Risk of recurrence after neoadjuvant chemotherapy and transoral robotic surgery in patients with oropharynx cancer that avoid adjuvant radiation.

BACKGROUND: De-escalation strategies for newly-diagnosed p16-positive oropharyngeal squamous cell carcinoma (p16+ OPSCC), aim to reduce treatment-related morbidity without compromising disease control. One strategy is neoadjuvant cisplatin and docetaxel chemotherapy (NAC + S) before transoral robotic surgery, with pathology-based risk-adapted adjuvant treatment. METHODS: We examined the recurrence-free survival (RFS) for patients who received NAC + S. RESULTS: Comparing outcomes in 103 patients between 2008 and 2023, 92% avoided adjuvant treatment and showed significantly higher 2-year recurrence-free survival (RFS) compared to those with adjuvant treatment (95.9% vs. 43.8%, p = 0.0049) CONCLUSION: Our findings suggest that pathology-based risk-adapted omission of adjuvant treatment following NAC + S does not appear to elevate recurrence risk and that NAC may identify patients with favorable tumor biology, yielding a 2-year RFS probability exceeding 95% without adjuvant treatment. Further, the study identifies a patient subset experiencing disease recurrence despite triple modality therapy. Despite limitations, including a retrospective design and modest sample size, the data advocate for controlled NAC + S studies.

Pulmonary Metastasectomy for Adrenocortical Carcinoma-Not If, but When.

BACKGROUND: Adrenocortical carcinoma (ACC) commonly metastasizes to the lungs, and pulmonary metastasectomy (PM) is utilized due to limited systemic options. METHODS: All ACC patients with initially only lung metastases (LM) from a single institution constituted this observational case series. Kaplan-Meier and Cox proportional hazard analyses evaluated the association with potential prognostic factors and outcomes. Overall survival (OS) was calculated from the date of the PM or, in those patients who did not undergo surgery, from the development of LM. RESULTS: A total of 75 ACC patients over a 45-year period met the criteria; 52 underwent PM, and 23 did not. The patients undergoing PM had a median OS of 3.1 years (95% CI: 2.4, 4.7 years) with the 5- and 10-year OS being 35.5% and 32.8%, respectively. The total resected LM did not impact the OS nor the DFS. The patients who developed LM after 11 months from the initial ACC resection had an improved OS (4.2 years; 95% CI: 3.2, NR; p = 0.0096) compared to those developing metastases earlier (2.4 years; 95% CI: 1.6, 2.8). Patients who underwent PM within 11 months of adrenalectomy demonstrated a reduced OS (2.2 years; 95% CI: 1.0, 2.7) compared to those after 11 months (3.6 years, 95% CI: 2.6, NR; p = 0.0045). PM may provide benefit to those patients with LM at presentation (HR: 0.5; p = 0.2827), with the time to first PM as a time-varying covariate. CONCLUSIONS: PM appears to have a role in ACC patients. The number of nodules should not be an exclusion factor. Patients developing LM within a year of primary tumor resection may benefit from waiting before further surgeries, which may provide additional insight into who may benefit from PM.

Combined immune checkpoint inhibition with durvalumab and tremelimumab with and without radiofrequency ablation in patients with advanced biliary tract carcinoma.

BACKGROUND: Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti-PD1/PD-L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4), with and without an interventional radiology (IR) procedure in advanced BTC. METHODS: Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Twenty-three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3-3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9-4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5-6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9-40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1-2. CONCLUSION: Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC.

National Institutes of Health Funding for Surgeon-Scientists in the US-An Update and an Expanded Landscape.

