Day 30 SUVmax Predicts Progression in Lymphoma Patients Achieving PR/SD After CAR T-cell Therapy

About 70% of patients with large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) who achieve a partial response (PR) or a stable disease (SD) on day 30 (D30) PET-CT scan progress, but predictive factors of progression are unknown. This a retrospective study of patients with LBCL treated with axi-cel at MD Anderson Cancer Center between 01/2018 and 02/2021. Among 50 patients with D30 PR/SD, 13 (26%) converted to complete response (CR). Among 95 patients with D30 CR, 72 (76%) remained in CR. On univariate analysis, the only day -5 characteristic associated with conversion from D30 PR/SD to subsequent CR was a higher platelet count (p=0.05). The only D30 factor associated with conversion from D30 PR/SD to subsequent CR was lower D30 SUVmax (p<0.001), and all patients with and D30 SUVmax ≥10 progressed. After a median follow-up of 12 months, no significant difference in median progression-free survival was observed when comparing patients who converted from D30 PR/SD to subsequent CR to those who had been in CR since D30 (p=0.19). Novel predictive and prognostic markers based on tissue biopsy and non-invasive diagnostic assays are needed to more effectively identify these patients and characterize the biology of their residual disease.

Randomized Trial of Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Long-Term Results of the ORATOR Trial

PURPOSE The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has risen rapidly, because of an epidemic of human papillomavirus infection. The optimal management of early-stage OPSCC with surgery or radiation continues to be a clinical controversy. Long-term randomized data comparing these paradigms are lacking. METHODS We randomly assigned patients with T1-T2, N0-2 (≤ 4 cm) OPSCC to radiotherapy (RT) (with chemotherapy if N1-2) versus transoral robotic surgery plus neck dissection (TORS + ND) (with or without adjuvant therapy). The primary end point was swallowing quality of life (QOL) at 1-year using the MD Anderson Dysphagia Inventory. Secondary end points included adverse events, other QOL outcomes, overall survival, and progression-free survival. All analyses were intention-to-treat. Herein, we present long-term outcomes from the trial. RESULTS Sixty-eight patients were randomly assigned (n = 34 per arm) between August 10, 2012, and June 9, 2017. Median follow-up was 45 months. Longitudinal MD Anderson Dysphagia Inventory analyses demonstrated statistical superiority of RT arm over time ( P = .049), although the differences beyond 1 year were of smaller magnitude than at the 1-year timepoint (year 2: 86.0 ± 13.5 in the RT arm v 84.8 ± 12.5 in the TORS + ND arm, P = .74; year 3: 88.9 ± 11.3 v 83.3 ± 13.9, P = .12). These differences did not meet the threshold to qualify as a clinically meaningful change at any timepoint. Certain differences in QOL concerns including more pain and dental concerns in the TORS + ND arm seen at 1 year resolved at 2 and 3 years; however, TORS patients started to use more nutritional supplements at 3 years ( P = .015). Dry mouth scores were higher in RT patients over time ( P = .041). CONCLUSION On longitudinal analysis, the swallowing QOL difference between primary RT and TORS + ND approaches persists but decreases over time. Patients with OPSCC should be informed about the pros and cons of both treatment options (ClinicalTrials.gov identifier: NCT01590355 ).

Using the MDASI-Adolescent for Early Symptom Identification and Mitigation of Symptom Impact on Daily Living in Adolescent and Young Adult Stem Cell Transplant Patients

