TPS8608
Background: Targeting of oncogenic driver alterations has proven to be an effective clinical approach across many tumor types. As a result of the approval of targeted therapies against ...oncogenic driver alterations, molecular biomarker testing is commonly recommended for patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment. Although there are emerging clinical trial data using targeted therapies in patients with early-stage NSCLC, currently molecular biomarker testing is not universally performed as part of routine clinical practice in the early-stage setting. Screening platforms can be utilized to provide comprehensive, validated biomarker testing to facilitate access to clinical trials for appropriate investigational therapies, based on biomarker status. This type of approach aims to be more efficient and to streamline patient recruitment and improve patient access to clinical trials where biomarker testing is not currently performed as part of routine care, especially when the biomarkers of interest are at low prevalence. Methods: This global, non-Investigational Medicinal Product (non-IMP), multicenter master screening study (NCT05419375) provides centralized tissue-based testing to determine patients’ biomarker eligibility for linked Roche clinical trials. Currently this study is only open to screening patients for a linked platform study in unresectable stage III NSCLC (NCT05170204). However, it is envisaged that this screening study will be expanded to support additional clinical trials and indications in the future. Eligible patients must be aged ≥18 years with locally advanced, unresectable stage III NSCLC (according to AJCC 8
th
edition), an ECOG PS of 0–2, confirmed availability of a formalin-fixed paraffin-embedded tumor specimen obtained prior to chemoradiation, and adequate hematologic and end-organ function. If a patient is found to have an oncogenic driver mutation and is considered a good candidate for a linked clinical trial, the investigator may propose that they be screened into the respective study. Tumor tissue samples will be centrally tested by validated molecular tests for the presence of specific genetic alterations: EGFR, ALK, ROS1, KRAS, BRAF, HER2, RET, MET, and NTRK1/2/3. Immunohistochemistry may also be performed to determine PD-L1 expression as required by the linked trial eligibility criteria. The primary objective of this screening trial is to determine the biomarker status of patients and their eligibility to participate in a linked clinical trial. Exploratory objectives include characterization of biomarker profiles and patients’ subsequent treatment. No therapeutic intervention will be administered in this study. Enrolment is ongoing across 51 sites in ten countries, with a target enrolment of 15,000 patients. As of 9 February 2023, 27 patients have been enrolled. Clinical trial information: NCT05419375 .
TPS8651 Background: The KRAS G12C mutation, present in ~12% of NSCLC patients, drives oncogenic signaling and cancer formation and is associated with poor prognosis. The current first-line treatment ...for advanced KRAS G12C+ NSCLC is checkpoint inhibitor (CPI) ± chemotherapy (CT). Novel combinations using a more targeted, biomarker-directed approach are supported by pre-clinical evidence and may further improve outcomes. Divarasib is an oral KRAS G12C inhibitor with potent pre-clinical and clinical anti-tumor activity. We hypothesize that divarasib + CPI ± CT may improve outcomes for patients with KRAS G12C+ NSCLC. Methods: Krascendo-170 Lung (NCT05789082) is a phase Ib/II, open-label study evaluating the safety and activity of divarasib + pembrolizumab in patients with PD-L1 tumor cell expression ≥1% (Cohort A) and of divarasib + pembrolizumab with platinum-based CT and pemetrexed in patients with any PD-L1 tumor cell expression level (Cohort B). Patients must be ≥18 years old with untreated unresectable/metastatic non-squamous NSCLC (measurable per RECIST v1.1), a confirmed KRASG12C mutation, and an Eastern Cooperative Oncology Group performance status 0/1. Each cohort will have two stages: divarasib combination dose finding and dose expansion, with two planned dose levels of divarasib (Table). Tumor assessments will be performed at baseline and every 6 weeks for 48 weeks, then every 9 weeks thereafter. Plasma samples will be taken at various timepoints before and after divarasib and pembrolizumab dosing to characterize pharmacokinetics. Patients will be treated until disease progression per RECIST v1.1 or unacceptable toxicity. The co-primary endpoints are adverse events and change from baseline in targeted safety parameters. Key secondary endpoints include objective response rate, progression-free survival and duration of response (all investigator assessed per RECIST v1.1). Enrollment into the combination dose finding stage of Cohort A has been completed without dose-limiting toxicities and enrollment into the dose expansion stage is continuing. Clinical trial information: NCT05789082 . Table: see text