Importance: Current reports suggest that the surgeon-scientist phenotype is significantly threatened. However, a significant increase in the proportion of surgeons in the workforce funded by the National Institutes of Health (NIH) from 2010 (0.5%) to 2020 (0.7%) was recently reported and showed that surgeons primarily performed basic science research (78% in 2010; 73% in 2020) rather than clinical research. Objective: To provide an update on the status of surgeons funded by the NIH for fiscal year (FY) 2022. Evidence Review: NIH-funded surgeons were identified in FY2012 and FY2022, including those who were awarded grants with more than 1 principal investigator (PI) by querying the internal database at the NIH. The main outcome for this study was the total number of NIH-funded surgeons in FY2012 and FY2022, including total grant costs and number of grants. The secondary analysis included self-reported demographic characteristics of the surgeons in FY2022. The research type (basic science vs clinical) of R01 grants was also examined. Findings: Including multiple PI grants, 1324 surgeon-scientists were awarded $1.3 billion in FY2022. Women surgeons increased to 31.3% (339 of 1084) of the population of surgeon PIs in FY2022 compared with 21.0% (184 of 876) in FY2012. Among surgeon PIs awarded grants, a total of 200 (22.8%) were Asian, 35 (4.0%) were Black or African American, 18 (2.1%) were another race (including American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and more than 1 race), and 623 (71.1%) were White. A total of 513 of 689 R01 grants (74.5%) were for basic science, 131 (19.0%) were for clinical trials, and 45 (6.5%) were for outcomes research. Conclusions and Relevance: NIH-funded surgeons are increasing in number and grant costs, including the proportion of women surgeon PIs, and are representative of the diversity among US academic surgical faculty. The results of this study suggest that despite the many obstacles surgeon-scientists face, their research portfolio continues to grow, they perform a myriad of mostly basic scientific research as both independent PIs and on multidisciplinary teams.

VB-111 (ofranergene obadenovec) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single center, single arm, phase II trial.

BACKGROUND: Microsatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response. METHODS: This was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood. RESULTS: Between August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40-75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3-4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+ T cells and HLA-DRhigh T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs. CONCLUSION: In patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+ T cells systemically that was poorly sustained. TRIAL REGISTRATION NUMBER: NCT04166383.

Bridging Health Disparities: a Genomics and Transcriptomics Analysis by Race in Prostate Cancer.

As the era of cancer genomics expands, disproportionate rates of prostate cancer incidence and mortality by race have demonstrated increasing relevance in clinical settings. While Black men are most particularly affected, as data has historically shown, the opposite is observed for Asian men, thus creating a basis for exploring genomic pathways potentially involved in mediating these opposing trends. Studies on racial differences are limited by sample size, but recent expanding collaborations between research institutions may improve these imbalances to enhance investigations on health disparities from the genomics front. In this study, we performed a race genomics analysis using GENIE v11, released in January 2022, to investigate mutation and copy number frequencies of select genes in both primary and metastatic patient tumor samples. Further, we investigate the TCGA race cohort to conduct an ancestry analysis and to identify differentially expressed genes highly upregulated in one race and subsequently downregulated in another. Our findings highlight pathway-oriented genetic mutation frequencies characterized by race, and further, we identify candidate gene transcripts that have differential expression between Black and Asian men.

Current status of National Institutes of Health funding for thoracic surgeons in the United States: Beacon of hope or candle in the wind?

OBJECTIVE: Increasing forces threaten the viability of thoracic surgeon-initiated research, a core component of our academic mission. National Institutes of Health funding is a benchmark of research productivity and innovation. This study examined the current status of National Institutes of Health funding for thoracic surgeons. METHODS: Thoracic surgeon principal investigators on National Institutes of Health-funded grants during June 2010, June 2015, and June 2020 were identified using National Institutes of Health iSearchGrants (version 2.4). American Association of Medical Colleges data were used to identify all surgeons in the United States. Types and total costs of National Institutes of Health-funded grants were compared relative to other surgical specialties. RESULTS: A total of 61 of 4681 (1.3%), 63 of 4484 (1.4%), and 60 of 4497 (1.3%) thoracic surgeons were principal investigators on 79, 76, and 87 National Institutes of Health-funded grants in 2010, 2015, and 2020, respectively; these rates were higher than those for most other surgical specialties (P ≤ .0001). Total National Institutes of Health costs for Thoracic Surgeon-initiated grants increased 57% from 2010 to 2020, outpacing the 33% increase in total National Institutes of Health budget. Numbers and types of grants varied among cardiovascular, transplant, and oncology subgroups. Although the majority of grants and costs were cardiovascular related, increased National Institutes of Health expenditures primarily were due to funding for transplant and oncology grants. Per-capita costs were highest for transplant-related grants during both years. Percentages of R01-to-total costs were constant at 55%. Rates and levels of funding for female versus male thoracic surgeons were comparable. Awards to 5 surgeons accounted for 33% of National Institutes of Health costs for thoracic surgeon principal investigators in 2020; a similar phenomenon was observed for 2010 and 2015. CONCLUSIONS: Long-term structural changes must be implemented to more effectively nurture the next generation of thoracic surgeon scientists.

