Liu, Emily L.

TPS3182 Background: MTAP deletion in solid tumors causes intracellular accumulation of methylthioadenosine (MTA) which partially inhibits activity of the key methylating enzyme, protein arginine methyltransferase 5 (PRMT5) and creates synthetic lethal dependencies on PRMT5 and methionine adenosyltransferase 2A (MAT2A), the rate limiting step in the synthesis of PRMT5 substrate, S-adenosyl methionine. PRMT5 and MAT2A are essential to transcription modulation, gene splicing, and DNA damage response. IDE892 is an MTA-cooperative PRMT5 inhibitor designed to exploit this vulnerability in MTAPdel tumors. Preclinical studies report robust antitumor activity with IDE892 monotherapy in MTAPdel xenograft models and an enhanced response when combined with IDE397 (an allosteric MAT2A inhibitor). IDE892-001 is a Phase 1 study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of IDE892 alone and in combination with IDE397. Methods: IDE892-001 is an ongoing, open-label, multicenter four-part study: IDE892 monotherapy dose escalation (Part 1), monotherapy dose expansion in MTAPdel NSCLC (Part 2), IDE892 + IDE397 dose escalation (Part 3), and combination expansion in MTAPdel NSCLC (Part 4). Adults with advanced or metastatic MTAPdel solid tumors including lung, urothelial, gastrointestinal cancers (including pancreatic and biliary tract cancers) and mesothelioma are eligible following disease progression on standard therapies. Key exclusion criteria include symptomatic brain metastases, cardiac disease, active severe infection, and prior treatment with a PRMT5 or MAT2A inhibitor. Part 1 uses a Bayesian optimal interval design to determine maximum tolerated dose (MTD) and recommended doses for expansion (RDE). Part 3 uses a modified toxicity probability interval design to evaluate escalating combinations of IDE892 and IDE397. Oral treatment is given QD in 21-day cycles until progression or unacceptable toxicity. Serial blood samples are collected for PD analyses. Imaging will be performed every 6 weeks through week 24, then every 9–12 weeks. Efficacy endpoints will be assessed by RECIST v1.1. Primary objectives for dose-escalation cohorts (Parts 1 and 3) are safety and tolerability, including determination of MTD/RDE. In expansion cohorts (Parts 2 and 4), co-primary objectives include safety and preliminary antitumor activity (objective response rate and duration of response). Secondary endpoints for all parts include PK of IDE892 alone and in combination with IDE397. Exploratory assessments include progression free survival, changes in circulating and tumor-based markers of PRMT5 pathway modulation, molecular predictors of response, exposure–response relationships, and metabolite characterization. Clinical trial information: NCT07277413 .

ABSTRACT Background The impact of psychosocial health and socioeconomic status (SES) on long‐term lung transplant survival remains unclear. Methods We conducted a single‐center, retrospective 2:1 matched case‐control study of adult lung transplant recipients (1999–2019). Cases survived ≥6 years post‐transplant; controls survived <6 years. Matching was based on transplant year (±5 years) and indication. Psychosocial health and SES were assessed using the Psychosocial Assessment of Candidates for Transplant (PACT) score, Mayo Clinic Housing‐Based Socioeconomic Status (HOUSES) index, and Area Deprivation Index (ADI). Secondary covariates included insurance, marital status, employment, caregiver relationship, and proximity to the transplant center. Conditional logistic regression adjusted for age and gender was used. Results Among 189 patients (63 cases, 126 controls), PACT score, HOUSES index, and ADI were not significantly associated with long‐term survival. Patients with non‐family caregivers had lower odds of survival compared to those with a spouse or partner (OR = 0.16, p = 0.022). Regional residents had lower odds of long‐term survival compared to local recipients (OR = 0.55, p = 0.001). Conclusions Pre‐transplant psychosocial and SES measures were not significantly associated with long‐term survival. Caregiver relationships and geographic proximity may have a greater impact on outcomes, highlighting the importance of support systems and access to care.

