Time Of Immune Checkpoint Inhibitors Initiation Research Articles

Delayed immune-related adverse events in patients with advanced melanoma treated with immune checkpoint inhibitors.

12047 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of melanoma but can have serious or life-altering immune-related adverse events (irAEs). Most toxicities associated with ICIs occur within the first few months (mo) of treatment initiation, but delayed irAEs occurring 12 mo after ICI start are not well characterized. Further, clinical trials often have limited follow-up of AEs and thus, real world data is valuable. Methods: Patients (pts) ≥18 years with advanced melanoma who received ≥1 cycle of an ICI at BC Cancer from 2012-2019 with ≥12 mo of follow-up from time of ICI initiation were identified using the BC Cancer Registry and Pharmacy databases. Data on baseline clinicopathologic factors prior to the first cycle of ICI, and delayed irAE history and management were extracted. Delayed irAEs were graded using CTCAEv5. Results: In total, 530 pts treated with ≥1 cycle of an ICI were identified of which 309 pts had ≥12 mo of follow-up. Median follow-up for alive pts was 65.3 mo (13.0-143.5 mo). 96 (31%), 147 (48%), 19 (6%), and 47 (15%) pts received combination ICI (nivolumab/ipilimumab ± nivolumab maintenance), PD-1 inhibitor monotherapy (nivolumab or pembrolizumab), CTLA-4 inhibitor monotherapy (ipilimumab), and sequential CTLA-4 and PD-1 inhibitors, respectively. A total of 142 delayed irAEs were recorded in 94 (30%) pts. Median time to onset of delayed irAEs was 20.0 mo (12.2-80.6 mo). The most common delayed irAEs were dermatologic (27%), gastrointestinal (23%), and rheumatologic (20%). Most delayed irAEs were grade ≤2 (84%), but some were grade ≥3 (16%). Of individual delayed irAEs, 75 (51%) occurred on ICI treatment at time of onset, 39 (26%) after ≤3 mo of the last ICI cycle, and 34 (23%) after >3 mo of the last ICI cycle. 79 (56%) and 20 (14%) delayed irAEs were treated with systemic steroids and immunomodulators, respectively. Further, 12 (8%) delayed irAEs led to hospitalization, and 64 (45%) required subspecialty consultation. Pts with a history of autoimmune disease were more likely to have a delayed irAE (p=0.02), as were pts who achieved a partial or complete response (p=0.02). There was a trend towards a greater frequency of delayed irAEs in pts treated with PD-1 (37%) compared with combination (28%), CTLA-4 (11%), or sequential CTLA-4 and PD-1 (28%) (p=0.068). Conclusions: Delayed irAEs occurred in almost a third of pts with advanced melanoma treated with ICIs and followed for at least 1 year. Extended follow-up to monitor for delayed irAEs should be considered as many events required immunosuppressive therapy and rarely, may be life threatening. [Table: see text]

Off-label prescribing of immune checkpoint inhibitor therapy at a single pediatric cancer center.

Immune checkpoint inhibitors (ICI) have improved outcomes in a variety of adult cancers and are prescribed with increasing frequency across oncology. However, patterns of off-label use of ICI in pediatrics remain unclear. This is a single-institution, retrospective cohort study evaluating off-label ICI use in pediatric and young adult patients with cancer treated at our institution from 2014 to 2022. Response was based on clinician assessment derived from clinical records. Immune-related adverse events (iRAEs) were classified according to CTCAE v5.0. We identified 50 unique patients treated with off-label ICI (28 with solid tumors, 20 with central nervous system (CNS) tumors, 2 with hematologic malignancies). At time of ICI initiation, only five patients (10%) had localized disease, and all but one patient was treated in the relapsed/refractory setting. All patients were treated with the FDA-approved weight-based dosing recommendations. Overall, there was disease control in 21 patients (42%), with best response including one complete response (melanoma), two partial responses (high-grade glioma, CNS nongerminomatous germ cell tumor), and 18 patients with stable disease. Forty-four patients (88%) eventually experienced disease progression. Among 22 patients (44%) experiencing iRAEs, 10 (20%) had a grade ≥3 irAE, 12 (24%) required corticosteroids, and 14 (28%) required ICI discontinuation. irAE occurrence was associated with significantly improved progression-free survival (HR 0.35; 95% CI: 0.18 to 0.68; p = 0.002) and overall survival (HR 0.33; 95% CI: 0.17 to 0.66; p = 0.002). At our institution, ICI was most commonly prescribed in the relapsed/refractory setting to patients with metastatic disease. The treatment was generally well-tolerated in the pediatric population. The overall response rate was low, and the majority of patients eventually experienced disease progression. A few patients, however, had durable treatment responses. Further studies are needed to identify which pediatric patients are most likely to benefit from ICI.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis

BackgroundRecent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and...

Clinical and Genomic Characterization of Long-Term Responders Receiving Immune Checkpoint Blockade for Metastatic Non–Small-Cell Lung Cancer

ObjectivesUnderstand from a real-world cohort the unique clinical and genomic determinants of a durable response to immune checkpoint inhibitors (ICIs). Materials and MethodsThis is a retrospective study of patients with NSCLC who received any ICI-based regimen as first or second line therapy. Long-term responders (LTR) achieved an overall survival (OS) ≥ 3 years from time of treatment start, while nonresponders (NR) were patients who had an OS of 6 to 12 months from time of treatment start. Clinical and demographic covariables were collected from electronic medical records. Fisher's exact test and Mann-Whitney test were used to analyze the association of a long-term response to ICI in relation to clinical and genomic variables. All P-values were considered significant at P-value < .05. ResultsA total of 72 patients were included in this study (LTR n = 37, NR n = 35). There were no significant differences in age, sex, race, and BMI between groups. The presence of liver metastases at the time of ICI initiation and PD-L1 status were not associated with LTR to ICIs. Patients in the LTR were more likely to experience irAEs at 3-,6- and 12-months. KRAS mutant tumors were numerically more common in the LTR group (n = 13 vs. 8). ConclusionWe observe no strong clinical and biomarkers of a prolonged response to ICIs. Additional large prospective cohort studies are needed to investigate the genomic footprint of long-term responders.

Real-world data on immune-checkpoint inhibitors use and immune-related adverse events in lung cancer.

156 Background: Immune-checkpoint inhibitors (ICIs) have revolutionized lung cancer therapy. The data on the use of ICIs in underrepresented populations with lung cancer (older patients, patients with autoimmune disease (ADs), and patients with poor performance status) are limited from trials. The real-world pattern of immune-related adverse effects (irAEs) and the association between the occurrence of irAEs and prognosis remain unclear. Methods: Patients with lung cancer newly started on ICIs from 10/01/2018 to 09/30/2021 were identified in the Tufts Medical Center cancer registry. Patient information, disease characteristics, treatment history, and outcomes were collected from the electronic health record. Time to ICI treatment initiation (TTI) was analyzed via log-rank tests. Multivariable Cox regression was used to assess the impact of the occurrence of irAEs on overall survival (OS). Results: 125 lung cancer patients were identified with a median age of 70 (range 50-80) years old at time of ICIs initiation. 68 (54.4%) were males and 103 (82.4%) were White. Most of the patients were past or current smokers (95.2%). 16 (12.8%) had a history of ADs and 44 (35.2%) had an ECOG status &gt;1. Most of the cohort had non-small cell lung cancer (80.8%) and advanced-stage diseases (stage III 20.8%, stage IV 77.6%). 37.6% had PD-L1 expression and 25.6% had detected molecular alterations. ICIs were mostly used in frontline settings (65.6%) and for palliative intent (86.4%). Pembrolizumab was used most frequently (64%), followed by durvalumab, atezolizumab, nivolumab, and ipilimumab plus nivolumab. About half (49.6%) of ICIs were delivered concurrently with chemotherapy. A total of 50 irAEs occurred in 39 (31.2%) individuals. The most common irAEs were pneumonitis, thyroid disorders, dermatitis, and gastrointestinal toxicity. TTIs were similar comparing those ≥65 vs &lt;65 years old (median TTI: 1.4m vs 1.17m, p=0.82), those with vs without ADs (median TTI: 1.53m vs 1.27m, p=0.53), and those with ECOG &gt;1 vs ≤1 (median TTI: 1.6m vs 1.17m, p=0.06) in newly diagnosed stage IV lung cancer patients (N=62). After adjusting for age, BMI, stage, histology, performance status, and comorbidities, no differences were found in OS between those with irAEs and those without (HR=0.84, p=0.65). Conclusions: Our findings suggested that in the real world, older patients, patients with ADs, and patients with poor performance had no significant delays in ICIs initiation. The pattern of irAEs was similar to that reported in clinical trials without erosion of OS among those with irAEs.