Development and pilot validation of a novel disfigurement severity scale for plexiform neurofibromas in children with neurofibromatosis type 1.

BACKGROUND/AIMS: We developed an observer disfigurement severity scale for neurofibroma-related plexiform neurofibromas to assess change in plexiform neurofibroma-related disfigurement and evaluated its feasibility, reliability, and validity. METHODS: Twenty-eight raters, divided into four cohorts based on neurofibromatosis type 1 familiarity and clinical experience, were shown photographs of children in a clinical trial (NCT01362803) at baseline and 1 year on selumetinib treatment for plexiform neurofibromas (n = 20) and of untreated participants with plexiform neurofibromas (n = 4). Raters, blinded to treatment and timepoint, completed the 0-10 disfigurement severity score for plexiform neurofibroma on each image (0 = not at all disfigured, 10 = very disfigured). Raters evaluated the ease of completing the scale, and a subset repeated the procedure to assess intra-rater reliability. RESULTS: Mean baseline disfigurement severity score for plexiform neurofibroma ratings were similar for the selumetinib group (6.23) and controls (6.38). Mean paired differences between pre- and on-treatment ratings was -1.01 (less disfigurement) in the selumetinib group and 0.09 in the control (p = 0.005). For the disfigurement severity score for plexiform neurofibroma ratings, there was moderate-to-substantial agreement within rater cohorts (weighted kappa range = 0.46-0.66) and agreement between scores of the same raters at repeat sessions (p > 0.05). In the selumetinib group, change in disfigurement severity score for plexiform neurofibroma ratings was moderately correlated with change in plexiform neurofibroma volume with treatment (r = 0.60). CONCLUSION: This study demonstrates that our observer-rated disfigurement severity score for plexiform neurofibroma was feasible, reliable, and documented improvement in disfigurement in participants with plexiform neurofibroma shrinkage. Prospective studies in larger samples are needed to validate this scale further.

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Clinical protocol: Feasibility of evaluating abemaciclib neuropharmacokinetics of diffuse midline glioma using intratumoral microdialysis.

Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in part to the function of the BBB. Intratumoral microdialysis sampling is an effective tool to determine brain entry of varied agents and could help to provide a better understanding of the relationship of drug permeability to DMG treatment responsivity. This is a non-randomized, single-center, phase 1 clinical trial. Up to seven young adult (18-39 years) patients with recurrent high-grade or diffuse midline glioma will be enrolled with the goal of 5 patients completing the trial over an anticipated 24 months. All patients will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. Patients will undergo resection or biopsy, placement of a microdialysis catheter, and 48 hours of dialysate sampling coupled with timed plasma collections. If intratumoral tumor or brain dialysate sampling concentrations are >10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. Trial registration: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis.

Metabolic syndrome prevalence and impact on outcomes in patients with chronic graft-versus-host disease.