Hematopoietic stem cell transplantation (HSCT) requires an intensive pre- and post-procedure course that leads to symptoms including fatigue, nausea/vomiting, and pain, all of which interfere significantly with activities of daily living. These symptoms place a substantial burden on patients during the time period surrounding transplant as well as during long-term recovery. The MD Anderson Symptom Inventory (MDASI) is a symptom-reporting survey that has been successfully used in adult patients with cancer and may have utility in the adolescent and young adult (AYA) population. At the Children’s Cancer Hospital at MD Anderson Cancer Center, we adopted a modified version of the MDASI, the MDASI-adolescent (MDASI-Adol), as a standard of care for clinical practice in assessing the symptom burden of patients in the peri-transplant period. We then conducted a retrospective chart review to describe the clinical utility of implementing this symptom-screening tool in AYA patients admitted to our pediatric stem cell transplant service. Here, we report our findings on the symptom burden experienced by pediatric and AYA patients undergoing stem cell transplantation as reported on the MDASI-Adol. Our study confirmed that the MDASI-Adol was able to identify a high symptom burden related to HSCT in the AYA population and that it can be used to guide symptom-specific interventions prior to transplant and during recovery. Implementing a standard symptom-screening survey proved informative to our clinical practice and could mitigate treatment complications and alleviate symptom burden.

A Predictive Score for Outcomes of Tyrosine Kinase-Inhibitor Therapy in Persons with Chronic Myeloid Leukaemia Presenting in Accelerated Phase

Background Chronic myeloid leukaemia (CML) presenting in accelerated phase (AP) is uncommon and there are few data on predictive co-variates for outcomes of tyrosine kinase-inhibitor (TKI)-therapy. Moreover, it is unknown which outcomes of TKI-therapy in these persons correlate with European LeukemiaNet (ELN) definitions of warning and failure which were developed in people in chronic phase or whether imatinib and 2 nd generation tyrosine kinase-inhibitors (TKIs) are equally effective. Objective Identify co-variates correlated with outcomes of TKI-therapy in persons with CML presenting in AP diagnosed by MD Anderson or World Health Organization (WHO) criteria and develop a predictive score. Determine which outcomes correlate with ELN criteria of warning and failure. Compare outcomes of initial therapy with imatinib versus 2 nd-generation TKIs. Methods We interrogated data from 312 and 334 consecutive subjects with CML presenting in AP and receiving imatinib or a 2 nd-generation TKI as initial therapy. Diagnosis of AP was based on widely-accepted MD Anderson or WHO criteria. Demographic, clinical and laboratory co-variates significantly correlated with outcomes were analyzed in a Cox multi-variable regression model. Propensity score matching was done to compare outcomes of initial therapy with imatinib versus a 2 nd generation TKIs. Results In the cohort defined by MD Anderson criteria there were 197 males (63%) with a median age of 41 years (Interquartile Range [IQR], 30 - 54 years). 106 subjects (34%) had ≥ 1 co-morbidities. Median haemoglobin concentration was 99 g/L (range, 40-176 g/L), WBC concentration, 138 x 10E+9/L (range, 3-797 x10E+9/L), platelet concentration, 450 x 10E+9/L (range, 11-4094 x10E+9/L) and percentage blood or bone marrow blasts (whichever was higher), 4% (range, 0-27%). Non-mutually exclusive criteria for classifying subjects as AP included: (1) 15-29% blasts (n = 22, 7%); (2) blood basophils ≥ 20% (n = 184, 59%); (3) platelets < 100 × 10E+9/L unrelated to therapy (n = 31, 10%); (4) clonal evolution (n = 45, 15%); (5) ≥ 2 features (n = 30, 10%). Co-variates associated with failure-free survival (FFS) were haemoglobin concentration < 100 g/L (HR = 1.9; 95% Confidence Interval [CI], 1.1, 3.1; p = 0.014) and blasts > 4.5% (HR = 1.8 [1.1 - 2.9]; p = 0.013). Co-variates associated with progression-free survival (PFS) were platelets < 230 × 10E+9/L (HR = 3.3 [1.7, 6.5]; p < 0.001), blasts > 4.5% (HR = 2.4 [1.3, 4.6]; p = 0.007) and ≥ 1 co-morbidities (HR = 2.4 [1.2, 4.7]; p = 0.010). Co-variates associated with survival were haemoglobin concentration < 100 g/L (HR = 3.3 [1.1, 10.2]; p = 0.04), platelets < 230 × 10E+9/L (HR = 11.4 [3.9, 33.3]; p < 0.001) and ≥ 1 co-morbidities (HR = 6.7 [2.3, 19.5]; p < 0.001). Next, we divided subjects into 4 cohorts: (1) low-risk (no adverse co-variate; n = 49); (2) intermediate-1 risk (1 adverse co-variate; n = 116); (3) intermediate-2 risk (2 adverse co-variates; n = 92); and (4) high-risk (≥ 3 adverse co-variates; n = 47) with significant different probabilities of FFS, PFS and survival (all p-values < 0.001). Using the 2020 ELN criteria for w arning at 3 months was significantly-associated with worse FFS (HR = 3.1 [1.7, 5.7]; p < 0.001). Failure at 3 months was significantly associated with worse PFS (HR = 9.3 [4.3, 18.8]; p < 0.001) and survival (HR = 6.2 [2.0, 19.2]; p = 0.002). In propensity score matching analyses subjects receiving initial therapy with imatinib had lower probabilities of complete cytogenetic response (CCyR; HR = 1.3 [1.0, 1.8]; p = 0.079), major molecular response (MMR; HR = 1.2 [0.8, 1.7; p = 0.386) and molecular response 4.5 (.5; HR = 1.8 [1.1, 3.1]; p = 0.019). However, other endpoints including FFS, PFS and survival were similar for both interventions. Similar results in the subjects diagnosed as AP using the WHO criteria. Conclusions We identify co-variates associated with several outcomes of TKI-therapy in persons presenting in AP CML and used these to develop a prognostic score. We show the 2020 ELN criteria for warning and failure to TKI-therapy developed in persons in chronic phase also operate in subjects diagnosed in AP. Lastly, using propensity score matching we show that whilst some landmarks are achieved more rapidly in persons initially treated with a 2 nd generation TKI, FFS, PFS and survival are similar to those in persons initially treated with imatinib. Our data should help inform physicians treating person with CML presenting in AP. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

