Improved Quality of Life (QOL) with Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Compared with Standard of Care (SOC) As Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Phase 3 Transform Study

Background: Pts with previously treated R/R aggressive LBCL have compromised health-related QOL (HRQOL). Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In a prespecified interim analysis of TRANSFORM (NCT03575351), a randomized, open-label, pivotal trial, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint of event-free survival and key secondary endpoints (complete response rate and progression-free survival) in adults with R/R LBCL after failure of first-line (1L) immunochemotherapy compared with SOC, with no new safety signals. Here we present results of the pt-reported outcomes (PRO) analysis from TRANSFORM. Methods: Adults (age ≤ 75 yrs) with R/R LBCL (≤ 12 mo after 1L therapy), who were eligible for autologous stem cell transplantation (ASCT), were randomized to receive either SOC (3 cycles of salvage chemotherapy [CT] and BEAM + ASCT for responding pts) or liso-cel after lymphodepletion. Crossover to receive liso-cel was allowed in the SOC arm for pts who failed treatment. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - 30 items (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) were administered at randomization (baseline) and on Days 29 (infusion of liso-cel or 2 cycles of salvage CT), 64 (1 mo post liso-cel or completion of CT), 126 (3 mos post liso-cel or 2 mos post ASCT), and Mo 6 and other prespecified timepoints up to Mo 36 or end of study. No PRO data were collected after crossover. The analysis was based on the PRO-evaluable population (pts with a baseline and ≥ 1 post-baseline assessment). Predefined thresholds determined clinically meaningful changes. Global health/QOL (GH/QOL), physical functioning, cognitive functioning, fatigue, pain, and FACT-LymS were the primary domains of interest based on their relevance to the study population and treatment. A linear mixed model for repeated measures (MMRM) analysis was performed to assess the between-treatment difference in overall least squares (LS) mean change from baseline for each primary domain, using data collected up to Day 126 for visits with a sample size per arm ≥ 10. Proportions of pts with meaningful change from baseline were assessed for each primary domain up to Mo 6. All analyses were descriptive only. Results: Of 184 randomized pts, 90 (49%) and 85 (46%), respectively, were included in the PRO-evaluable population for the EORTC QLQ-C30 (SOC vs liso-cel n=43 vs 47) and FACT-LymS (n=40 vs 45, respectively). The PRO assessment completion rate from baseline up to Mo 6 was ≥ 45%, which was lower than expected primarily due to operational challenges during the COVID-19 pandemic but was comparable for both arms. In the MMRM analysis, the liso-cel arm had more favorable overall LS mean changes from baseline to Day 126 than the SOC arm in most of the EORTC QLQ-C30 domains and FACT-LymS. In particular, the between-treatment differences for cognitive functioning (−2.09 vs 2.21) and fatigue (3.75 vs −1.95) for SOC versus liso-cel, respectively, exceeded the prespecified minimal important difference threshold (Table); in those domains, the SOC arm deteriorated while the liso-cel arm improved. In individual-level analyses, the proportion of pts with meaningful improvement for fatigue and GH/QOL was higher, while deterioration was lower, in the liso-cel arm versus SOC arm from baseline up to Mo 6 (Figure). At Mo 6, a higher proportion of pts experienced worsened fatigue (71% vs 18%) and a lower proportion experienced improved fatigue (29% vs 47%) in the SOC arm compared with the liso-cel arm; for GH/QOL, a higher proportion of pts worsened (57% vs 18%) and lower proportion improved (14% vs 53%), respectively. For the other primary domains, the proportions of pts with improvement or deterioration favored liso-cel or were similar between arms. Conclusions: Compared with SOC, liso-cel showed favorable improvement in most primary PRO domains, particularly EORTC QLQ-C30 cognitive functioning and fatigue and more pts showed PRO improvements and fewer showed deterioration by Mo 6 with liso-cel. The results were achieved despite only responders remaining in the SOC arm after salvage CT. HRQOL was either improved or maintained after liso-cel treatment in pts with R/R LBCL after failure of 1L therapy. Figure 1 Figure 1. Disclosures Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Kite Pharma: Consultancy; Kymera: Consultancy; Incyte Corporation: Consultancy; Bluebird Bio: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; BeiGene: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman: BMS: Current Employment, Current equity holder in publicly-traded company. Guo: Daiichi Sankyo: Consultancy; UCB: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Bristol Myers Squibb: Consultancy; EMD Serono: Consultancy; Evidera: Current Employment. Shi: Bristol Myers Squibb: Consultancy. Kamdar: ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; SeaGen: Speakers Bureau; Celgene: Other; Genetech: Other; Celgene (BMS): Consultancy.