Toxicity, disease management and outcome of treatment with immune checkpoint inhibitors by sex in patients with cancer and preexisting autoimmune disease.

Female sex is associated with a higher risk for autoimmune diseases (ADs) and immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs). While the safety of ICIs in AD cohorts has been reported, sex-segregated data on patient characteristics and outcomes are lacking. In the present study, the disease and treatment characteristics of 51 patients with cancer and preexisting AD (PAD) treated with ICIs at Bern University Hospital Cancer Center (Bern, Switzerland) between January 2017 and June 2021 were analyzed by sex. Rheumatic (n=12/27, 44.4%) and endocrine (n=11/24, 45.8%) PADs were most common among male and female patients, respectively. At the time of ICI initiation, 29.6% (n=8/27) of male and 20.8% (n=5/24) of female patients received immunosuppression for their PAD. Female patients were more likely to experience an irAE (58.3 vs. 48.1%), and less likely to encounter an exacerbation of their PAD (38.5 vs. 14.3%) compared with male patients. Multiple-site irAEs (46.2 vs. 21.4%), implication of an organ specialist for irAEs (100.0 vs. 57.1%) and use of additional immunosuppressive drugs (38.4 vs. 7.7%) were more common in male patients. IrAEs were resolved and ICIs were discontinued in 69.2% (n=9/13) and 71.4% (n=10/14) of the total male and female patients, respectively. Median progression-free survival was higher in male than female patients with irAEs (19.9 vs. 10.7 months) and without irAEs (4.4 vs. 1.8 months). The median overall survival time was higher in male than female patients with irAEs (not estimable vs. 22.5 months) and without irAEs (10.1 vs. 7.4 months). Taken together, these results suggested that sex-related differences existed regarding the clinical presentation of irAEs and treatment outcome.

#3958 PROTON PUMP INHIBITORS AND THE RISK OF ACUTE KIDNEY INJURY IN PATIENTS RECEIVING IMMUNE CHECKPOINT INHIBITORS: A POPULATION-BASED COHORT STUDY

Abstract Background and Aims Proton pump inhibitors (PPI) are commonly used in cancer patients. Multiple studies have found that PPI use is associated with a more than 2-fold increased risk of acute kidney injury (AKI) in patients treated with immune checkpoint inhibitors (ICI). However, this association could possibly be explained by confounding by indication for PPI use. Method In a population-based cohort study, we compared the risk of AKI in users and non-users of PPI among cancer patients treated with ICI in Denmark during 2011-2021. We assessed exposure to PPI by filled prescriptions for PPI within 90 days before ICI initiation and identified AKI events within the first year after ICI initiation using plasma creatinine measurements from laboratory databases. We included information on potential confounders including important comorbidities and comedication. We estimated the propensity score for PPI use using logistic regression and calculated unweighted and standardized mortality ratio (SMR)-weighted absolute risks and hazard ratios (HRs) of AKI. To address any switch in PPI exposure during follow-up, we did an additional per-protocol analysis censoring patients upon switch in PPI exposure. We furthermore applied inverse probability of censoring (IPC) weights to mitigate informative censoring. Results We included 9,955 cancer patients treated with ICI. Among these, 2,668 (26.8%) were users of PPI. During the first year of follow-up, AKI occurred in 1,932 of the included patients, yielding an overall unweighted incidence rate of 30.1 per 100 person-years and a 1-year AKI risk of 21.3%. PPI users had an increased risk of AKI compared with non-users (1-year risk, 24.4% versus 20.2%; HR, 1.37 [95% CI, 1.24-1.51]); however, this association attenuated when accounting for confounders by SMR weighting (SMR-weighted 1-year risk, 24.0% versus 23.3%; SMR-weighted HR, 1.05 [95% CI, 0.93-1.18]). In the per-protocol analysis, the unweighted HR was 1.82 (95% CI, 1.60-2.07), while the SMR- and IPC-weighted HR was 1.22 (95% CI, 1.03-1.45). Conclusion PPI use at the time of ICI initiation was not associated with an increased risk of AKI after SMR weighting. When considering switching of PPI exposure during follow-up, we observed that PPI use was associated with an increased risk of AKI; however, the association was much weaker than previously reported.