236 Predictors of ICI renal toxicity: a pathological approach

BackgroundInflammatory response in unintended tissues and organs associated with the use of immune checkpoint inhibitors also known as immune related adverse events (irAEs) is a management challenge, and renal irAEs are associated with increased patient morbidity and mortality. The most common renal toxicity is acute interstitial nephritis (AIN), characterized by infiltration of renal tissue with immune cells, and may be analogous to kidney transplant rejection. Using both clinical variables and tissue findings we evaluated a large cohort of ICI cases to determine predictors of renal response and overall survival.MethodsWe retrospectively reviewed all patients treated with ICI (August 2007 to August 2020) at MD Anderson Cancer Center. A total of 38 patients with biopsy confirmed AIN and available tissue were identified. All slides were reviewed by two board certified renal pathologists and the severity of inflammation and chronicity was graded using transplant rejection BANFF criteria. Patients were categorized as renal responders if creatinine improved or returned to baseline after treatment and non-responders if it did not. Fisher’s exact tests for categorical variables and t-test/ANOVA or the counterparts of the non-parametric approaches (Wilcoxon rank-sum or Kruskal-Wallis) for continuous variables were used to compare patient‘s characteristics between groups. The distribution of overall survival (OS) was estimated by the Kaplan-Meier method. Log-rank test was performed to test the difference in survival between groups.ResultsBased on the detailed pathological findings, patients with increased interstitial fibrosis were less likely to have renal response with treatment compared to patients with less fibrosis, (p < 0.05). Inflammation, tubulitis, number of eosinophils and neutrophils had no impact on renal response. Patients with response within 3 months of AKI treatment had a superior OS in comparison to patients who responded late (12-month OS rate: 77% vs 27%, p < 0.05). Notably, patients who received concurrent ICI and achieved renal response within 3 months had the best OS while those who did not receive concurrent ICI nor achieved renal response had worst OS (12-month OS rate: 100% (renal response and concurrent ICI) vs 72% ( renal response with no concurrent ICI), vs 27% ( no renal response and nonconcurrent ICI) (p < 0.05).ConclusionsThis is the first analysis of ICI induced nephritis where a detailed pathological and clinical evaluation was performed to predict renal response. Our findings highlight the importance of early diagnosis and treatment of ICI-AIN while continuing concurrent ICI therapy.Ethics ApprovalThis retrospective study was approved by the institutional review board at The University of Texas MD Anderson Cancer Center, and the procedures followed were in accordance with the principles of the Declaration of Helsinki.

