) Improved 14 (9.8%) 11 (15.7%) Day 85 n 93 33 0.0587 Worsened 33 (35.5%) 7 (21.2%) Stable 53 (57.0%) 19 (57.6%) Improved 7 (7.5%) 7 (21.2%) Day 127 n 52 17 0.1973 Worsened 26 (50.0%) 5 (29.4%) Stable 21 (40.4%) 8 (47.1%) Improved 5 (9.6%) 4 (23.5%) Day 169 n 39 11 0.6453 Worsened 12 (30.8%) 2 (18.2%) Stable 19 (48.7%) 7 (63.6%) Improved 8 (20.5%) 2 (18.2%) EORTC QLQ-C30 role function Day 43 n 143 71 0.7417 Worsened 64 (44.8%) 28 (39.4%) Stable 53 (37.1%) 28 (39.4%) Improved 26 (18.2%) 15 (21.1%) Day 85 n 93 33 0.0352 Worsened 45 (48.4%) 14 (42.4%) Stable 22 (23.7%) 15 (45.5%) Improved 26 (28.0%) 4 (12.1%) Day 127 n 52 17 0.0298 Worsened 30 (57.7%) 5(29.4%) Stable 15 (28.8%) 11 (64.7%) Improved 7 (13.5%) 1 (5.9%) MCT values: QLQ-C30 functioning and pain =10. 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