Background : The presence of TP53 aberrations (defined as del(17p) or TP53 gene mutation) is a strong negative predictor of survival in patients (pts) with CLL. First-line chemoimmunotherapy is suboptimal in pts with CLL bearing TP53 aberrations, with 3-year progression-free survival (PFS) and overall survival (OS) rates of only 18% and 38%, respectively, with fludarabine, cyclophosphamide, and rituximab (Hallek, Lancet 2010). Ibrutinib is the only once-daily Bruton's tyrosine kinase (BTK) inhibitor with significant PFS and OS benefit demonstrated in multiple randomized phase 3 studies (eg, RESONATE-2, ECOG1912) in the first-line treatment of CLL/small lymphocytic lymphoma (SLL). Previous reports of single-agent ibrutinib or ibrutinib-based combination treatments have further demonstrated favorable PFS benefit in pts with TP53 aberrations in both the first-line and relapsed/refractory settings. Despite these study-specific subgroup analyses, there are limited data on long-term outcomes in pts with TP53 aberrations treated with first-line BTK inhibitors. We performed a pooled analysis of data across 4 studies to evaluate the long-term efficacy and safety of first-line ibrutinib-based therapy in pts with CLL bearing TP53 aberrations. Methods : Data for first-line ibrutinib treatment in pts with TP53 aberrations were pooled across 4 clinical trials in CLL/SLL: PCYC-1122e (NCT01500733; single-agent ibrutinib; n=34), PCYC-1130 (NCT02264574; ibrutinib + obinutuzumab; n=18), ECOG1912 (NCT02048813; ibrutinib + rituximab; n=26), and RESONATE-2 (NCT01722487; single-agent ibrutinib; n=11). ECOG1912 and RESONATE-2 excluded pts with del(17p) but did not exclude pts with TP53 mutations. Long-term PFS (assessed by investigator), OS, and safety are reported. Results : Eighty-nine pts with TP53 aberrations receiving first-line ibrutinib treatment were included in this pooled analysis. Median age was 65 years (range 33-87), and 69% of pts were male. At baseline, 53% had Rai stage III/IV, 38% had bulky disease (lymph nodes ≥5 cm), and 69% (of 87 evaluable) had unmutated IGHV. All patients had either del(17p) or TP53 mutation; 53% (of 89 evaluable) had del(17p) and 91% (of 58 evaluable) had TP53 mutation. Among 16 pts with del(17p) who had TP53 sequencing results available, 11 (69%) had both del(17p) and TP53 mutation. Forty-five pts received ibrutinib as a single agent and 44 received ibrutinib in combination with an anti-CD20 agent. With a median follow-up of 50 months (range 0.1 to 95.9 months), median PFS was not reached (95% CI: 67 months to not estimable; Figure 1A). At 48 months, the PFS rate was 79% and the OS rate was 88% (Figure 1B). Median duration of ibrutinib treatment was 46 months (range 0.1 to 95.5 months). Reasons for treatment discontinuation were progressive disease (20%), study closure (12%), adverse event (10%), withdrawal by pt (7%), death (3%), and other (physician decision due to scheduled pt surgery; 1%). Grade ≥3 adverse events of clinical interest with up to 8 years of treatment with ibrutinib were infection (22%; most commonly pneumonia in 7%), hypertension (13%), atrial fibrillation (12%), and major hemorrhage (7%). With the current follow-up, 46% of pts with TP53 aberrations remained on ibrutinib treatment. Conclusions : With a median follow-up of 4 years, first-line ibrutinib-based treatment resulted in sustained efficacy with high PFS and OS rates in CLL pts with TP53 aberrations, a population with historically poor outcomes. Although pts with TP53 aberrations remain at risk for progression, first-line treatment with ibrutinib has partially overcome the poor prognosis in this high-risk population with 4-year PFS and OS rates of 79% and 88%, respectively. No new safety signals were identified in this analysis. These results from a large, pooled, multi-study dataset demonstrated the long-term benefit of first-line ibrutinib-based treatment in pts with TP53 aberrations. Disclosures Allan: Janssen, AbbVie, and AstraZeneca: Other: Travel/accommodations/expenses; Celgene, Genentech, AstraZeneca, TG Therapeutics, and Janssen: Research Funding; AstraZeneca, Pharmacyclics LLC, an AbbVie Company, Genentech, AbbVie, Ascentage, and Cellectar: Consultancy; Janssen, AstraZeneca, and AbbVie: Honoraria. Shanafelt:Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding; Mayo Clinic: Patents & Royalties: and other intellectual property. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Moreno:Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy; AbbVie and Janssen: Research Funding; Janssen: Speakers Bureau. O'Brien:Eisai: Consultancy; Juno Therapeutics: Consultancy; Aptose Biosciences: Consultancy; GlaxoSmithKline: Consultancy; Sunesis: Research Funding; Acerta: Research Funding; Amgen: Consultancy; Celgene: Consultancy; Pfizer: Research Funding; Pharmacyclics: Research Funding; Astellas: Consultancy; Gilead: Consultancy; TG Therapeutics: Research Funding; Vida Ventures: Consultancy; KITE: Research Funding; Vaniam Group LL: Consultancy; Alexion: Consultancy; Regeneron: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Janssen Oncology: Consultancy. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Liu:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Dean:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Lai:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie and Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Other: Travel/accommodations/expenses.