Elad Sharon

The bispecific CD19/CD3 T-cell engaging antibody blinatumomab is efficacious in front-line therapy in B-cell acute lymphoblastic leukemia (B-ALL) but the biological determinants of response and resistance are incompletely understood. To examine the genomic determinants of outcome, we analyzed genomic and clinical data of 569 adults registered to the ECOG-ACRIN E1910 study of blinatumomab in BCR::ABL1-negative B-ALL (ClinicalTrials.gov NCT02003222). We identified 23 molecular subtypes including the high-risk subtypes BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A-R (12%), and 267 putative driver genes. We identified a subtype characterized by CEBPA overexpression or elevated CEBPB expression due to chromosomal translocation-mediated enhancer hijacking, or insertions downstream of CEBPA that generate neoenhancers. Attainment of MRD-negativity patients after induction and intensification chemotherapy was more common in PAX5alt, TCF3::PBX1 and ZNF384-R B-ALL, and less common in BCR::ABL1-like and KMT2A-R B-ALL. Integration of genomic and clinical data suggested that the addition of blinatumomab to chemotherapy was associated with improved relapse-free and overall survival for several B-ALL subtypes, including hyperdiploid, PAX5alt, PAX5 P80R, BCR::ABL1-like JAK-STAT and KMT2A-R B-ALL, although small sample sizes for several subtypes indicate that confirmation is required. Alteration of TP53 or mutations associated with myeloid clonal hematopoiesis of indeterminate potential (CHIP) were identified in 15.3% and 9.8% of patients, respectively. The presence of these mutations was associated with older age at diagnosis and inferior outcome to chemotherapy. In summary, we define the landscape of genomic alterations of adult B-ALL, and identify genomic subtypes that may influence the efficacy of blinatumomab when combined with chemotherapy.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are associated with immune-related adverse events, including ICI-associated AKI (ICI-AKI). ICI-AKI presents diagnostic and management challenges and can influence decisions regarding immunosuppression and ICI rechallenge, with important implications for both kidney and cancer outcomes. An international, multidisciplinary panel convened at the 34th Acute Disease Quality Initiative (ADQI) consensus conference in September 2024. Systematic literature searches of PubMed were conducted to identify studies on the epidemiology, mechanisms, diagnosis, management, rechallenge, and outcomes of ICI-AKI. The meeting followed the established ADQI process and used a modified Delphi method to achieve consensus. Evidence was reviewed and appraised by workgroups, and consensus statements were developed through structured discussion and voting. Observational data suggest that AKI occurs in up to 20% of patients receiving ICIs, with ICI-AKI accounting for approximately 2%–5% of cases. Acute tubulointerstitial nephritis is the most common lesion, observed in 80%–90% of biopsies, although glomerular diseases are increasingly recognized. No clinical features reliably distinguish ICI-AKI from other causes of AKI, and kidney biopsy remains the diagnostic gold standard. Emerging urinary, circulating, and imaging biomarkers show promise but are not yet ready for routine clinical use. Early glucocorticoid initiation (within 3 days of ICI-AKI diagnosis versus >3 days after diagnosis) is associated with higher rates of kidney recovery, although optimal dosing and duration remain uncertain. Recurrent ICI-AKI occurs in fewer than 20% of patients undergoing ICI rechallenge. Management of high-risk populations, including kidney transplant recipients and patients with autoimmune disease or advanced CKD, requires individualized, multidisciplinary decision making. ICI-AKI is an important and potentially reversible complication of cancer immunotherapy; these consensus statements provide a framework for diagnosis and management, support cautious ICI rechallenge in selected patients, and identify priorities for future research.

Baseline tumor burden is a powerful, tumor‐agnostic, prognostic marker across rare cancers, and patients with greater disease volume at treatment initiation face significantly worse survival, independent of cancer type. Critically, tumor burden predicts prognosis rather than immunotherapy response, underscoring that earlier diagnosis and earlier line intervention remain the most consequential opportunities to improve outcomes in rare malignancies.

Purpose: The addition of MEK inhibition to PD-L1 blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer (BTC). While MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance anti-tumor immunity in this combination. Patients and Methods: We conducted a randomized, phase 2 trial evaluating atezolizumab (840mg IV days 1,15) in combination with the CD27 co-stimulatory mAb (CDX-1127/varlilumab [3mg/kg IV days 1, 15]), with/without the addition of a MEK inhibitor (cobimetinib [60mg oral daily days 1-21, off 22-28]) in unresectable BTC following at least 1 metastatic therapy. Overall response rate (ORR) and PFS were co-primary endpoints. Treatment-related changs in CD8+ tumor infiltrating lymphocytes (TIL) was the primary correlative outcome. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled (n=29[CAV],n=28[AV]. A majority (67%) had intrahepatic cholangiocarcinoma and 32% were immunotherapy-experienced. Both regimens were well-tolerated without new safety signals. Objective responses were rare (0%[CAV],3.8%[AV]). Median PFS was 2.40(CAV) and 1.84(AV) months (HR 0.67,95%CI[0.38,1.18]). Among immunotherapy-experienced patients, mPFS was 3.62(CAV) and 1.84(AV) months (HR 0.54,95%CI:[0.18-1.62]). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe but neither meaningfully improved outcomes in BTC treated in the later lines. Correlative tissue studies validated preclinical work that MEK inhibition increases CD8+TILs.