Safety and efficacy of immune checkpoint inhibitors (ICIs) in patients (pts) with cardiac metastases (mets) from solid tumors.

2653 Background: Given underlying differences in the tumor microenvironment across metastatic sites, ICIs demonstrate variable efficacy depending on sites of met involvement. Data on the safety and outcomes of pts on ICIs with cardiac mets are limited. Methods: In an international multi-center retrospective study, pts with solid tumors and baseline mets to the heart who had received ≥1 cycle of ICIs were included. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Objective response rates (ORR) were evaluated by RECIST1.1 when available. Median overall survival (mOS) and median progression-free survival (mPFS) were calculated from time of ICI initiation using the Kaplan-Meier method. Results: 110 pts across 20 institutions were identified with a median follow-up of 36 (95% CI 26-51) months. Melanoma (38%, n=42) and non-small cell lung cancer (NSCLC, 24%, n=26) were the most common cancers. Median age at ICI initiation was 65 (IQR: 59-75) years and 29% (n=26) received combination ICI therapy with anti-PD1 and anti-CTLA4. Overall, 62% (n=68) received ICIs as 1st line. The mets were mostly located in the atria (37%, n=41) and ventricles (35%, n=39). At ICI initiation, 21% (n=23) had a cardiac thrombus. Of 78 pts with available echocardiographic data at time of ICI initiation, the mean ejection fraction was 61+/- 7.1%. Cardiology referrals and cardiac MRIs since time of cancer diagnosis were completed on 53% (n=58) and 47% (n=52) of pts, respectively. Overall, 36.4% (n=40) of pts had cardiac complications from the mets, including arrhythmias (13%, n=14), arterial/venous emboli (3.6%, n=4), and cardiac tamponade (2.7%, n=3). For NSCLC, ORR, mPFS (95% CI), and mOS (95% CI) were 23%, 4.4 months (3.0-7.5), and 9.9 months (5.9-14.7), respectively. For melanoma, ORR, mPFS, and mOS were 35.7%, 9.1 months (5.2-20), and 29 months (14-58), respectively. Cardiac met ORRs for NSCLC and melanoma were 27% and 43%, respectively. 74% (N=71/96) of pts with evaluable response data had concordant response in the burden of overall disease and cardiac disease. IrAEs are shown. Conclusions: Although cardiac mets are frequently associated with cardiac complications, ICIs demonstrate meaningful efficacy with no overtly concerning safety signals. Close to three-quarter of pts have concordant response in the overall disease and cardiac disease burden. Multi-disciplinary approach involving cardiologists and oncologists need to be implemented to appropriately manage pts with cardiac mets. [Table: see text]

The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: A real-world, multicenter, retrospective study.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n=370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3months; 95% CI, 6-20.1 months) (p<.001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p<.001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1plusanti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p=.01). These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.