Patients with chronic graft-versus-host disease (cGVHD) are at heightened risk for components of metabolic syndrome (MetS), yet the prevalence and impact of MetS in the cGVHD patient population remain unknown. Adult patients (n = 229) with cGVHD enrolled in the cross-sectional NIH cGVHD Natural History Study (NCT00092235) were evaluated for MetS at enrollment and for variables associated with MetS. A majority (54.1%, 124/229) of the cohort met the diagnostic criteria for MetS. Patients with higher body mass index and lower performance status scores were more likely to have MetS (P < 0.0001; P = 0.026; respectively). Higher circulating erythrocyte sedimentation rate, C-reactive protein, and creatinine concentrations, along with lower estimated glomerular filtration rate, were associated with MetS (P < 0.001; P < 0.004; P = 0.02; P = 0.002; respectively). Patients with MetS compared to patients without MetS had no statistical differences in survival or NRM (5-year OS: 64% [95% CI: 54.8-71.8%] vs. 75.1% [95% CI: 65.6-82.3%]; respectively; overall P = 0.20; 5-year NRM: 21.7% [95% CI: 13.6-30.9%] vs. 10.1% [95% CI: 4.4-18.7%]; respectively; overall P = 0.12). Additionally, there was no difference in cGVHD severity between the two groups. Given the high prevalence of MetS in this cohort, clinicians should screen for its presence before it develops into comorbidities that complicate the course of cGVHD treatment.

Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma.

PURPOSE: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701). PATIENTS AND METHODS: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT). RESULTS: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response. CONCLUSIONS: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.

Chimeric Antigen Receptor T Cells as Salvage Therapy for Post-Chimeric Antigen Receptor T Cell Failure.

Outcomes for post-chimeric antigen receptor (CAR) T cell therapy (CART) relapse are poor. The utilization of a unique CAR T cell construct for post-CART failure is increasing, but this approach is not well described. In this study, with CART-A the first unique CAR T cell construct received and CART-B the second, the primary objective was to characterize outcomes following CART-B. Secondary objectives included evaluating safety and toxicity with sequential CART infusions; investigating the impact of potential factors, such as antigen modulation and interval therapy, on CART-B response; and characterizing long-term outcomes in patients receiving multiple CARTs. This was a retrospective review (NCT03827343) of children and young adults with B cell acute lymphoblastic leukemia (B-ALL) undergoing CART therapy who received at least 2 unique CART constructs, excluding interim CART reinfusions of the same product. Of 135 patients, 61 (45.1%) received 2 unique CART constructs, including 13 who received >2 CARTs over time. Patients included in this analysis received 14 distinct CARTs targeting CD19 and/or CD22. The median age at CART-A was 12.6 years (range, 3.3 to 30.4 years). The median time from CART-A to CART-B was 302 days (range, 53 to 1183 days). CART-B targeted a different antigen than CART-A in 48 patients (78.7%), owing primarily to loss of CART-A antigen target. The rate of complete remission (CR) was lower with CART-B (65.5%; 40 of 61) than with CART-A (88.5%; 54 of 61; P = .0043); 35 of 40 (87.5%) CART-B responders had CART-B targeting a different antigen than CART-A. Among the 21 patients with a partial response or nonresponse to CART-B, 8 (38.1%) received CART-B with the same antigen target as CART-A. Of 40 patients with CART-B complete response (CR), 29 (72.5%) relapsed. For the 21 patients with evaluable data, the relapse immunophenotype was antigennegative in 3 (14.3%), antigendim in 7 (33.3%), antigenpositive in 10 (47.6%), and lineage switch in 1 (4.8%). The median relapse-free survival following CART-B CR was 9.4 months (95% confidence interval [CI], 6.1 to 13.2 months), and overall survival was 15.0 months (95% CI, 13.0 to 22.7 months). Given the limited salvage options for post-CART relapse, identifying optimizing strategies for CART-B is critical. We raise awareness about the emerging use of CART for post-CART failure and highlight clinical implications accompanying this paradigm shift.

Predictors and significance of kidney dysfunction in patients with chronic graft-versus-host disease.