Endogenous circadian programs coordinate physiology across tissues, including immune cell trafficking and drug metabolism. Previous retrospective studies suggested that the timing of immune checkpoint inhibitor delivery may be a modifiable determinant of survival in patients with cancer, with earlier infusions often associated with improved outcomes. Recently, the prospective randomized phase III LungTIME-C01 trial reported that earlier time-of-day (before 3:00 pm) administration of chemoimmunotherapy nearly doubled progression-free survival in patients with non–small cell lung cancer. In this commentary, we examine the trial’s clinical design and execution, including protocol amendments and safety reporting that warrant clarification. We consider the mechanistic interpretation of the results, highlighting that the observed effects may reflect contributions from cytotoxic chronopharmacology, circadian immune regulation, and healthcare delivery factors rather than immunotherapy timing alone. We outline implications for future trial design, including factorial approaches to disentangle the timing of immunotherapy from chemotherapy and the need for multicenter validation before scheduling recommendations are widely adopted.

PURPOSE: Multiple reports have suggested that receiving immunotherapy infusions earlier in the day is associated with improved outcomes, including longer overall survival (OS) and lower toxicity rates. However, the definition of early varies between publications. Reports also fail to account for confounding factors (including distance to infusion center), are subject to survivor bias (analyzing postbaseline factors at baseline), and do not adjust P values for multiple comparisons when evaluating multiple potential thresholds for early versus late time of day of infusion. METHODS: We analyzed a previously reported multicenter clinical trial evaluating pembrolizumab as adjuvant therapy for participants with resectable high-risk melanoma. Standard statistical methodologies that account for potential biasses were used to evaluate the association between time of day of infusion and clinical outcomes. RESULTS: A total of 628 participants received pembrolizumab and had time of first infusion recorded. The median age was 55 years, range, 20-82. Odds of infusion before 11:00 hours increased by 32% over 12 months of therapy ( P = .013). Participants living further from their treating institution had later infusion times on average: odds of infusion before 11:00 decreased by 9% for each additional 50 miles ( P = .017). The optimal cut point for first infusion time for OS was 15:48 with hazard ratio (HR) = 1.40; changing the cut point by 30 minutes earlier to 15:18 decreased HR to 0.98, indicating lack of robustness of the threshold. No significant association was identified between proportion of early infusions and outcomes in multivariable time-dependent Cox regression models. CONCLUSION: In this multicenter trial of adjuvant pembrolizumab for participants with high-risk melanoma, analyses that account for common sources of bias found no significant association between recurrence-free or OS and time of day of infusion.

We previously reported initial results of the pivotal phase II trial of atezolizumab for patients with alveolar soft part sarcoma (ASPS; ClinicalTrials.gov identifier: NCT03141684 ). Here, we report on three additional years of observation. Fifty-three patients with ASPS received atezolizumab. Median duration of response increased to 37.0 months. Objective response rate (ORR) and median progression-free survival (mPFS) remained essentially as previously reported (35.8% [95% CI, 23.1 to 50.2] and 20.8 months [IQR, 7.6-not reached], respectively). ASPSCR1::TFE3 fusion type was determined for 47/53 patients; ORR and mPFS were higher among the 41 patients expressing type 1 (43.9% [95% CI, 28.5 to 60.2] and 28.3 months [IQR, 9.2-not reached], respectively) than the six patients expressing type 2 (0% [95% CI, 0 to 45.9] and 7.5 months [IQR, 3.9-not reached], respectively, PFS HR, 3.2 [95% CI, 1.01 to 10.2]). Eleven patients chose a per-protocol drug holiday (range, 3.5-26.4 months) after ≥2 years of treatment; two experienced disease progression during the holiday. Nine eligible patients elected to receive bevacizumab plus atezolizumab after progressing on monotherapy; ORR was 0% and mPFS was 18.5 months (IQR, 7.9-21.1) in this small cohort. Long-term results support using atezolizumab to treat ASPS, even for several years; a drug holiday with careful monitoring may be an option for some patients.