Primary Analysis Set Research Articles

Severe Acute Respiratory Syndrome Coronavirus 2 Household Transmission During the Omicron Era in Massachusetts: A Prospective, Case-Ascertained Study Using Genomic Epidemiology.

Households are a major setting for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but there remains a lack of knowledge regarding the dynamics of viral transmission, particularly in the setting of preexisting SARS-CoV-2 immunity and evolving variants. We conducted a prospective, case-ascertained household transmission study in the greater Boston area in March-July 2022. Anterior nasal swabs, along with clinical and demographic data, were collected for 14 days. Nasal swabs were tested for SARS-CoV-2 by polymerase chain reaction (PCR). Whole genome sequencing was performed on high-titer samples. We enrolled 33 households in a primary analysis set, with a median participant age of 25 years (range, 2-66 years), 98% of whom had received at least 2 doses of a coronavirus disease 2019 (COVID-19) vaccine. Fifty-eight percent of households had a secondary case during follow-up and the secondary attack rate (SAR) for contacts was 39%. We further examined a strict analysis set of 21 households that had only 1 PCR-positive case at baseline, finding an SAR of 22.5%. Genomic epidemiology further determined that there were multiple sources of infection for household contacts, including the index case and outside introductions. When limiting estimates to only highly probable transmissions given epidemiologic and genomic data, the SAR was 18.4%. Household contacts of a person newly diagnosed with COVID-19 are at high risk for SARS-CoV-2 infection in the following 2 weeks. This is, however, not only due to infection from the household index case, but also because the presence of an infected household member implies increased SARS-CoV-2 community transmission.

OP36 Risankizumab Versus Ustekinumab for the Achievement of Clinical Outcomes and Symptom Improvement in Patients With Moderate To Severe Crohn’s Disease: Results From the Phase 3b SEQUENCE Trial

Abstract Background The efficacy and safety of risankizumab (RZB) and ustekinumab (UST) in patients (pts) with moderate to severe Crohn's disease (CD) refractory to prior anti-tumour necrosis factor (TNF)α therapy were compared in the SEQUENCE head-to-head study. Previously, wk24 CD activity index (CDAI) clinical remission rates (CDAI<150) were reported for 50% of pts (first primary endpoint);1 here, the efficacy of RZB versus (vs) UST for achieving wk24 clinical remission and other symptomatic improvements in the full pt population was assessed. Methods SEQUENCE (NCT04524611) was an open-label, multicenter, randomised, efficacy assessment-blinded study in pts with moderate to severe CD (defined in Figure footnote) refractory to TNFα therapy. Pts in the primary efficacy analysis set were randomised 1:1 to receive RZB (intravenous [IV] 600mg induction at BL, week (wk)4 and wk8, then 360mg subcutaneous [SC] maintenance every 8 wks [Q8w], starting at wk12) or UST (single weight-based IV induction followed by a 90mg Q8w SC maintenance starting at wk8) up to wk48. A mandatory steroid taper began at wk2. Randomisation was stratified by BL steroid use and number of failed anti-TNFs. Prespecified non-ranked endpoints included CDAI clinical response and stool frequency (SF)/abdominal pain score (APS) clinical remission (definitions in Figure footnote). CDAI clinical remission at wk48 was a ranked secondary endpoint. CDAI clinical remission at wks 8 and 24, and changes from BL in avg daily APS, SF, and CDAI, were evaluated post-hoc. Binary endpoints were analysed using non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. Continuous endpoints were analysed using a mixed-effect model with repeated measures. All P values are nominal, except for wk48 CDAI clinical remission (ranked secondary endpoint). Results With RZB vs UST, respectively, greater rates of CDAI clinical remission (59.6% [152/255] vs 42.6% [113/265]; P=0.0001), SF/APS clinical remission (55.7% vs 41.1%; P<0.001) and CDAI clinical response (69.8% vs 54.3%; P<0.001) were observed at wk24; similar results were observed at wk48 (Figure). Mean BL APS in the RZB and UST groups was 1.9 (both groups), SF was 5.5 and 5.6, and CDAI was 309.4 and 310.1, respectively. Least square (LS) mean changes from BL in APS, SF, and CDAI were greater with RZB vs UST and observed early as wk8 (APS: -0.9 vs -0.8; SF: -3.0 vs -2.3; P<0.001; CDAI: -136.3 vs -117.1; P<0.05) (Figure). The safety profiles of RZB and UST were consistent with published results.1 Conclusion In this head-to-head study, improvements in symptomatic outcomes in pts with CD were greater with RZB than UST over 48 wks of treatment. 1doi.org/10.1002/ueg2.12474

DOP10 Risankizumab Versus Ustekinumab for the Achievement of Endoscopic Outcomes in Patients With Moderate-to-Severe Crohn’s Disease: Results From the Phase 3b SEQUENCE Trial