The current study examined the inmates’ mental healthcare needs in local county jails in Madison County, Illinois and explored approaches for future improvement. It used a mixed method with both a ...quantitative descriptive study design and a qualitative case study design. Non-probability sampling was used to recruit study participants. Mental health screening data from 222 adult inmates at a local Madison County jail were included in the quantitative study, and 15 professionals working with Madison County’s criminal justice system participated in the qualitative case study to complete an online in-depth survey. Results indicated that at the initial screening, about 30.6% of inmates reported that they had a psychiatric history (n=68), and 69.4% did not think that they ever had a psychiatric history (n=154). However, at the second assessment, 50 (23%) more inmates showed psychiatric symptoms. Female inmates were more likely to report a psychiatric history than males (40% vs. 30%); inmates who were younger than 48 years old had a higher rate of psychiatric history than those at the age of 48 and above (43.7% vs. 33%); and Hispanic inmates had the highest rate of psychiatric history compared to other races (75.0%). Participants in the case study stated that there was a significant lack of mental healthcare services provided in diagnosis, treatment, and referral while a considerable proportion of jail inmates were suffering from serious mental illness. Recommendations were made for future improvement, such as strengthening partnerships with mental health professionals and agencies to ensure the adequate and prompt mental health services in jails; increasing facilities to host mentally ill inmates; improving the comprehensiveness and accuracy of mental health screening/assessment tools. The study advocated for structural/systemic changes and more innovative and evidence-based practice to address inmates’ mental health concerns.
TPS8605
Background: Durvalumab following chemoradiation (CRT) is a standard of care for unresectable stage III NSCLC, but there remains an unmet need for improved therapeutic options among patients ...with driver-mutated tumors that are unresponsive to immunotherapy. As targeting of specific driver mutations (e.g. ALK, RET, ROS1) has proven effective in the metastatic setting, it is hypothesized that outcomes could also be improved for patients with driver-mutated stage III NSCLC. Methods: BO42777 (NCT05170204) is a phase I–III platform study evaluating the safety and efficacy of multiple targeted therapies versus durvalumab following CRT in patients with locally advanced, unresectable stage III NSCLC. Biomarker eligibility is determined via local tissue testing or central testing within the BX43361 master screening study (NCT05419375). Biomarker-eligible patients are enrolled into the relevant cohort and randomized 1:1 to receive durvalumab or targeted therapy (alectinib ALK+, entrectinib ROS1+, or pralsetinib RET fusion+). New cohorts may be added in the future. Key inclusion criteria: locally advanced, unresectable stage III NSCLC, age ≥18 years, ≥2 prior cycles of concurrent or sequential CRT (cCRT or sCRT), and ECOG PS 0–2. Patients are stratified based on staging (IIIA vs IIIB or IIIC), CRT type (cCRT vs sCRT), and PD-L1 status (tumor cell score < 1% vs ≥1% vs unknown) and will receive investigational treatment for three years or durvalumab for one year, until progression or maximum duration of treatment, unacceptable toxicity, consent withdrawal, or death. Primary endpoint: progression-free survival (RECIST v1.1) by blinded independent central review. Key secondary endpoints: distant metastasis-free survival, time to CNS progression, objective response rate, duration of response, overall survival, and safety (adverse events). Time to confirmed deterioration and patient-reported outcomes will be assessed through questionnaires. Tumor response will be assessed by CT/MRI imaging at regular intervals. Enrolment is ongoing (target of 320 patients) across 200 sites in 11 countries. As of 7 February 2023, five patients have been randomized. This trial in progress was previously presented at ELCC, Luis Paz-Ares et al. (#744), and reused with permission. Clinical trial information: NCT05170204 .