COVID-19 Pandemic Impact on Chronic Lymphocytic Leukemia (CLL) Patients' Preferences Towards Therapies: The Italian Experience (CHOICE Study)

Introduction: All the available CLL therapies differ for relevant aspects as duration of response, mode of administration, treatment duration and adverse events: the CHOICE study was designed to investigate CLL patients' Quality of Life (QoL) and preferences towards different treatment attributes through a Discrete Choice Experiment (DCE) in Italy. Due to the timeline of the study, started in Feb2020, the collected data offer an insight of patients' perception and attitude during the 1 st wave of the COVID-19 pandemic, as opposed to other DCE results available in CLL (1-2). Methods: This cross-sectional multi-center observational study enrolled patients (pts) with CLL, WATCH&WAIT (W&W) or already TREATED (around 50% each, controlled at site level), who signed the informed consent for study participation. Exclusion criteria were inability to take oral drugs, cognitive disorders that could impair questionnaire's comprehension and concomitant therapy for other malignancies. Pts were asked to fill in 3 QoL questionnaires: EQ-5D-5L, EORTC QLQ-C30, QLQ CLL-16, described elsewhere. DCE Questionnaire was composed of 9/10 blocks (for W&W/TREATED, respectively) each composed of 8 comparisons between 2 profiles with the following attributes: "Treatment and relevant duration", "PFS", "Possibility of infections", "Possible occurrence of organ damage", "Possible occurrence of diarrhea", with levels specified in Fig1. Each patient (pt) was centrally assigned to 1 block of 8 comparisons. Each pt could ask questionnaire explanations to the medical staff but self-completed it on an App specifically developed for the study. Results: 401 pts were enrolled in Italy across 16 centers (Feb-Jul 2020),199 W&W and 198 TREATED pts completed the DCE questionnaire and were included in the evaluable population. Main pts' characteristics are shown in Table 1. 73.7% of TREATED pts were ON-treatment (30.8% in 1st-line, 69.2% in further lines) and 26.3% were OFF-treatment. DCE results showed that W&W pts rated as most important the 'Possibility of infections' (relative importance, RI=36.2%), followed by 'Treatment and Relevant duration' (RI=28.0%), 'PFS' (RI=16.9%), while 'Possible occurrence of organ damage' (RI=12.5%) and 'Possible occurrence of Diarrhea' (RI=6.4%) had lower impact on the preference (Fig 1A). DCE in TREATED pts showed that they gave more importance to 'Treatment and relevant duration' (RI =33.3%) followed by 'Possibility of infections' (RI =28.8%). The RI of the other attributes was lower: 'Possible occurrence of organ damage' (RI =19.4%), 'PFS' (RI =9.8%), 'Possible occurrence of diarrhea' (RI =8.7%, Fig 1B). A sub-analysis stratifying pts from Northern regions (more impacted during the 1 st wave of the pandemic) and Center-Southern regions showed that in W&W pts from North Regions the attribute with a higher impact is 'Treatment and Relevant duration' (RI=40.3%) followed by 'Possibility of infection' (RI=27.2%), while in W&W pts from Central-Southern area, the attribute with a higher impact is 'Possibility of infection' (RI=43.4%) followed by 'Possible occurrence of Organ damage' (RI=21.6%). In TREATED pts no difference between the 2 groups has been shown and the results are consistent with the total population. Conclusions: CHOICE study was planned to understand CLL patients' preferences towards different treatment attributes, but the results have been impacted by the concurrent COVID-19 pandemic. In contrast to previously published DCEs (1-2), where PFS was the most important attribute, in the CHOICE study pts put much more emphasis on their concerns about possible infections: this could be due to the influence of the 1 st Covid-19 pandemic wave, with the relevant feeling of uncertainty, also due to the great attention that media has dedicated to the issue of infection in general, especially for vulnerable individuals such as CLL pts. The limitation in hospital access during the 1 st wave and the overall need of personal protection (masks usage) and social distancing might have influenced patients' responses too. The "infodemic" and the uncertainty had probably such a strong effect on patient's feelings, that PFS was no longer the most important attribute being substituted by the fear of hospitals access and infections. We thereby suggest that the pandemic had a great impact not only on the conduct of the study but also on patients' perception of their disease, if not properly reassured. Figure 1 Figure 1. Disclosures Molica: Astrazeneca: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Laurenti: AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; BeiGene: Honoraria. Ghia: Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Coscia: Gilead: Honoraria; Janssen: Honoraria, Other, Research Funding; AstraZeneca: Honoraria; AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Honoraria; Janssen: Honoraria, Speakers Bureau; AstraZeneca: Honoraria; AbbVie: Honoraria, Speakers Bureau; Incyte: Honoraria. Mauro: Takeda: Consultancy, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy. Gualberti: AbbVie: Current Employment. Iannella: AbbVie: Current Employment. Finsinger: AbbVie: Current Employment. Caira: AbbVie: Current Employment. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

Real-world efficacy and safety of pangenotypic direct-acting antivirals against hepatitis C virus infection in Taiwan

Clinical trials showed pangenotypic direct-acting antivirals’ (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.

Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Final results of a phase 1b study of isatuximab short-duration fixed-volume infusion combination therapy for relapsed/refractory multiple myeloma

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.

Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study.

505 Background: Talazoparib (TALA) is a poly(ADP-ribose) polymerase inhibitor approved as monotherapy for treating adult patients (pts) with g BRCA1/2-mutated HER2-negative locally advanced or metastatic BC. Methods: This phase 2, non-randomized, single-arm, open-label study (NCT03499353) evaluated the efficacy and safety of TALA in the neoadjuvant setting for pts with early g BRCA1/2-mutated HER2− BC. Primary endpoint was evaluation of pathologic complete response (pCR) as assessed by Independent Central Review (ICR) after completing 24 weeks of neoadjuvant TALA monotherapy 1 mg QD (0.75 mg for moderate renal impairment) followed by surgery. Secondary endpoints included pCR by investigator (INV) and residual cancer burden (RCB) by ICR (RCB: 0 [pCR], I [minimal], II [moderate], III [extensive]). The evaluable population included pts who received at least 80% of the TALA dose prescribed at treatment start and underwent breast surgery and pCR assessment, plus those who progressed before pCR could be assessed. The intent-to-treat (ITT) population included all pts who received at least 1 dose of TALA. Results: Of 61 pts treated with TALA (ITT and safety populations), 48 comprised the evaluable population. All pts had triple-negative BC. 60 pts had adenocarcinoma and 1 had squamous cell histology, with the following staging: I=20, II=27, III=14. Mean age was 44.6 years, mean duration of 4.5 wks since disease onset, mean duration of treatment of 23.3 wks, and mean overall relative dose intensity of 84.5% (ITT population). pCR (assessed by ICR and INV) and RCB (by ICR) for the evaluable and ITT populations are shown in the table below. Ten (16.4%) patients discontinued treatment due to progressive disease. One pt had a disruption of treatment as a result of COVID-19 restrictions, 2 pts for other reasons: to undergo surgery early and consent withdrawal; 9 patients received <80% dose. Treatment-emergent adverse events (AEs) were reported in 98.4% of pts (27.9% grade [G] 1, 23.0% G2, 45.9% G3, 1.6% G4); the most common were fatigue (78.7%; G1 54.1%; G2 21.3%; G3 3.3%), nausea (68.9%; G1 54.1%; G2 13.1%; G3 1.6%), and alopecia (57.4%; G1 54.1%; G2 3.3%). Three (4.9%) pts discontinued treatment due to AEs (G3 anemia [n=2] and G3 vertigo [n=1]) and continued on study. Conclusions: TALA monotherapy in the neoadjuvant setting was active and showed pCR rates comparable to those observed with combination anthracycline and taxane-based chemotherapy regimens and was generally well tolerated. Clinical trial information: NCT03499353. [Table: see text]

434 Updated clinical data from the melanoma expansion cohort of an ongoing Ph1/1b Study of eganelisib (formerly IPI-549) in combination with nivolumab