Abstract Background The SEQUENCE study compared the efficacy and safety of risankizumab (RZB) and ustekinumab (UST) in patients (pts) with moderate-to-severe Crohn's disease (CD) who previously failed ≥1 anti-tumour necrosis factor (TNF)a therapies. The second primary endpoint of SEQUENCE, week (wk) 48 endoscopic remission, demonstrated superiority of RZB versus (vs) UST.1 Here, additional endoscopic and clinical/endoscopic composite outcomes are reported. Methods SEQUENCE (NCT04524611) was an open-label, multicenter, randomised, efficacy assessment-blinded study. Pts had a baseline (BL) CD Activity Index (CDAI) of 220-450, average (avg) daily stool frequency ≥4 and/or avg daily abdominal pain score ≥2, and Simple Endoscopic Score for CD (SES-CD) ≥6 (≥4 for isolated ileal disease). Pts in the primary efficacy analysis set were randomised 1:1 to receive RZB (intravenous [IV] 600mg induction at BL, wk4 and wk8, then 360mg subcutaneous [SC] maintenance doses every 8 wks [Q8w], starting at wk12) or UST (single weight-based IV induction followed by a 90mg Q8w SC maintenance treatment starting at wk8) up to wk48. Randomisation was stratified by BL steroid use and number of failed anti-TNFa therapies. A mandatory steroid taper began at wk2. Here, we assessed at wks 24 and 48 endoscopic remission (SES-CD ≤4 and at least a 2-point reduction versus BL and no subscore >1 in any individual variable, as scored by a central reader), mucosal healing (SES-CD ulcerated surface subscore of 0 in pts with SES-CD ulcerated surface subscore ≥1 at BL, as scored by a central reader), and deep remission (endoscopic remission + clinical remission [CDAI<150]); all were prespecified, non-ranked endpoints, except for wk48 endoscopic remission (second primary endpoint). Treatment differences were adjusted for the randomisation stratification factors. Missing data were handled using non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. P values were reported as nominal, except for wk48 endoscopic remission. Results With RZB vs UST, a greater proportion of pts achieved endoscopic remission (wk24: 29.4% vs 17.4%, P= 0.001; wk48: 31.8% vs 16.2%, P<0.0001), mucosal healing (wk24: 25.1% vs 14.4%, P<0.01; wk48: 30.2% vs 12.1%, P<0.0001), and the composite endpoint of deep remission (wk24: 22.0% vs 10.2%, P< 0.001; wk48: 22.7% vs 10.9%, P<0.001) at wk24 and wk48 (Figure). The safety profiles of RZB and UST were consistent with published results.1 Conclusion Exploration of endoscopic outcomes demonstrated that pts with moderate-to-severe CD and prior anti-TNFa failure showed greater achievement of endoscopic remission, mucosal healing, and deep remission with RZB compared to UST. 1doi.org/10.1002/ueg2.12474

Quantum-First (Q-F): Clinical Bridging Study for FMS-like Tyrosine Kinase 3-Internal Tandem Duplication ( FLT3-ITD) Companion Diagnostic Development

Background Q-F (NCT02668653) showed that the highly potent, selective, type 2 FLT3 inhibitor quizartinib (Q) + standard chemotherapy ± transplantation, followed by Q monotherapy for ≥36 cycles, reduced the relative risk of death by 22.4% vs placebo (P) in newly diagnosed (nd) FLT3-ITD+ AML, with HR of 0.776 and P value of 0.0324 (PMID: 37116523). In Q-F, FLT3-ITD mutation status was determined using a FLT3-ITD mutation detection clinical trial assay (CTA) validated under design control by Navigate BioPharma Services, Inc. We describe the results of the bridging study, aimed to show agreement between the CTA & the LeukoStrat CDx FLT3 Mutation Assay (CDx, by Invivoscribe) in FLT3-ITD+ pt selection and to determine if Q efficacy (overall survival [OS]) was maintained in nd FLT3-ITD+ AML pts from Q-F, if pts had been selected using the CDx. Methods In both CTA & CDx, DNA, extracted from bone marrow (n=884 each) or peripheral blood (n=139 each), was amplified via PCR and amplicons were detected via capillary electrophoresis. A sample was considered CTA+ if the variant allele frequency ( FLT3-ITD/total FLT3) was ≥3% and CDx+ if the signal ratio (SR; FLT3-ITD/ FLT3 WT) was ≥0.05. The agreement between CTA & CDx was based on evaluating CTA+ & CTA− samples with the CDx assay. A primary analysis included the CDx detected (CDx+ & CDx−) and the CDx invalid results. A secondary analysis used CDx+ and CDx− results only. To establish agreement between CDx & CTA, positive % agreement (PPA) and negative % agreement (NPA) were determined using CTA results as reference for the agreement analysis set (AAS). Concordance was established if the lower bounds of the 95% CIs for both PPA & NPA exceeded 90% for the analysis that included the invalid CDx results. Median OS in the subgroups was calculated based on Kaplan-Meier estimates. Stratified Cox proportional hazards regression model was used to estimate HRs, 95% CI, and P value. Results Full analysis set (N=3468) included all Q-F screened CTA+ pts (n=863), all screened CTA− pts (n=2556), and pts with unknown CTA status not eligible for randomization due to other criteria (n=49). Of these, 1032 pts formed the primary analysis set (PAS), including all pts randomized in Q-F with samples available for CDx testing (N=513: Q, n=254; P, n=259) and a randomly selected subset of CTA− pts (n=519). The ascertainment rate was 95.2% (513/539), as 26 of the 539 pts randomized in Q-F were excluded from the bridging study. Within the PAS, 3 samples were not tested by CDx due to insufficient volume/DNA amount. The AAS (N=1029: CTA+, n=513; CTA−, n=516) included pts in the PAS with valid CTA results and tested with CDx. In the AAS, 6 samples (3 CTA+, 3 CTA−) did not yield valid CDx results, resulting in 1023 CDx-evaluable total pts (CTA+, n=510; CTA−, n=513). Among 510 CTA+ samples, 483 were CDx+. Among 513 CTA− samples, 513 were CDx−. Therefore, 996 samples yielded concordant results, 27 samples yielded discordant results, and 6 samples did not yield a valid CDx result for comparison. Point estimates of PPA & NPA were 94.2% & 99.4%, respectively, with invalid CDx results included in the calculation, and 94.7% & 100%, respectively, without invalid CDx results. The lower bounds of the 95% CIs were all above the corresponding acceptance criterion of 90% for PPA & NPA (Table 1). In Q-F, the prevalence of CTA+ was 24.9% among screened pts (863/3468), whereas in the bridging study, 49.9% (510/1023) of pts were CTA+: this enrichment in CTA+ pts could lead to a biased estimate of the agreement between CDx & CTA when using CDx as reference. The positive predictive value (PPV) and negative predictive value (NPV) of the CDx adjusted for this enrichment ± invalid CDx results, showed that the lower bounds of the 95% CIs were all >95% (Table 1). The efficacy OS analysis in the intent-to-treat (ITT) CDx+ population (ITT CDx+=CTA+ & CDx+; N=483: Q, n=242; P, n=241) demonstrated a clinically relevant OS improvement with Q (median OS of 29.4 months) vs P (median OS of 14.8 months), resulting in 14.6 months prolongation of median OS, with an HR of 0.794 (95% CI 0.621-1.014), corresponding to a 20.6% reduction in relative risk of death (Figure 1). Conclusions This study showed 1) agreement between CDx & CTA in identifying nd FLT3-ITD+ AML pts and 2) that OS benefit provided by Q in the ITT CDx+ population is comparable with the OS benefit in the ITT population of Q-F. The LeukoStrat CDx FLT3 Mutation Assay aids in assessing AML pts for Q therapy.