280 Clinical outcomes of immunotherapy continued beyond radiographic progression in older adults with advanced non-small cell lung cancer

BackgroundWhile the clinical outcomes of immune checkpoint inhibitor (ICI) use in older adults with advanced-stage non-small cell lung cancer (NSCLC) have been described, the role of ICI use continued beyond disease progression (BDP) remains to be well defined for this population. This retrospective single-center study explored the clinical outcomes of continuing ICIs BDP among older adult patients with advanced NSCLC.MethodsUsing MD Anderson’s Gemini Lung Cancer database, we retrospectively reviewed the clinical outcomes of older adults (≥70 years) diagnosed with advanced-stage NSCLC treated with anti-PD-(L)1 monotherapy from March 2015 through April 2019 to correlate clinicopathologic features with clinical outcomes. Clinical therapy responses were evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Toxicities were assessed using Common Terminology Criteria for Adverse Events (CTCAE), version 5. Patients treated BDP were defined as individuals receiving ICIs for ≥8 weeks prior to documentation of progression who subsequently remained on ICIs for ≥6 weeks.ResultsOf the 159 older adults meeting the inclusion criteria, 33 (21%) received ICIs BDP (64% male, median age 74.9 years (70.1–82.0) at the start of ICI treatment, 3 received first-line ICI therapy). Most patients were former (85%) or current (6%) smokers. 79% had adenocarcinoma histology. The median duration of immunotherapy continued BDP was 7.1 months (95% CI: 3.0–8.2). After a follow-up of 30.1 months, the median overall survival (mOS) was 31.5 months (95% CI: 16.5-not reached). Eight (24%) received local consolidative radiotherapy with a median duration of ICI BDP of 8.2 months (95% CI: 1.9–13.3). Twenty-five (76%) did not receive local consolidative therapy and achieved a median duration of ICI BDP of 4.1 months (95% CI: 2.3–7.8). Six (18%) exhibited pseudo-progression (i.e. delayed response to immunotherapy with decreased tumor burden on subsequent radiologic studies), with 4 achieving ”stable disease” as best response and 2 achieving a partial response. The median duration of immunotherapy continued beyond pseudo-progression was 11.7 months (95% CI: 7.1–35.7), and the mOS was 26.2 months (95% CI: 16.5–40.0). Patients treated with ICI BDP most commonly experienced fatigue (18%), pneumonitis (12%), rash (9%), and hypothyroidism (9%). Three patients (9%) experienced grade 3 or higher toxicities (one grade 3 arthralgias and two grade 3 pneumonitis).ConclusionsICI-use BDP in older adults with advanced NSCLC may benefit a subset of patients. Additionally, local consolidative therapy with radiation may offer prolonged duration of ICI treatment.AcknowledgementsSupported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Moon Shot Program and the MD Anderson Cancer Center Support Grant P30 CA01667. Special acknowledgment to the GEMINI team.Ethics ApprovalThis study was approved and conducted in accordance with the institutional review board at the University of Texas MD Anderson Cancer Center; approval number (PA13-0589).