Kidney complications have been studied in allogeneic hematopoietic stem cell transplant patients but not specifically among chronic graft-versus-host disease (cGVHD) patients. Participants (n = 365) enrolled in the cross-sectional cGVHD natural history study (NCT00092235) were assessed for kidney dysfunction and overall survival. Kidney dysfunction was analyzed for associations in univariate and multivariable analyses. Kidney dysfunction (eGFR < 60) was found in 64 patients, and 29 patients had moderate-severe kidney dysfunction (eGFR < 45). Patients with kidney dysfunction were more likely treated with cyclosporine at evaluation or to have received it for GVHD prophylaxis, or prior treatment of GVHD. Patients with kidney dysfunction were less severely affected by cGVHD of skin, mouth, and joints/fascia. In multivariable modeling, history of cyclosporine use (OR = 2.19, 95% CI 1.13-4.25), angiotensin receptor blocker use (OR = 5.57, 95% CI 1.49-20.84), proteinuria (OR = 2.39, 95% CI 1.19-4.79), lower CRP (OR = 0.95, 95% CI 0.91-0.99), lower C3 (OR = 0.98, 95% CI 0.97-0.99), and lower hemoglobin (OR = 0.70, 95% CI 0.58-0.84) were jointly associated with kidney dysfunction. Overall survival was lower in those with moderate-severe kidney dysfunction (p = 0.015), demonstrating the importance of addressing kidney dysfunction in this population. The association of kidney dysfunction with less severe cGVHD suggests an etiology unrelated to cGVHD but potentially a consequence of drug-related toxicities.

A comprehensive analysis of adverse events in the first 30 days of phase 1 pediatric CAR T-cell trials.

The tremendous success of chimeric antigen receptor (CAR) T cells in children and young adults (CAYAs) with relapsed/refractory B-cell acute lymphoblastic leukemia is tempered by toxicities such as cytokine release syndrome (CRS). Despite expansive information about CRS, profiling of specific end-organ toxicities secondary to CAR T-cell therapy in CAYAs is limited. This retrospective, single-center study sought to characterize end-organ specific adverse events (AEs) experienced by CAYAs during the first 30 days after CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events were retrospectively analyzed for 134 patients enrolled in 1 of 3 phase 1 CAR T-cell trials (NCT01593696, NCT02315612, and NCT03448393), targeting CD19 and/or CD22. A total of 133 patients (99.3%) experienced at least 1 grade ≥3 (≥Gr3) AE across 17 organ systems, of which 75 (4.4%) were considered dose- or treatment-limiting toxicities. Excluding cytopenias, 109 patients (81.3%) experienced a median of 3 ≥Gr3 noncytopenia (NC) AEs. The incidence of ≥Gr3 NC AEs was associated with the development and severity of CRS as well as preinfusion disease burden (≥ 25% marrow blasts). Although those with complete remission trended toward experiencing more ≥Gr3 NC AEs than nonresponders (median, 4 vs 3), nonresponders experiencing CRS (n = 17; 37.8%) had the highest degree of NC AEs across all patients (median, 7 vs 4 in responders experiencing CRS). Greater understanding of these toxicities and the ability to predict which patients may experience more toxicities is critical as the array of CAR T-cell therapies expand. This retrospective study was registered at www.clinicaltrials.gov as NCT03827343.

Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas.

BACKGROUND: Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies. METHODS: This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index). RESULTS: For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment. CONCLUSIONS: With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.

Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial.