Pirtobrutinib, a Non-Covalent (reversible) BTK Inhibitor, in Mantle Cell Lymphoma Patients Previously Treated with a Covalent BTK Inhibitor: Results from a China Phase 2 Study

Background Pirtobrutinib, a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi), inhibits both wildtype and C481-mutant BTK and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of protein turnover, and shows promising efficacy and favorable safety profile in patients with pre-treated B-cell malignancies including a covalent BTKi (cBTKi). This study (NCT04849416) was a China only phase 2, open-label, multi-center trial aiming to evaluate the safety and efficacy of oral pirtobrutinib as a monotherapy for patients with B-cell malignancies. This abstract summarizes the findings on the efficacy in a cBTKi pre-treated mantle cell lymphoma (MCL) population and safety outcomes among all enrolled patients. Methods Eligible Chinese patients with relapsed/refractory B-cell malignancies were enrolled and assigned to one of three cohorts based on tumor histology and prior treatment history. All enrolled patients received pirtobrutinib monotherapy at a daily dose of 200 mg, until disease progression (PD), unacceptable side effects, or other reasons for discontinuation. The primary analysis set (PAS) comprised patients with centrally confirmed non-blastoid MCL, who received a prior cBTKi, and with measurable lesion(s) at baseline. The efficacy analysis set (EAS) was extended into all MCL patients treated with a prior cBTKi. The safety population included all patients who received at least one dose of pirtobrutinib. The primary objective was to evaluate the effectiveness by assessing the overall response rate (ORR) based on Lugano criteria and was conducted by an independent review committee (IRC). Secondary objectives included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety profile. Results As of April 10, 2023, of 39 enrolled MCL patients, 28 were in the PAS and 35 were in the EAS for efficacy analysis. The safety analysis included a total of 87 enrolled patients and the median duration of therapy was 4.2 months. In the PAS population (N=28) with cBTKi pre-treated non-blastoid MCL, patients had a median of 3.0 prior lines of therapy (range, 1-8). The majority received prior chemotherapy (96.4%) and an anti-CD20 antibody (85.7%). The most common reason for discontinuation from the prior cBTKi was PD (85.7%). The IRC-assessed ORR was 71.4% (95% CI, 51.3-86.8), with 4 patients (14.3%) achieving complete responses (CR) and 16 patients (57.1%) achieving partial responses (PR). The median DOR assessed by IRC was not reached at the cut-off date with a 6-month DOR rate of 66.02% (95% CI, 39.29-83.14). The median IRC-assessed PFS was 9.43 months (95% CI: 5.32-not evaluable [NE]), and the median OS was 15.47 months (95% CI, 8.67-NE). The EAS (N=35), demonstrated similar efficacy results with IRC-assessed ORR 62.9% (95% CI, 44.9-78.5) and the 6-month DOR rate was 64.45%. In the safety population (N=87) of all enrolled B-cell malignancy patients, common treatment-emergent adverse events (TEAEs) of any grade included decreased neutrophil count (40.2%*), anemia (31%), and increased bilirubin (23.0%, with 2.3% grade ≥3 and none led to dose modification). The most frequent grade ≥3 TEAE was decreased neutrophil count (25.3%*). All grade hemorrhage was observed in 19.5% patient (n=17, with 2.3% grade ≥3), while all grade hypertension was 5.7% (n=5, with 2.3% grade ≥3), and no patient developed atrial fibrillation/flutter. Three patients (3.4%) stopped treatment due to treatment-related TEAEs, and 2 patients (2.3%) experienced treatment related fatal TEAEs (one infection and one patient with reported tumor lysis syndrome, tumor necrosis, and hemorrhage). Conclusion Pirtobrutinib demonstrated clinically meaningful and durable antitumor activity in a cBTKi pre-treated MCL Chinese population and showed a well-tolerated safety profile in patients with B-cell malignancies. * Aggregate of neutropenia and neutrophil count decreased

Lisocabtagene Maraleucel (liso-cel) in R/R CLL/SLL: 24-Month Median Follow-up of TRANSCEND CLL 004