926 Immune profiling of KEAP1-deficient NSCLC: development of therapeutic strategies to overcome resistance to immunotherapy

BackgroundIn LUAD, KEAP1 is the third most common tumor suppressor and loss-of-function mutations in KEAP1 commonly co-occur with STK11/LKB1 and KRAS mutations. KEAP1 protein that regulates the degradation of the antioxidant transcription factor NRF2. The role of STK11/LKB1 mutations in immunotherapy resistance has been characterized, however the mechanistic understanding of KEAP1 deficiency in shaping LUAD phenotype and therapy response is still very limited. Recent clinical data has been reported suggesting that mutations in STK11/LKB1 and KEAP1 are strongly associated with immune checkpoint blockade resistance in LUAD, particularly those with KRAS mutations. Nevertheless, the biology of KEAP1-deficient tumors and the immune suppression mechanisms are to be characterized.MethodsWe have first validated response to anti-PD1 treatment in vivo using subcutaneous murine models, and performed a deep profiling and characterization of tumor microenvironment (TME) heterogeneity of KRAS-mutant (K) and LKB1 (KL), and/or KEAP1 deficient (KK and KLK) tumors using single-cell RNA sequencing (scRNA-seq) and multiplex staining. Data from pre-clinical models has been used to survey the immune genomic data available from the MD Anderson ICON study (a cohort of early stage lung cancer untreated 148 resected tumors) and TCGA lung cohorts to further validate our findings.ResultsWhile K tumors showed significant response to anti-PD1 treatment, KEAP1 loss completely impaired therapeutic response to this immunotherapy. KEAP1-deficient tumors were characterized by low immune infiltration while displayed an enrichment of cancer associated fibroblasts (CAFs) and endothelial cells. scRNA-seq data indicated a significant reduction of T cell infiltration, in particularly, CD8 and NK T cells, pronounced decreased of B cell population and a marked M2 macrophages polarization. Likewise, IHC and multiplex analysis of CD3 and F4/80 markers confirmed these previous findings. In TCGA lung cancer cohort, CD8B expression was dramatically decreased while MIF (macrophage migration inhibitory factor) was upregulated in KK compared to K LUADs tumors, and expression of KEAP1 inversely correlated with CD163, ARG2 and IL10, which are mainly secreted by macrophages. Concordantly, KEAP1-deficient pre-clinical tumors showed a significant upregulation of MIF expression and secretion, and CRISPR-Cas9 deletion of MIF dramatically impaired in vivo tumor growth in KK and KLK but not in K or KL models.ConclusionsThese findings indicate that loss of KEAP1, alone or in combination with STK11/LKB1 alterations, unfavorably reprograms TME. These changes appear to be mediated at least in part through MIF upregulation, providing a potential therapeutic strategy for overcoming KEAP1-dependent resistance to immunotherapy.

479 AGEN1181, an Fc-enhanced anti-CTLA-4 antibody, alone and in combination with balstilimab (anti-PD-1) in patients with advanced solid tumors: Initial phase I results