BackgroundEganelisib is a first-in-class, oral, selective PI3K-γ inhibitor. Preclinically, eganelisib reprograms macrophages/myeloid derived suppressor cells (MDSCs) from an immune-suppressive to an immune-activating phenotype and enhances efficacy of checkpoint inhibitors. Efficacy of eganelisib + nivolumab in patients with advanced melanoma resistant to immediate prior anti-PD(L)1 therapy is presented.MethodsIPI-549-01 (NCT02637531) evaluates eganelisib in advanced solid tumors, as monotherapy and in combination with nivolumab. The combination expansion dose was eganelisib 40 mg QD PO + nivolumab 240 mg Q2W IV. Combination expansion cohorts include unresectable stage III/IV melanoma patients resistant to immediate prior anti-PD(L)1 therapy. Safety, preliminary clinical activity, PK, and correlative study of blood and tumor biopsy samples were mandated.ResultsAs of June 1, 2020, 180 patients were treated with eganelisib + nivolumab including 40 with melanoma.The most common (>20% of patients) treatment-emergent adverse events in patients treated with eganelisib + nivolumab (N = 180) were fatigue (34.4%), increased AST (30.0%), increased ALT (26.7%), nausea (25.0%), pyrexia (25.0%), anemia (22.8%), decreased appetite (20.6%), and cough (20.6%). 85 (47.2%) patients experienced at least 1 treatment-emergent serious adverse event (SAE) and 19 (10.6%) had a treatment-related SAE. There was no toxicity unique to the melanoma cohort, and no treatment-related death as assessed by investigators.Preliminary data from the melanoma cohort show that in the efficacy-evaluable population which includes all patients (n=39) who had at least 1 post-baseline response assessment or discontinued treatment due to disease progression, the overall response rate (ORR, ie. CR [complete response] or PR [partial response] per RECIST v1.1) is 7.7%, the disease control rate (DCR, ie. CR, PR, or SD [stable disease]) is 35.9%, and the clinical benefit rate (CBR, ie. CR, PR, or SD of at least 24 weeks from first treatment) is 17.9%, per RECIST v1.1. For patients that received ≤ 2 lines of prior systemic therapy (n=19), the ORR is 15.8%, the DCR is 52.6%, and the CBR is 36.8%. In total, there are 3 patients with PR (duration of response 4–12 months) and 4 with SD > 6 months‘ treatment duration.Translational data evaluating blood MDSCs, cytokines, and proliferation of previously exhausted CD8 memory T-cells as well as changes in immune cell infiltrates from tumor biopsies will be presented.ConclusionsEganelisib + nivolumab demonstrates an acceptable safety profile and clinical activity in patients with melanoma who were resistant to immediate prior anti-PD(L)1 therapy. Updated clinical and translational data will be presented.Ethics ApprovalThe study was approved by WIRB, Study Number 1188591 and IRB Tracking Number: 20180297.

352 Updated clinical data from the squamous cell carcinoma of the head and neck (SCCHN) expansion cohort of an ongoing Ph1/1b Study of eganelisib (formerly IPI-549) in combination with nivolumab

BackgroundEganelisib is a first-in-class, oral, selective PI3K-γ inhibitor. Preclinically, eganelisib reprograms macrophages/myeloid derived suppressor cells (MDSCs) from an immune-suppressive to an immune-activating phenotype and enhances efficacy of checkpoint inhibitors. Efficacy of eganelisib + nivolumab in patients with SCCHN resistant to immediate prior anti-PD(L)1 therapy is presented.MethodsIPI-549-01 (NCT02637531) evaluates eganelisib in advanced solid tumors, as monotherapy and in combination with nivolumab. The combination expansion dose was eganelisib 40 mg QD PO + nivolumab 240 mg Q2W IV. Combination expansion cohorts include SCCHN patients resistant to immediate prior anti-PD(L)1 therapy. Safety, preliminary clinical activity, PK, and correlative study of blood and tumor biopsy samples were mandated.ResultsAs of June 1, 2020, 180 patients were treated with eganelisib + nivolumab including 21 with SCCHN.The most common (>20% of patients) treatment-emergent adverse events in patients treated with eganelisib + nivolumab (N = 180) were fatigue (34.4%), increased AST (30.0%), increased ALT (26.7%), nausea (25.0%), pyrexia (25.0%), anemia (22.8%), decreased appetite (20.6%), and cough (20.6%). 85 (47.2%) patients experienced at least 1 treatment-emergent serious adverse event (SAE) and 19 (10.6%) had a treatment-related SAE. There were no treatment-related grade 5 adverse events as assessed by investigators. Preliminary data from the SCCHN cohort show that in the efficacy-evaluable population which includes all patients (n=20) who had at least 1 post-baseline response assessment or discontinued treatment due to disease progression, the overall response rate (ORR, ie. CR [complete response] or PR [partial response] per RECIST v1.1) is 10.0%, the disease control rate (DCR, ie. CR, PR, or SD [stable disease]) is 45.0%, and the clinical benefit rate (CBR, ie. CR, PR, or SD of at least 24 weeks from first treatment) is 25.0%, per RECISTv1.1. For patients that received ≤ 2 lines of prior systemic therapy (n=11), the ORR is 20.0%, the DCR is 40.0%, and the CBR is 30.0%. In total, there are 2 patients with PR (duration of response 1.6–9.3 months) and 3 with SD for greater than 6 months‘ treatment duration. Translational data including T cell proliferation in peripheral blood as well as markers of inflammation in baseline biopsy of PR patient will be presented.ConclusionsEganelisib + nivolumab demonstrates an acceptable safety profile and preliminary clinical activity in patients with SCCHN who were resistant to immediate prior anti-PD(L)1 therapy. Updated clinical and translational data will be presented.Ethics ApprovalThe study was approved by WIRB, Study Number 1188591 and IRB Tracking Number: 20180297.