Background:Patients with R/R CLL/SLL who experience intolerance to or disease progression after Bruton tyrosine kinase inhibitor (BTKi) and venetoclax treatment have no established standard of care and poor outcomes, indicating a critical unmet need. Liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell product, has demonstrated efficacy in large B-cell lymphoma and CLL/SLL. In the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study, a single administration of liso-cel demonstrated rapid, deep, and durable responses and a manageable safety profile in patients with R/R CLL/SLL, including those with progression on previous BTKi and venetoclax failure (Siddiqi T, et al. Lancet 2023). The primary endpoint was met in the prespecified subset of efficacy-evaluable patients with disease progression on BTKi and venetoclax failure (primary efficacy analysis set [PEAS]) at a target dose of 100 × 10 6 CAR + T cells (null hypothesis: ≤ 5%) with the rate of complete response/remission (CR) and CR with incomplete marrow recovery (CRi) by an independent review committee (IRC) per 2018 International Workshop on CLL (iwCLL) criteria at 18.4% ( P = 0.0006). Here we report results from TRANSCEND CLL 004 with a median follow-up of 23.5 months. Methods: Patients must have received ≥ 2 prior lines of therapy, including a BTKi. Eligible patients received liso-cel at a target dose of either 50 × 10 6 (dose level [DL] 1) or 100 × 10 6 (DL2) CAR + T cells after lymphodepleting chemotherapy. The primary endpoint was CR/CRi in the PEAS at DL2. Key secondary endpoints were ORR and rate of undetectable MRD (uMRD; 10 −4 by next-generation sequencing) in blood. All null hypotheses were tested at the primary analysis and not retested in this analysis. Results:Of 137 leukapheresed patients, 118 received liso-cel (safety set), 97 (DL1 = 9; DL2 = 88) were efficacy evaluable, and 54 (DL1 = 4; DL2 = 50) were in the PEAS. In the safety set, median (range) age was 65 years (49-82), 83% had high-risk cytogenetics (del[17p], 42%; TP53 mutation, 47%; unmuted immunoglobulin heavy-chain variable gene, 47%; ≥ 3 chromosomal aberrations, 61%), median (range) lines of prior therapy was 5 (2-14), and all patients had prior BTKi. As of data cutoff (February 28, 2023), median (range) on-study follow-up was 23.5 months (0.4-59.6) for the safety set. In the PEAS at DL2, CR/CRi rate was 20% (95% CI, 10.0-33.7; Table 1). ORR was 44% (95% CI, 30.0-58.7). One patient who had best overall response (BOR) of partial response/remission (PR) at primary analysis had deepened to CR/CRi at 18 months without any additional therapy. Of 9 patients who had BOR of CR/CRi at the primary analysis, 8 had ongoing CR/CRi and 1 completed the study with the last assessment as CR/CRi. The uMRD rate was 64% (95% CI, 49.2-77.1) in blood and 60% (95% CI, 45.2-73.6) in marrow. Median (95% CI) duration of response was 35.3 months (12.4-not reached [NR]) and median duration of CR/CRi was NR. Median (95% CI) PFS was 11.9 months (5.7-26.2). Median (95% CI) OS was 30.3 months (15.0-NR). The efficacy outcomes were similar in the full population at DL2. Of 16 patients who had BOR of CR/CRi at primary analysis, 10 had ongoing CR/CRi. In the safety set, rates of any-grade and grade ≥ 3 treatment-emergent AEs were similar across age groups (Table 2). The rate of any-grade cytokine release syndrome (CRS) was 85% (grade 3, 8%; no grade 4/5) and neurological events (NE) was 45% (grade 3, 18%; grade 4, 1%; no grade 5); 69% received tocilizumab and/or corticosteroids for CRS/NEs. Median (range) time to onset and resolution was 4 days (1-18) and 6 days (2-37) for CRS and 7 days (1-21) and 7 days (1-83) for NEs, respectively. Prolonged cytopenia (grade ≥ 3 at Day 30 after liso-cel infusion), grade ≥ 3 infections, hypogammaglobulinemia, tumor lysis syndrome, second primary malignancy, and macrophage activation syndrome occurred in 54%, 18%, 15%, 11%, 9%, and 3%, respectively. Forty-five (33%) of 137 leukapheresed patients died after liso-cel infusion (disease progression, n = 27 [20%]; AE, n = 6 [4%]; other reasons, n = 12 [9%]). Conclusions: With longer follow-up, liso-cel continued to demonstrate durable CR/CRi, high uMRD rates, and a manageable safety profile in patients with heavily pretreated, high-risk R/R CLL/SLL. The safety results from longer follow-up were similar to those reported in the primary analysis with no new safety signals and were consistent across age groups.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study

Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. Juno Therapeutics, a Bristol-Myers Squibb Company.

Methylated DNA biomarkers and incident cancer in the American Cancer Society (ACS) Cancer Prevention Study-3 (CPS-3) cohort.

3004 Background: Multi-cancer early detection (MCED) tests are being developed to complement current single-cancer screening, and are based on next-generation sequencing of cell-free DNA in blood plasma with subsequent analysis of genomic features by machine-learning algorithms. To evaluate the detectability of cancer signals in individuals without known cancer at the time of blood draw, we assessed pre-diagnostic signals using a previously validated locked, methylation-based assay in plasma samples from the ACS CPS-3 cohort. Methods: CPS-3 is a prospective cohort study of cancer incidence and mortality. Participants (N=294,000) donated a blood sample (36 mL) at enrollment (2006-2013) and are followed for cancer outcomes via routine linkages with population-based cancer and death registries. Selected participants diagnosed with cancer within 3 years (Y) of blood donation and an equivalent number of matched non-cancer participants were chosen for processing. Despite differences in sample collection (tube, protocol) and long storage time in freezer, standard requirements for MCED sample quality were applied. Primary outcome: demonstrate that cancer signal was detectable via the MCED test up to 3Y prior to conventional diagnosis. Secondary outcomes: assess detectability based on time from blood draw and other clinical factors. Sampling weights were considered in the statistical analyses. Results: Of 268,726 CPS-3 participants, 2,850 were selected and assayed by cohort sampling, and 2,754 were included in the primary analysis set. CPS-3 cohort demographics and cancer incidence patterns compared to Surveillance, Epidemiology, and End Results suggested that this cohort is younger and healthier than the U.S. population. The test negative rate was 100% among non-cancers. The test positive rate (TPR) stratified by time between blood draw and clinical diagnosis was 2.3% (3Y), 6.0% (2Y), 15.2% (1Y). For eventually fatal cancers, TPR was 5.1% (3Y), 21.6% (2Y), 55.1% (1Y) vs 1.8%, 4.1%, 10.2% for non-fatal cancers. By stage, within 1Y, TPR was 73.7% for Distant at 4-6 months (M) and 94.1% at 1-3M vs 26.7% for Regional at 4-6M and 71.0% at 1-3M. The overall accuracy of predicting cancer signal origin was 95% (1Y). Many cancers were detected 3Y prior to clinical diagnosis: for example, a case of colon/rectum cancer at Regional stage was detected at 991 days. Conclusions: The ACS CPS-3 cohort includes persons at lower-than-average risk of cancer but offered a biospecimen repository with sufficient plasma samples to assess the preclinical detectability of cancer signals by retrospective evaluation. Rapid changes in detectability over time underscore the short preclinical time scales for aggressive cancers to develop, and therefore to be detected. These insights into cancer biology reinforce the importance of pre-diagnostic samples in the study of cancer signals for early detection.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Lisocabtagene maraleucel (liso-cel) in R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of TRANSCEND CLL 004.