Abstract Background: In the randomized phase II LOTUS trial, combining ipatasertib with first-line paclitaxel for triple-negative breast cancer (TNBC) improved progression-free survival (PFS), ...particularly in patients with PIK3CA/AKT1/PTEN-altered tumors. We aimed to validate these findings in a biomarker-selected TNBC population. Patients and methods: In Cohort A of the randomized double-blind placebo-controlled phase III IPATunity130 trial, taxane-eligible patients with PIK3CA/AKT1/PTEN-altered measurable advanced TNBC and no prior chemotherapy for advanced disease were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, both plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Results: Between February 2018 and April 2020, 255 patients were randomized (168 to ipatasertib, 87 to placebo). At the primary analysis there was no significant difference between treatment arms in PFS (hazard ratio 1.02, 95% CI, 0.71–1.45; median 7.4 months with ipatasertib vs. 6.1 months with placebo). The final analysis showed no difference in overall survival between treatment arms (hazard ratio 1.08, 95% CI, 0.73–1.58; median 24.4 vs. 24.9 months, respectively). Ipatasertib was associated with more grade ≥3 diarrhea (9% vs. 2%) and adverse events leading to dose reduction (39% vs. 14%) but similar incidences of grade ≥3 adverse events (51% vs. 46%). Exploratory subgroup analyses by PAM50 and Burstein gene expression showed inconsistent results. Conclusions: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood.
BACKGROUND:Valganciclovir (VGCV) effectively prevents cytomegalovirus disease in adult and pediatric solid organ transplant recipients. A dosing algorithm for VGCV for pediatric patients, based on ...body surface area and renal function, provides a personalized dose using age-appropriate formulations. The suitability of this dosing algorithm has not been assessed specifically in infants and neonates 4 months of age and younger receiving a solid organ transplant.
METHODS:This multicenter prospective study evaluated the pharmacokinetics (PK) and safety of VGCV oral solution in 17 heart transplant recipients 4 months of age and younger who received 2 doses of VGCV on consecutive days using the pediatric dosing algorithm. Plasma concentrations of ganciclovir (GCV) were analyzed at specified times up to 24 hours post VGCV administration.
RESULTS:GCV concentration data were available from 16 patients. The combined data from this study and historic study datasets were used to establish a 2-compartment population PK model with first-order formation to describe the PK of GCV after oral VGCV administration in patients across all pediatric age ranges, including those younger than 4 months of age. Estimated mean area under the curve during the 0–24 hours dosing interval for these patients was 68.1 μg·h/mL.
CONCLUSIONS:The pediatric dosing algorithm for VGCV (utilizing individuals’ body surface area and renal function) provides systemic GCV exposures in patients younger than 4 months that are similar to those observed in older pediatric populations. The data indicate that this dosing algorithm is appropriate across the entire pediatric age range, including this youngest age group.
Abstract
Background: In the randomized phase II LOTUS trial Kim, Lancet Oncol 2017, adding IPAT to PAC improved progression-free survival (PFS), with a more pronounced effect in patients with ...PIK3CA/AKT1/PTEN-altered tumors. This effect provided the rationale for the biomarker-selected IPATunity130 phase III trial. Here we report primary results from Cohort A in aTNBC. Patients and methods: In Cohort A of this pivotal phase III trial (NCT03337724), eligible patients had PIK3CA- and/or AKT1- and/or PTEN-altered measurable aTNBC, ECOG performance status 0/1, were appropriate candidates for taxane monotherapy, and had received no prior chemotherapy for aTNBC. Patients were randomized 2:1 to receive either oral IPAT 400 mg or PBO (days 1-21), both combined with IV PAC 80 mg/m2 (days 1, 8, & 15). Cycles were repeated every 28 days until disease progression, unacceptable toxicity, or patient withdrawal. Stratification factors were: prior (neo)adjuvant chemotherapy (yes vs no); geographic region (Asia-Pacific vs Europe vs North America vs rest of world); and tumor alteration status (PIK3CA/AKT1-activating mutation vs PTEN alteration without PIK3CA/AKT1-activating mutation). The primary endpoint was investigator-assessed PFS; secondary endpoints included overall survival (OS; key secondary), objective response rate (ORR), duration of response, clinical