Piotrowska, Zofia

8567 Background: Adjuvant osimertinib (osi) improves disease-free survival (DFS) in patients (pts) with resected, early-stage, EGFR-mutant (EGFRmut) NSCLC, yet the benefit of osi after CRT in pts with unresectable locally advanced NSCLC is unknown. Post-hoc analysis of the PACIFIC trial showed a lack of survival benefit with consolidation durva versus placebo in pts with EGFRmut NSCLC. Comparisons between consolidation durva and EGFR TKIs in unresectable EGFRmut NSCLC following CRT are lacking. Methods: We conducted a multi-institutional retrospective analysis of pts with stage III unresectable EGFRmut NSCLC (exon19 deletion, exon21 L858R), who received EGFR TKI or durva after ≥ 2 cycles of platinum-based chemotherapy plus definitive radiation therapy between 2015-2022. Baseline characteristics including age, sex, smoking history, PD-L1 status, and outcomes on DFS, overall survival (OS), and safety were collected. Multivariable (MVA) cox regression analysis was used for statistical analysis. Treatment-related adverse events (trAE) were defined using CTCAE 5.0. Results: Seventeen pts from 12 institutions received an EGFR TKI (osi, n=15; erlotinib, n=2), and 13 pts received consolidation durva. Median follow-up was 23 months. Median age of all pts was 61 years (IQR:52-72) and 76.7% were female. Most pts in both groups had never-smoked and had adenocarcinoma. All pts received ≥ 60 Gy of radiation with concurrent chemotherapy. PD-L1 expression was ≥ 50% in 1/10 (10%) pts treated with durva vs 6/13 (46.2%) treated with TKI, p=0.09. Median duration on treatment for EGFR TKI and durva was 12.2 months and 4.8 months, respectively. Pts treated with EGFR TKI had significantly longer 24-month DFS versus pts treated with durva after adjusting for stage (3A vs 3B vs 3C) (Table). Any grade tRAE occurred in 58.8% (10/17) of pts treated with EGFR TKI vs 38.5% (5/13) with durva. Grade > 3 tRAE occurred in 15.4% (1 pneumonitis and 1 AST/ALT elevation) of pts treated with durva but in none of pts treated with EGFR TKI. Three pts within each arm came off treatment due to toxicity (EGFR TKI: 1 pneumonitis and 2 dermatitis; durva: 1 of each pneumonitis, Type 1 diabetes, AST/ALT elevation). Conclusions: EGFR TKI therapy after definitive CRT was associated with significantly longer DFS compared to durva in this retrospective study of pts with stage III unresectable EGFRmut NSCLC, without unanticipated safety signals. Follow-up is ongoing and OS outcomes will be evaluated subsequently. Further investigation is warranted to define the optimal therapy for locally advanced EGFRmut NSCLC. [Table: see text]

Abstract Introduction: The development of immune checkpoint inhibitors (ICPis) has ushered in a new paradigm for the treatment of both solid and liquid malignancies. However, these therapies, which promote an activated T cell phenotype, can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (IRAEs), which can affect a variety of organ systems. Autoimmune hemolytic anemia (AIHA) has been described as a rare complication of ICPis, but existing data are mostly limited to isolated case reports. Further, guidelines for the diagnosis and treatment of these patients are lacking. We describe the clinical and laboratory features of 14 patients who developed ICPi-associated AIHA. Methods: We contacted hematology departments at 18 academic medical centers across the U.S. to inquire about potential cases of ICPi-associated AIHA. Nine centers contributed a total of 14 cases to the current series. We defined AIHA as an abrupt decrease in hemoglobin ≥2g/dL, the presence of at least two laboratory features of hemolysis (elevated serum lactate dehydrogenase [LDH], elevated reticulocyte percentage, low or absent serum haptoglobin, and spherocytes), and the exclusion of other causes of anemia. We collected data on demographics and comorbidities, features of AIHA, and response to treatment. We defined complete recovery (CR) and partial recovery (PR) of hemoglobin as an increase from the nadir hemoglobin to within 1 and 2 g/dL of the baseline value, respectively, in the absence of recent transfusion. Results: The clinical features of the 14 patients in our cohort with ICPi-associated AIHA are summarized in the Figure (panel A). Underlying malignancies included melanoma (n = 9), non-small cell lung cancer (n = 3), colorectal cancer (n = 1), and acute myelogenous leukemia (n = 1). Four patients had a pre-existing diagnosis of a lymphoproliferative disorder, and two of these patients were known to have a positive direct antiglobulin test (DAT) prior to initiation of ICPi. ICPis used included ipilimumab, nivolumab, a combination of ipilimumab and nivolumab, and pembrolizumab. Representative hemoglobin and LDH trends are shown in the Figure (panels B and C). The median (interquartile range [IQR]) interval from initiation of ICPis to AIHA was 55 (22-110) days. Eight patients (57%) were DAT positive: 3 were positive for both IgG and C3; 3 were positive for IgG alone; 2 were positive for C3 alone; and 1 was weakly positive on polyspecific testing. Five patients (36%) were DAT negative, and in one patient a DAT was not performed. The median (IQR) hemoglobin nadir was 6.3 (6.1-8.0) g/dL,and 11 patients (79%) required red blood cell transfusion. All patients were treated with glucocorticoids, with 3 requiring additional immunosuppressive therapy. All patients achieved a CR or PR of hemoglobin in response to treatment (CR, n = 11; PR, n =3). The median (IQR) time from the hemoglobin nadir to CR or PR was 47 (30-62) days. Seven patients (50%) experienced at least one other IRAE. Seven patients (50%) were re-challenged with ICPis, and one patient developed recurrent AIHA with re-challenge. Conclusion: ICPi-associated AIHA is a recently-described phenomenon, which will be encountered more frequently with the widespread use of ICPis. ICPi-associated AIHA shares many clinical features with other forms of AIHA; however, a unique aspect of ICPi-associated AIHA appears to be a relatively high incidence of DAT negativity (36% in our series, compared with 3-11% in other forms of AIHA). It is possible that more advanced DAT testing - i.e., "super-Coombs" - which was not performed in any of the patients in this series, would have yielded different results. Glucocorticoids appear to be an effective first-line regimen in most patients with ICPi-associated AIHA. Furthermore, we found that AIHA does not necessarily recur with ICPi re-challenge. Additional studies are needed to better understand the mechanisms underlying ICPi-associated AIHA and optimal treatment strategies. Disclosures Anagnostou: ASH Research Training Award for Fellows 2018: Research Funding; Mayo Clinic SPORE: Research Funding; Mayo Clinic Immune Monitoring Core: Research Funding; Mayo Clinic Hematology Research Division: Research Funding. Salama:BMS: Research Funding; Celldex: Research Funding; Dynavax: Research Funding; Genentech: Research Funding; Merck: Research Funding; Reata: Research Funding; Incyte: Research Funding; Immunocore: Research Funding; Array: Consultancy; Merck: Consultancy; Biocryst: Consultancy; BMS: Speakers Bureau.

AbstractImmune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi‐AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22‐110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2‐12.9 g/dL) and 6.3 g/dL (IQR, 6.1‐8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi‐AIHA were similar in DAT positive and negative patients. ICPi‐AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi‐AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first‐line treatment in the majority of patients with ICPi‐AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.