7501 Background: In patients (pts) with R/R CLL/SLL that progressed on BTKi and failed venetoclax (ven)-based regimens, achieving CR with current treatment is uncommon. New therapies that achieve deep and durable responses are needed. We report the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study evaluating liso-cel in pts with R/R CLL/SLL. Methods: Pts must have received at least 2 prior lines of therapy, including a BTKi. Eligible pts received liso-cel at a target dose of either 50 (DL1) or 100 (DL2) × 106 CAR+ T cells. The primary endpoint was rate of CR and CR with incomplete marrow recovery (CRi) by IRC per 2018 iwCLL criteria in the prespecified subset of efficacy-evaluable pts with disease progression on BTKi and ven failure (primary efficacy analysis set [PEAS]) at DL2 (null hypothesis [H0]: ≤ 5%). Key secondary endpoints were ORR (H0: ≤ 40%) and rate of undetectable minimal residual disease (uMRD; 10−4) in blood (H0: ≤ 5%). Results: Of 137 leukapheresed pts, 117 received liso-cel (safety set), 96 (DL1 = 9; DL2 = 87) were efficacy evaluable, and 53 (DL1 = 4; DL2 = 49) were in the PEAS. In the safety set, median (range) age was 65 y (49–82), 83% had high-risk features, median (range) lines of prior therapy was 5 (2–12), and all pts had prior BTKi. Median (range) on-study follow-up was 21.1 mo (0.4–55.6) for the safety set. In the PEAS at DL2, the primary endpoint of CR/CRi rate was met at 18.4% (95% CI, 8.8–32.0; 1-sided P = 0.0006; Table). ORR was 42.9% and was not statistically significant (95% CI, 28.8–57.8; 1-sided P = 0.3931). The uMRD rate was 63.3% in blood and 59.2% in marrow. Median (95% CI) DOR was 35.3 mo (11.01–not reached [NR]) with a median follow-up of 19.7 mo. Median duration of CR/CRi was NR. In the safety set, rate of any-grade CRS was 84.6% (gr 3, 8.5%; no gr 4/5) and neurological events (NE) was 45.3% (gr 3, 17.9%; gr 4, 0.9%; no gr 5); 69.2% received tocilizumab and/or corticosteroids for CRS/NEs. Rate of gr ≥ 3 infections, hypogammaglobulinemia, and prolonged cytopenia was 17.1%, 15.4%, and 53.8%, respectively. One death related to liso-cel was due to hemophagocytic lymphohistiocytosis. Liso-cel exhibited rapid in vivo expansion and was detected by qPCR in blood up to 36 mo after infusion. Conclusions: Liso-cel demonstrated durable CR/CRi, high uMRD rates, and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL and high unmet need. Clinical trial information: NCT03331198 . [Table: see text]

Kinetics of the Antibody Response to Symptomatic SARS-CoV-2 Infection in Vaccinated and Unvaccinated Individuals in the Blinded Phase of the mRNA-1273 COVID-19 Vaccine Efficacy Trial.

Hybrid immunity is associated with more durable protection against coronavirus disease 2019 (COVID-19). We describe the antibody responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vaccinated and unvaccinated individuals. The 55 vaccine arm COVID-19 cases diagnosed during the blinded phase of the Coronavirus Efficacy trial were matched with 55 placebo arm COVID-19 cases. Pseudovirus neutralizing antibody (nAb) activity to the ancestral strain and binding antibody (bAb) responses to nucleocapsid and spike antigens (ancestral and variants of concern [VOCs]) were assessed on disease day 1 (DD1) and 28 days later (DD29). The primary analysis set was 46 vaccine cases and 49 placebo cases with COVID-19 at least 57 days post-first dose. For vaccine group cases, there was a 1.88-fold rise in ancestral antispike bAbs 1 month post-disease onset, although 47% had no increase. The vaccine-to-placebo geometric mean ratios for DD29 antispike and antinucleocapsid bAbs were 6.9 and 0.04, respectively. DD29 mean bAb levels were higher for vaccine vs placebo cases for all VOCs. DD1 nasal viral load positively correlated with bAb levels in the vaccine group. Following COVID-19, vaccinated participants had higher levels and greater breadth of antispike bAbs and higher nAb titers than unvaccinated participants. These were largely attributable to the primary immunization series.