First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

8500 Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity. Methods: A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts. Eligible pts had progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for currently available therapies. Several treatment schedules tested escalating doses of CC-92480 + DEX (40 mg; 20 mg if ≥75 yrs). Results: As of Dec 24, 2019, 66 pts had received CC-92480 + DEX. Median age was 67 yrs (range 40–78), median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses explored included 0.1–1.0 mg QD (10/14 days × 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days × 2), and 1.6–2.0 mg QD (7/14 days × 2). MTD was 1.0 mg for both 10/14 × 2 and 21/28 schedules. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) pts. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among different cohorts,10 pts had dose-limiting toxicities (the majority related to neutropenia). Overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 PRs) for efficacy evaluable population (n = 66). Efficacy was dose and schedule dependent; across two 1.0 mg QD schedules (10/14 × 2 and 21/28), 10 of 21 (48%) pts responded (7 VGPR and 3 PR), with response independent of immunomodulatory drug (IMiD) refractoriness. Plasma exposure increase and peripheral blood Ikaros and Aiolos degradation were dose dependent. Ikaros and Aiolos significantly decreased in bone marrow plasma cells of LEN- and POM-refractory pts. Conclusions: TEAEs of CC-92480 were mainly related to myelosuppression in heavily pretreated, including triple-class-refractory, RRMM pts. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize dose and schedule, with combination studies underway and dose expansion cohorts planned. Clinical trial information: NCT03374085 .

Intracranial activity of selpercatinib (LOXO-292) in RET fusion-positive non-small cell lung cancer (NSCLC) patients on the LIBRETTO-001 trial.

9516 Background: Patients with RET fusion-positive NSCLC have an ~50% lifetime prevalence of developing central nervous system (CNS) metastases. Selpercatinib is a highly selective oral RET inhibitor with CNS penetration. Its intracranial antitumor activity was previously demonstrated in an orthotopic RET fusion-positive preclinical model. The activity of selpercatinib in RET fusion-positive NSCLC patients with CNS metastases was evaluated as a prespecified subgroup analysis in LIBRETTO-001, a registrational phase 1/2 trial (NCT03157128). Methods: This global (89 sites, 16 countries) trial enrolled patients with advanced RET-altered solid tumors, including patients with RET fusion-positive advanced NSCLC with baseline CNS metastases. The selpercatinib recommended phase 2 dose was 160 mg twice daily, dosed orally in 28-day cycles. CNS metastases were assessed by MRI/CT scan at baseline, then every 8 weeks for 1 year, and every 12 weeks thereafter. The primary endpoint for this analysis was intracranial objective response rate (ORR, confirmed; RECIST v1.1) as assessed by independent review committee (IRC). Secondary endpoints included intracranial duration of response (DoR) by IRC. To be included in the efficacy analysis, patients were required to have adequate follow-up time (opportunity for ≥6 months follow-up from the first dose). Analyses were based on 17Jun2019 data cutoff date. Results: 79 patients with RET fusion-positive NSCLC and baseline CNS metastases were enrolled. Per IRC, 22 of 79 patients had measurable (≥10 mm) CNS disease; 14 of the 22 patients had adequate follow-up time for analysis. This efficacy-evaluable population had a median age of 64 yrs (range 43-80), ECOG PS 0/1 = 21% / 79%, and all had prior systemic therapy. 5 of the 14 patients received prior intracranial radiotherapy; all radiotherapy was completed > 2 months prior to selpercatinib. The intracranial ORR in the 14 patients was 93% (n = 13; 95% CI = 66.1 – 99.8), including 2 complete responses (14%) and 11 partial responses (79%). The median intracranial DoR was 10.1 months (95% CI = 6.7 – NE), with CNS progression events (n = 5) or death (n = 1) reported in 6 of 13 responders. The remaining responders (n = 7) were ongoing and censored. Presentation will include updated IRC data as of 16Dec2019. Conclusions: Selpercatinib had marked intracranial anti-tumor activity in RET fusion-positive NSCLC patients with CNS metastases. Tumor responses were durable, independently-confirmed, and observed in patients with prior systemic chemotherapy. Clinical trial information: NCT03157128 .