BACKGROUND: Lymphomatoid granulomatosis is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder with a median overall survival of less than 2 years. In this study, we hypothesised that low-grade lymphomatoid granulomatosis is immune-dependent and high-grade lymphomatoid granulomatosis is immune-independent. On the basis of this hypothesis, we investigated the activity and safety of new treatment with immunotherapy in patients with low-grade disease and standard chemotherapy in patients with high-grade disease. METHODS: In this open-label, single-centre, phase 2 trial, we enrolled patients aged 12 years or older with untreated, or relapsed or refractory lymphomatoid granulomatosis at the National Cancer Institute (National Institutes of Health, Bethesda, MD, USA). Patients with low-grade disease received dose-escalated interferon alfa-2b, starting at 7·5 million international units subcutaneously three times per week for up to 1 year past best response, and patients with high-grade disease received six cycles every 3 weeks of intravenous, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). Starting doses were 50 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for etoposide; 60 mg/m2 twice daily by mouth from day 1 to day 5 for prednisone; 0·4 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for vincristine; 750 mg/m2 intravenous on day 5 for cyclophosphamide; 10 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for doxorubicin; and 375 mg/m2 intravenous on day 1 for rituximab. The doses of doxorubicin, etoposide, and cyclophosphamide were adjusted up or down on the basis of neutrophil and platelet nadirs. Patients with residual or progressive disease after initial therapy crossed over to alternative therapy. The primary endpoint was the proportion of patients who had an overall response and the 5-year progression-free survival after initial or cross-over treatment. Analysis of response included all participants who underwent restaging imaging; safety analysis included all patients who received any dose of study drugs. The trial is open for enrolment and is registered at ClinicalTrials.gov, NCT00001379. FINDINGS: 67 patients were enrolled between Jan 10, 1991, and Sept 5, 2019 (42 [63%] were male). 45 patients received initial treatment with interferon alfa-2b (16 of whom crossed over to DA-EPOCH-R) and 18 received initial treatment with DA-EPOCH-R (eight of whom crossed over to interferon alfa-2b); four underwent surveillance only. After initial treatment with interferon alfa-2b, the overall response was 64% (28 of 44 evaluable patients) with 61% (27 of 44) having a complete response, whereas, after cross-over treatment with interferon alfa-2b, the overall response was 63% (five of eight evaluable patients) with 50% (four of eight) having a complete response. After initial treatment with DA-EPOCH-R, the overall response was 76% (13 of 17 evaluable patients) with 47% (eight of 17) having a complete response, whereas, after cross-over treatment with DA-EPOCH-R, the overall response was 67% (ten of 15 evaluable patients) with 47% (seven of 15) having a complete response. 5-year progression-free survival was 48·5% (95% CI 33·2-62·1) after initial treatment with interferon alfa-2b, 50·0% (15·2-77·5) after cross-over treatment with interferon alfa-2b, 25·4% (8·2-47·2) after initial treatment with DA-EPOCH-R, and 62·5% (34·9-81·1) after cross-over treatment with DA-EPOCH-R. The most common grade 3 or worse adverse events in patients treated with interferon alfa-2b included neutropenia (27 [53%] of 51 patients), lymphopenia (24 [47%]), and leukopenia (24 [47%]). The four most common grade 3 or worse adverse events in patients treated with DA-EPOCH-R included neutropenia (29 [88%] of 33 patients), leukopenia (28 [85%]), infection (18 [55%]), and lymphopenia (17 [52%]). Serious adverse events occurred in 13 (25%) of 51 patients receiving treatment with interferon alfa-2b and 21 (64%) of 33 patients receiving DA-EPOCH-R, with five treatment-related deaths: one thromboembolic, one infection, and one haemophagocytic syndrome with interferon alfa-2b, and one infection and one haemophagocytic syndrome with DA-EPOCH-R. INTERPRETATION: Interferon alfa-2b is efficacious for treating low-grade lymphomatoid granulomatosis and hence reducing progression to high-grade disease, whereas patients with high-grade lymphomatoid granulomatosis showed expected responses to chemotherapy. Uncontrolled immune regulation of Epstein-Barr virus is hypothesised to result in the emergence of low-grade disease after chemotherapy, for which treatment with interferon alfa-2b is efficacious. FUNDING: Intramural Research Programs of the National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer.

BACKGROUND: Oncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial. METHODS: Adult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring. RESULTS: Thirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment. CONCLUSION: PexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers. TRIAL REGISTRATION NUMBER: NCT03206073.