LB749. High HBsAb Seroprotection Achieved 4 Weeks after 3 doses of HepB-CpG Vaccine in People Living with HIV (PLWH) without Prior HBV Vaccination (ACTG A5379 Group B Preliminary Results)

Abstract Background Three-dose series of conventional alum-adjuvanted Hepatitis B surface antigen (HBsAg)-based vaccines achieve seroprotection rates (SPRs) of 35-70% in PLWH. HepB-CpG, a HBsAg vaccine adjuvanted with a TLR-9 agonist, achieves high SPR in immunocompetent adults with a 2-dose regimen, but limited data exist in PLWH. Methods A5379 is an ongoing prospective, open-label study to evaluate immunogenicity of the HBV vaccine HepB-CpG in PLWH. The HBV vaccine-naïve group consisted of PLWH without past HBV infection on antiretroviral therapy with CD4 ≥100 cells/mm3 and HIV-1 RNA < 1000 copies/mL. Participants received 0.5 mL of HepB-CpG intramuscularly (20 mcg recombinant HBsAg and 3000 mcg of CpG 1018® adjuvant) at Wks 0, 4, and 24. Primary objectives were to determine the proportion of participants who achieve seroprotection (HBsAb≥10 mIU/mL) at Wk 28 and to assess safety. This study was designed to conclude SPR >55%, with up to 10% loss to follow-up prior to 28 wks. Results Of the 74 eligible participants enrolled at 13 global sites: 46% were male, 66% Asian, 16% Black,15% White and median age was 47 years (range 23-68). 27% were enrolled in the US, 65% in Thailand. Median CD4 was 625 cells/mm3, 96% had HIV-1 RNA < 60 copies/mL, and 9% had diabetes. Primary analysis set per analysis plan consisted of 68 participants (excluded: 3 missed visit, 3 out of visit window). All 68 completed 3 doses and achieved seroprotection (100% [95% CI: 94.7%, 100%]). 88% had HBsAb >1000 mIU/mL (assay upper limit). The SPR was also 100% [CI: 94.2%,100%] in the per protocol analysis set of 62 participants. At 8 wks after the 2nd dose, the SPR was 94.4% followed by 98.5% at Wk 24, prior to the 3rd dose. The proportion of participants with HBsAb >1000 mIU/mL increased from 27.9% at Wk 24 to 83.8% at Wk 28. One or more AEs related to study treatment were experienced by 61% of participants (39% Grade 1, 20% Grade 2, Grade 3 malaise in one participant). Vaccination site pain (40%), malaise (26%), fatigue (23%), myalgia (22%) and headache (22%) were the most frequent AEs. Seroprotection achieved by study week. Percentage of participants achieving seroprotection over the first 28 study weeks. HepB-CpG vaccine was administered at Entry, Week 4, and Week 24. Conclusion In this study of PLWH with no history of HBV vaccination or evidence of prior HBV exposure, 100% seroprotection was achieved at 4 weeks after 3 doses of the HepB-CpG. No unexpected safety issues were observed. Disclosures Kristen Marks, MD, MS, Gilead Sciences: Grant/Research Support Andrea L. Cox, M.D. Ph.D., Janssen: Advisor/Consultant Jennifer C. Price, MD, PhD, AbbVie: Grant/Research Support|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Merck: Grant/Research Support|Theratechnologies: Advisor/Consultant Kelvin McKoy, M.D., M.B.A., Dynavax Technologies: Employee|Dynavax Technologies: Ownership Interest|Dynavax Technologies: Stocks/Bonds Kenneth E. Sherman, MD, PhD, AbbVie: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Helio: Grant/Research Support|Inovio: DSMB|Intercept: Grant/Research Support|MedPace: DSMB|Theratechnologies: Advisor/Consultant|Zydus: Grant/Research Support.

Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis

Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections. To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis. A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens. Eligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline). The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified. Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events. Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis. ClinicalTrials.gov Identifier: NCT03687255.

SKYSCRAPER-02: Primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo) + carboplatin + etoposide (CE) with or without tiragolumab (tira) in patients (pts) with untreated extensive-stage small cell lung cancer (ES-SCLC).

LBA8507 Background: Atezo, in combination with CE, was the first cancer immunotherapy approved for 1L treatment of ES-SCLC. However, most pts eventually experience disease progression. TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergise with other immunotherapies, such as PD-L1/PD-1 inhibitors, and further amplify the immune response to improve clinical outcomes. SKYSCRAPER-02 (NCT04256421) evaluates whether the antitumor effect and survival benefits of the combination of atezo + CE could be enhanced by adding tira in pts with ES-SCLC. Methods: Eligible pts with untreated ES-SCLC (asymptomatic treated or untreated brain metastases [BM] permitted) were randomized 1:1 to receive induction tira 600 mg IV or placebo (pbo) combined with atezo 1200 mg IV + CE for 4 x 21-day cycles followed by maintenance tira or placebo combined with atezo every 3 weeks until disease progression or loss of clinical benefit. Stratification factors include ECOG PS (0 vs 1); presence/history of BM (yes vs no); LDH (≤upper limit of normal [ULN] vs &gt;ULN). Co-primary endpoints were investigator-assessed PFS and OS in all randomized pts without the history/presence of BM at baseline (primary analysis set [PAS]). Additional endpoints include PFS and OS in all randomized pts regardless of BM status (full analysis set [FAS]), objective response rate, duration of response, and safety. Results: A total of 490 patients were randomized (tira + atezo + CE, n=243; pbo + atezo + CE, n=247). As of 6 Feb 2022, median duration of follow-up was 13.9 months (mo); data represent final analysis for PFS and interim analysis for OS. In the PAS, no additional benefit was seen for tira + atezo + CE in PFS or OS compared with pbo + atezo + CE (Table). PFS and OS in the FAS were consistent with those observed in the PAS (Table). Grade 3/4 TRAEs occurred in 52.3% (tira + atezo + CE) and 55.7% (pbo + atezo + CE) and Grade 5 TRAEs occurred in 0.4% (tira + atezo + CE) and 2.0% (pbo + atezo + CE). TRAEs leading to any treatment discontinuation occurred in 5.0% and 5.3% with tira + atezo + CE and pbo + atezo + CE, respectively. Conclusions: The addition of tira to atezo + CE did not provide benefit over atezo + CE in pts with untreated ES-SCLC with or without BM. The combination was well tolerated, and no new safety signals were identified. The study will continue to planned final OS analysis. Clinical trial information: NCT04256421. [Table: see text]

Crizotinib in ROS1-rearranged lung cancer (EUCROSS): Updated overall survival.