benefit rate (CBR), patient-reported outcomes, and safety. Results: Between 6 Feb 2018 and 8 Apr 2020, 255 patients were enrolled, of whom 51% had received (neo)adjuvant chemotherapy and 59% had visceral disease; 51% had PIK3CA/AKT1-activating mutations and the remaining 49% had PTEN alterations (without PIK3CA/AKT1-activating mutations). At the clinical cut-off date (7 May 2020), median duration of follow-up was 8.3 months (range 0-26.8 months) and 33% of patients remained on treatment. Mean duration of PAC was similar in the two groups (5.5 vs 5.4 months in the IPAT vs PBO arms, respectively). There was no difference in PFS between treatment groups overall (Table) nor in any prespecified subgroups. OS results are immature (deaths in 20% of patients). Similar proportions of patients in the IPAT and PBO arms experienced grade ≥3 adverse events (AEs) (46% vs 44%, respectively), fatal AEs (1% vs 1%), and AEs leading to discontinuation of any treatment (14% vs 15%), although AEs leading to dose reduction of any treatment were more common with IPAT (35% vs 14%). The most common AEs (any grade) were diarrhea (80% vs 31%; grade ≥3 9% vs 2%), alopecia (46% vs 44%), and nausea (36% vs 23%). Conclusions: In contrast to results from the phase II LOTUS trial, this trial showed no PFS improvement with the addition of IPAT to first-line PAC in patients with PIK3CA/AKT1/PTEN-altered aTNBC. Biomarker analyses are ongoing to evaluate potential markers of IPAT benefit. Safety was consistent with previously reported results for this combination.
Summary of efficacyIPAT + PAC PBO + PACITT population(n=168)(n=87)PFS events, n (%)92 (55)48 (55)Median PFS, months (95% CI)7.4 (5.6-8.5)6.1 (5.5-9.0)PFS stratified hazard ratio (95% CI)1.02 (0.71-1.45)Log-rank p=0.9237Measurable disease population(n=167)(n=86)ORR, n (%) 95% CI65 (39) 32-4730 (35) 25-46CBR, n (%) 95% CI78 (47) 39-5539 (45) 35-56
Citation Format: Rebecca Dent, Sung-Bae Kim, Mafalda Oliveira, Carlos Barrios, Joyce O’Shaughnessy, Steven J Isakoff, Shigehira Saji, Ruffo Freitas-Junior, Manuel Philco, Igor Bondarenko, Qinshu Lian, Denise Bradley, Heather Hinton, Matthew J Wongchenko, Aruna Mani, Nicholas Turner. Double-blind placebo (PBO)-controlled randomized phase III trial evaluating first-line ipatasertib (IPAT) combined with paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer (aTNBC): primary results from IPATunity130 Cohort A abstract. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-04.
Abstract
Background The PI3K/AKT signaling pathway plays a significant role in both HR+ BC and TNBC. IPATunity130 is a double-blind, placebo-controlled, randomized phase 3 trial of ipatasertib in ...combination with paclitaxel in patients with PI3K/AKT1/PTEN-altered HR+ or TNBC. A next-generation sequencing (NGS)-based assay from Foundation Medicine Inc. (FMI) was used to select patients prospectively for enrollment in this trial.Patients and methods An investigational clinical trial assay (CTA) of a composite 3-gene biomarker signature Kim, Lancet Oncol 2017 based on the FoundationOne® CDx assay was used to identify patients with PI3K/AKT pathway-activated tumors as eligible for enrollment in IPATunity130 (NCT03337724). Qualifying alterations for the 3-gene signature (referred to as ‘biomarker-positive’) comprised activating mutations in PIK3CA and/or AKT1, and/or loss of function (LOF) alterations in PTEN represented by homozygous or heterozygous deletions, dominant-negative mutations, or inactivating mutations under loss of heterozygosity. Study sites were required to submit formalin-fixed paraffin-embedded archival or fresh biopsy tissue derived from primary or metastatic tumors for patient screening. IPATunity130 includes three independent cohorts: Cohort A (biomarker-positive TNBC); Cohort B (biomarker-positive HR+/HER2– BC); and Cohort C (biomarker-negative TNBC). Results In total, 1736 patients were screened, from whom 1690 samples were tested by FMI. Of these, 1475 (87%) produced a valid NGS result. The remaining 215 (13%) failed quality control for reasons including insufficient tissue, DNA yield, lab error, and computational failure. Alteration status for PIK3CA and/or AKT1 and/or PTEN was positive in 703 (49%) of 1440 CTA-evaluable samples. In the HR+/HER2– cohort, the breakdown of CTA-positive samples was 301/356 (85%) PIK3CA/AKT1 mutations and 86/356 (24%) PTEN LOF alterations. In TNBC, 183/347 (53%) had PIK3CA/AKT1 mutations and 193/347 (56%) had PTEN LOF alterations. CTA results according to baseline characteristics are shown overall and by subtype below.