BackgroundAGEN1181 is a novel anti-CTLA-4 antibody with enhanced FcyR-dependent functionality, engineered to bind high and low binding alleles of FcyRIIIA, promoting superior T cell priming, memory responses, and depletion of intratumoral T regulatory cells. Further, AGEN1181 avoids complement recruitment, predictive of better tolerability. Here we report initial safety and efficacy findings from a phase I/Ib study of AGEN1181 as monotherapy and in combination with balstilimab (BAL; anti-PD-1).MethodsEligible patients (pts) had advanced solid tumors refractory to standard therapies. AGEN1181 was dosed Q3W (0.1–3 mg/kg) or Q6W (1–2 mg/kg) as monotherapy, or Q6W (0.1–2 mg/kg) in combination with BAL Q2W (3 mg/kg).ResultsAs of July 16th 2021, 102 pts received AGEN1181 (43 monotherapy, 59 combination). Median age, 63 years (29–83); 50.5% with ≥3 prior lines of therapy. MTD not yet reached with AGEN1181 dosing up to 3 mg/kg Q3W as monotherapy and 2 mg/kg in combination with BAL. The most common treatment-related adverse events (TRAEs) of any grade were fatigue (34.3%), diarrhea (32.4%), and nausea (19.6%) with grade ≥3 events in 21.6% (diarrhea/colitis, 11.8%, fatigue, 2.9%). Notably, no immune-related hypophysitis or pneumonitis has been observed. Discontinuation from AGEN1181 due to TRAEs occurred in 15% of pts. Grade 5 TRAEs occurred in two pts (colitis [chronic], intestinal perforation). The disease control rate in evaluable pts (completed ≥1 on-treatment scan) defined as best overall response of CR, PR, or SD ≥6 weeks was 48.1% for AGEN1181 monotherapy ≥1 mg/kg (1 CR, 3 PR, 9 SD) and 70% for combination (3 PR, 6 unconfirmed PR [uPR], 19 SD). Monotherapy responders include individual pts with MSS endometrial cancer (CR), PD-1-relapsed/refractory cervical cancer (PR), PD-1-relapsed/refractory melanoma (PR), and pancreatic cancer (PR). Enrollment is continuing in several disease expansion cohorts with combination therapy. For MSS CRC, 2 PR, 2 uPR, and 7 SD have been seen in 17 evaluable ≥1 mg/kg patients to date. In the ovarian cohort (n=6), 2 PRs and 3 SD are noted. Additional combination responders include one PR and uPR in MSS endometrial cancer, two uPRs in visceral angiosarcoma (uPRs) and one uPR in PD-1-relapsed/refractory NSCLC (uPR); the majority of the responses are recent and ongoing.ConclusionsAGEN1181 alone and in combination with BAL demonstrates favorable tolerability and compelling clinical activity, notably in poorly immunogenic tumor types and PD-1-refractory pts. These results underscore the significant potential of AGEN1181 to expand benefit of anti-CTLA-4 therapy to a broader patient population.Trial RegistrationNCT03860272Ethics ApprovalThe study obtained ethics approval at each participating center (UT Health Sciences Center at San Antonio, University of Colorado Cancer Center, St John’s Cancer Institute, and HonorHealth under WIRB Study number 1256391; USC Norris Comprehensive Cancer Center, Beth Israel Deaconess Medical Center, and MD Anderson Cancer Center, approval numbers HS19-00277, 19–132, and 140346, respectively). All patients provided written informed consent in accordance with federal, local, and institutional guidelines.

356. The Role of Procalcitonin in Antimicrobial Stewardship Among Cancer Patients Admitted with COVID-19

Background Procalcitonin (PCT) has been used to guide antimicrobial therapy in bacterial infections. With the wide spread use of empiric use of antibiotics in cancer patients admitted with COVID-19 disease, we aimed to evaluate the role of PCT in decreasing the duration of empiric antimicrobial therapy among cancer patients admitted with COVID-19. Methods We conducted a retrospective study of cancer patients admitted to MD Anderson Cancer Center who had a PCT test done within 72 hours of admission following their COVID-19 diagnosis between March 1, 2020 and June 6, 2021. Patients were divided into 2 groups of PCT &lt; 0.25 ng/mL and PCT &gt;=0.25 ng/mL. We assessed pertinent cultures including blood and respiratory, as well as antibacterial use and duration of empiric antibacterial therapy. Results We identified 544 patients with a median age of 62 years (range, 14-93). There were 312 (57%) patients that had at least one culture obtained from a sterile or infected site within 7 days following admission. None of the patients who had PCT&lt; 0.25 had a positive culture whereas 41/111 (37%) patients with PCT &gt;= 0.25 had at least one positive culture [P&lt; 0.0001]. Among the 373 patients who had a PCT &lt; 0.25, 129 (35%) patients received more than 72 hours of IV antibiotics compared to 87/171 (51%) among patients with PCT &gt;=0.25 [P= 0.0003]. Conclusion These results confirm the correlation between a PCT level greater than 0.25 and a documented bacterial infection. Furthermore, procalcitonin could be useful in enhancing antimicrobial stewardship in cancer patients with COVID-19 by reducing the duration of antimicrobial therapy beyond the initial empiric 72 hours until PCT results become available. Disclosures Natalie J Dailey Garnes, MD, MPH, AlloVir (Other Financial or Material Support, collaborator on research protocol)