9078 Background: ROS1 rearrangements are found in approximately 1% of non-small cell lung cancer (NSCLC) patients. Prospective clinical trials showed high efficacy of crizotinib in this molecular subset. Lately, we reported an overall response rate (ORR) of 70% and a median progression-free survival (PFS) of 19.4 months for patients treated within the EUCROSS trial (Michels et al. Clin Oncol, 37(15_suppl):9066-9066, 2019). Here we present an updated analysis of the overall survival. Methods: EUCROSS is a European multi-centre, single arm phase 2 trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria were ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation) and no or stable brain metastases at baseline. Crizotinib was given at a dose of 250 mg twice daily. Primary endpoint of the trial was investigator-assessed ORR in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1), with secondary endpoints of PFS and overall survival (OS). Results: Of the 34 patients who received at least one dose of crizotinib (intention-to-treat population, ITT), 30 were included the primary efficacy analysis set (PAS). After a median follow-up of 55.9 months, 13 (43%) patients in the PAS and 15 (44%) in the ITT had died. Median OS was not reached in either group (95% CI, 17.1-NR and 20.3-NR, respectively). OS was negatively correlated with the presence of brain metastases (Log-rank p = 0.1805) and TP53 mutations (Log-rank p = 0.015). Detailed listings of the survival rates are depicted in Table. No new safety signals were observed. Owing to the approval of crizotinib by the European Medicines Agency, all patients who were still on treatment by January 24th 2018 (n=8), were prescribed crizotinib outside the trial. Conclusions: Updated OS highlights the efficacy of crizotinib in patients with ROS1-rearranged lung cancer. Patients with co-occurring TP53 mutations or brain metastases had worse outcomes and represent challenging populations. Clinical trial information: NCT02183870. [Table: see text]

OP24 Clinical efficacy and safety of guselkumab maintenance therapy in patients with moderately to severely active Crohn’s Disease: Week 48 analyses from the phase 2 GALAXI 1 study

Abstract Background GALAXI 1 is a Phase 2, double-blind, placebo (PBO)-controlled, multicenter study evaluating efficacy/safety of guselkumab (GUS), a selective IL-23 p19 antagonist, in patients (pts) with moderately to severely active Crohn’s disease (CD) with inadequate response/intolerance to conventional therapies (corticosteroids, immunomodulators) and/or biologics (tumor necrosis factor antagonists, vedolizumab). At Week (Wk) 12, all GUS induction doses (200, 600, and 1200mg IV) had greater improvements vs PBO for key clinical/endoscopic outcomes. We report clinical efficacy and safety of maintenance treatment through Wk48. Methods GALAXI employed a treat-through design over 48 wks. In induction pts were randomized to GUS 200, 600, or 1200mg IV, ustekinumab (UST) ~6mg/kg IV, or PBO IV. Pts transitioned to maintenance dosing as follows: PBO non-responders to UST ~6mg/kg IV to 90mg SC q8w, PBO responders to PBO SC q4w, GUS 200mg IV to 100mg SC q8w, GUS 600mg IV to 200mg SC q4w, GUS 1200mg IV to 200mg SC q4w, and UST ~6mg/kg IV to 90mg SC q8w. Pts randomized to PBO were not included in Wk48 efficacy analyses. Primary and major secondary endpoints evaluated efficacy of GUS vs PBO at Wk12. Evaluations of Wk48 endpoints were prespecified but not multiplicity controlled. UST was a reference arm; the study was not powered to evaluate differences between treatment groups with respect to efficacy at Wk48. Results Through Wk48, 248 pts in the primary efficacy analysis set were randomized and evaluated. Baseline demographics were similar across groups (Table 1). Discontinuation rates were low across active treatment groups. No dose response was observed across clinical efficacy assessments (Table 2). Proportions of pts achieving clinical remission at Wk48 ranged from 57.4–73.0% among GUS dose groups. The vast majority of pts in clinical remission were also in corticosteroid-free remission at Wk48; with rates ranging from 55.7–71.4% among GUS dose groups. PRO-2 remission rates ranged from 50.8–69.8%, and proportions of pts achieving clinical response ranged from 67.2–84.1% among GUS dose groups. Proportions of pts achieving abdominal pain scores ≤1 or daily average number of liquid or very soft stools ≤3 are presented in Table 2. Outcomes in the reference UST group are also shown in Table 2. Key safety event rates were similar among GUS dose groups (Table 3); no opportunistic infections, cases of tuberculosis, or deaths were reported in any group. Conclusion In this treat-through Phase 2 study of pts with moderately to severely active CD, GUS was safe and effective. GUS induction followed by SC maintenance achieved high rates of clinical efficacy at Wk48. Safety results were consistent with the known safety profile in approved indications.

Comparative efficacy of tisagenlecleucel and lisocabtagene maraleucel among adults with relapsed/refractory large B-cell lymphomas: an indirect treatment comparison

This study compared overall survival (OS), progression-free survival (PFS), complete response rate (CRR), and overall response rate (ORR) of tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) in relapsed or refractory large B-cell lymphomas (r/r LBCL). Using matching-adjusted indirect comparison (MAIC), individual patient-level data from JULIET (tisa-cel) were weighted to match the patient population in TRANSCEND (liso-cel). The main analysis compared infused JULIET patients (N = 106) with the TRANSCEND efficacy-evaluable set (EES) (N = 256 [infused]). After adjustment, OS, PFS, and the CRR were comparable between tisa-cel and liso-cel EES patients. The estimated adjusted 2-year OS, 2-year PFS, ORR, and CRR were 45.6, 38.2, 62.9, and 47.7%, respectively, for tisa-cel vs. 43.8, 42.1, 72.7, and 53.1% for liso-cel. A scenario analysis compared JULIET patients to the TRANSCEND primary analysis set (PAS) (N = 133). ORR was significantly higher in the TRANSCEND PAS compared with matched JULIET patients, but no significant differences in CRR were observed.