The most common mutations detected outside the 3-gene biomarker signature in the screened population were in the TP53, BRCA1, RB1, BRCA2, and NF1 genes in the TNBC cohort and the TP53, GATA3, CDH1, MAP3K1, and ESR1 genes in the HR+/HER2– cohort. In the HR+/HER2– cohort, 30 (14%) of 213 metastatic tumors had ESR1 mutations compared with 10/414 (2%) primary tumors. Tumor BRCA1 mutations were more common in patients aged ≤50 years whereas MAP3K1 mutations were more common in those aged >50 years.Conclusions IPATunity130 is the first reported pivotal trial to utilize the 3-gene biomarker CTA in HR+/HER2– BC and TNBC to screen for patients with PI3K/AKT pathway-activated tumors. The 3-gene biomarker CTA detected alterations in 49% of screened patients, with a higher prevalence of PIK3CA/AKT1/PTEN alterations in HR+/HER2– BC than TNBC. Additional analyses are planned to assess correlations between clinical outcomes and tumor characteristics.
SubgroupPIK3CA/AKT1/PTEN alteration, n/N (%)OverallHR+/HER2–TNBCAll patient samples703/1440 (49)356/647 (55)347/793 (44)Age, years≤50219/475 (46)99/195 (51)120/280 (43)>50484/965 (50)257/452 (57)227/513 (44)Sample sourcePrimary456/941 (48)232/414 (56)224/527 (43)Metastatic222/448 (50)112/213 (53)110/235 (47)Geographic regionNorth America60/102 (59)33/49 (67)27/53 (51)Asia-Pacific172/330 (52)81/145 (56)91/185 (49)Europe301/633 (48)171/310 (55)130/323 (40)Rest of world170/375 (45)71/143 (50)99/232 (43)
Citation Format: Heidi Savage, Wendy Lin, Mafalda Oliveira, Carlos Barrios, Joyce O’Shaughnessy, Nicholas Turner, Rebecca Dent, Steven J Isakoff, Shigehira Saji, Qinshu Lian, Denise Bradley, Sarah-Jayne Reilly, Heather Hinton, Matthew J Wongchenko, Aruna Mani, Sung-Bae Kim. Prospective testing for PIK3CA/AKT1/PTEN alterations in tumor tissue from 1440 patients with advanced hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) or triple-negative breast cancer (TNBC) screened for the IPATunity130 randomized phase 3 trial abstract. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-06.
Interventions aimed at decreasing social exclusion in school or early childhood classrooms are typically targeted at changing the behavior of the rejected or isolated child, and do nothing to address ...the exclusionary behavior of the peer group. We suggest an alternative approach, wherein the classroom climate is altered to discourage social exclusion. Drawing on the work of Vivian Paley, an intervention study was conducted to assess the effect of implementing a rule that disallows overt exclusion among classmates. The year-long intervention was conducted in six kindergarten classes, with four additional classes serving as a control group. Observations and teacher reports did not differ between
Target and
Control classes, but significant intervention effects were found in two areas: Children in
Target classes reported via sociometric assessment that they liked each other significantly more at the end of the year than did children in
Control classes, yet reported higher levels of social dissatisfaction than did
Control children. Suggestions for future tests of this type of intervention are made, and ideas are offered for early childhood educators considering the use of a non-exclusion classroom rule.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