Total Bilirubin Level as a Predictor of Suboptimal Image Quality of the Hepatobiliary Phase of Gadoxetic Acid-Enhanced MRI in Patients with Extrahepatic Bile Duct Cancer.

ObjectiveThis study aimed to determine a factor for predicting suboptimal image quality of the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MRI in patients with extrahepatic bile duct (EHD) cancer before MRI examination.Materials and MethodsWe retrospectively evaluated 259 patients (mean age ± standard deviation: 68.0 ± 8.3 years; 162 male and 97 female) with EHD cancer who underwent gadoxetic acid-enhanced MRI between 2011 and 2017. Patients were divided into a primary analysis set (n = 184) and a validation set (n = 75) based on the diagnosis date of January 2014. Two reviewers assigned the functional liver imaging score (FLIS) to reflect the HBP image quality. The FLIS consists of the sum of three HBP features, each scored on a 0–2 scale: liver parenchymal enhancement, biliary excretion, and signal intensity of the portal vein. Patients were classified into low-FLIS (0–3) or high-FLIS (4–6) groups. Multivariable analysis was performed to determine a predictor of low FLIS using serum biochemical and imaging parameters of cholestasis severity. The optimal cutoff value for predicting low FLIS was obtained using receiver operating characteristic analysis, and validation was performed.ResultsOf the 259 patients, 140 (54.0%) and 119 (46.0%) were classified into the low-FLIS and high-FLIS groups, respectively. In the primary analysis set, total bilirubin was an independent factor associated with low FLIS (adjusted odds ratio per 1-mg/dL increase, 1.62; 95% confidence interval [CI], 1.32–1.98). The optimal cutoff value of total bilirubin for predicting low FLIS was 2.1 mg/dL with a sensitivity of 95.1% (95% CI: 88.9–98.4) and a specificity of 89.0% (95% CI: 80.2–94.9). In the validation set, the total bilirubin cutoff showed a sensitivity of 92.1% (95% CI: 78.6–98.3) and a specificity of 83.8% (95% CI: 68.0–93.8).ConclusionSerum total bilirubin before acquisition of gadoxetic acid-enhanced MRI may help predict suboptimal HBP image quality in patients with EHD cancer.

Efficacy and safety of selpercatinib in Chinese patients with advanced RET-altered thyroid cancers: results from the phase II LIBRETTO-321 study.

Background:Selpercatinib, a highly selective and potent REarranged during Transfection (RET) kinase inhibitor, is effective in advanced RET-altered thyroid cancer (TC). However, the efficacy and safety in Chinese patients are unknown.Patients and methods:In the open-label, multi-center phase II LIBRETTO-321 (NCT04280081) study, Chinese patients with advanced solid tumors harboring RET alterations received selpercatinib 160 mg twice daily. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DoR) and safety. Efficacy was assessed in the primary analysis set [PAS; treated patients with RET fusion-positive TC or RET-mutant medullary TC (MTC) confirmed by central laboratory] and all enrolled patients with MTC.Results:Of 77 enrolled patients, 29 had RET-mutant MTC and one had RET fusion-positive TC. In the PAS (n = 26), the ORR by IRC was 57.7% [95% confidence interval (CI), 36.9–76.6]. Median DoR was not reached and 93.3% of responses were ongoing at a median follow-up of 8.7 months. In all enrolled MTC patients (n = 29), the ORR by IRC was 58.6% (95% CI, 38.9–76.5). One RET fusion-positive TC patient treated for 23.4 weeks achieved a partial response at week 8 that was ongoing at cutoff. In the safety population (n = 77), 59.7% experienced grade ⩾3 treatment-emergent adverse events (TEAEs). TEAEs led to dose reductions in 32.5% (n = 25) and discontinuations in 5.2% [n = 4; 3.9% (n = 3) considered treatment related] of patients.Conclusions:Selpercatinib showed robust antitumor activity and was well tolerated in Chinese patients with advanced RET-altered TC, consistent with global data from LIBRETTO-001 (NCT04280081).ClinicalTrials.gov Identifier:NCT04280081 (first posted Feb 21, 2020)

Efficacy and safety of selpercatinib in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer: a phase II clinical trial (LIBRETTO-321).

Introduction:Oncogenic alterations in RET occur in 1–2% of non-small-cell lung cancers (NSCLCs). The efficacy and safety of the first-in-class, highly selective, and potent RET inhibitor selpercatinib in Chinese patients with RET fusion-positive NSCLC remains unknown.Methods:In this open-label, multicenter, phase II study (NCT04280081), patients with advanced RET-altered solid tumors received selpercatinib (160 mg orally twice daily) in a 28-day cycle. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included duration of response, central nervous system (CNS) response, and safety. Efficacy against NSCLC was assessed in the primary analysis set (PAS; centrally confirmed RET status) and in all enrolled patients with NSCLC.Results:Of 77 enrolled patients, 47 had RET fusion-positive NSCLC. After 9.7 months of median follow-up, IRC-assessed ORR in the PAS (n = 26) was 69.2% [95% confidence interval (CI), 48.2–85.7] and 94.4% of responses were ongoing; the ORR was 87.5% and 61.1% in treatment-naïve and pre-treated patients, respectively. IRC-assessed ORR in all patients with NSCLC (n = 47) was 66.0% (95% CI, 50.7–79.1). Among five patients with measurable CNS metastases at baseline, four (80%) achieved an IRC-assessed intracranial response. In the safety population (n = 77), most treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common grade ⩾3 TEAE was hypertension (19.5%). Three (3.9%) patients discontinued therapy due to treatment-related AEs; no deaths occurred due to treatment-related AEs.Conclusion:Selpercatinib, with potent and durable antitumor activity including intracranial activity, was well tolerated in Chinese patients with RET fusion-positive NSCLC, consistent with LIBRETTO-001 (ClinicalTrials.gov: NCT04280081).