S1014 Immune Checkpoint Inhibitors for Colorectal Cancer in Patients With Inflammatory Bowel Disease

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the management of many types of malignancies, including microsatellite instability high (MSI-H) colorectal cancers (CRC), but pose a unique challenge to patients with underlying inflammatory disorders such as inflammatory bowel disease (IBD). The safety and efficacy of ICI therapy for CRC in patients with underlying IBD has not been described. Methods: We queried the electronic health database for patients with IBD and CRC who were treated with ICI at tertiary care cancer center in New York City. We collected demographic data, IBD and cancer history, and outcomes of both IBD and CRC after treatment with ICIs. Results: Four patients with underlying IBD were treated with ICIs for MSI-H colorectal cancer (Table). All patients had long-standing IBD for greater than 20 years. Two of the patients were diagnosed with concomitant Lynch syndrome at the time of MSI-H cancer diagnosis. No patients were on active IBD therapies at the time of ICI initiation. All four patients were treated with anti-PD-1 therapy (Pembrolizumab) for stage 3 (n=2) or stage 4 (n=2) CRC. All four patients had robust cancer responses to ICI, three with partial responses and one with a complete response over a median follow-up time of 34 months. One patient with locally advanced rectal cancer had a complete response and has avoided the need for surgical resection and permanent stoma.Three patients had a flare of IBD while on ICI requiring initiation of 5-ASA (n=2) or immunosuppressive therapy (n=1) (Table). One patient required hospitalization for IBD flare. ICI therapy was held due to IBD flare for two patients who had already achieved significant response to ICI with stable disease. Conclusion: In this small series of patients with IBD and MSI-H colorectal cancer, treatment with ICIs was effective at achieving cancer response in all patients while IBD flares were common but manageable with standard medical therapy. Larger studies are needed to explore the safety and efficacy of ICIs for CRC in patients with IBD. Table 1. - Baseline Characteristics and Outcomes of CRC and IBD after ICI Therapy Patient Age of ICI Initiation & IBD type IBD Duration (years) & Prior IBD Medications Lynch Syndrome Cancer Stage ICI Type & Doses of ICI Treatment for IBD Flare Best overall Cancer Response to ICI Surgery for CRC 1 51, Crohn's 38; SSZ, CS, IFX No IV PD- 1, 33 Prednisone, Adalimumab, Ustekinumab Partial Response Subtotal colectomy (before ICI) 2 50, Crohn's 23; 6-MP No IV PD- 1, 10 N/A Partial Response Total proctocolectomy with end ileostomy (before ICI) 3 35, UC 22; 5-ASA Yes III PD- 1, 33 5-ASA Complete Response None 4 34, UC 22; 5-ASA, CS,AZA Yes III PD- 1, 4 5-ASA Partial Response Total proctocolectomy with ileoanal anastomosis (after ICI) ADA: adalimumab, AZA: azathioprine; CRC- Colorectal Cancer; CS: corticosteroids; CTCAE: Common Terminology Criteria for Adverse Events, IBD: inflammatory bowel disease, ICI: immune checkpoint inhibitor; IFX: infliximab; PD-1: Programmed Death 1; SSZ: sulfasalazine; 5-ASA: 5-aminosalicylate; 6- MP : 6-mercaptopurine; UC: ulcerative colitis

S963 Characteristics, Treatment and Outcome of Patients With Previously Diagnosed Autoimmune Disease After Immune Checkpoint Inhibitor Exposure

Introduction: Immune checkpoint inhibitors (ICI) can predispose to immune related adverse events (irAEs) and autoimmune disease (AD) flare-ups. irAE characteristics among patients with previously diagnosed AD have not been well studied. We aim to describe the clinical course, complications, treatment, and outcomes of patients with AD on ICIs. Methods: This is a retrospective chart review of adult cancer patients at the MD Anderson Cancer Center diagnosed with AD (based on ICD code) prior to the first dose of ICI treatment between 01/01/2010 and 04/30/2021. Patients’ clinical course, treatment and outcomes related to both AD and irAE were collected and analyzed. Results: A total of 197 patients were included in this study. A majority of our sample were female (55.4%) most frequently having melanoma (28.4%) and receiving PD-1/L1 inhibitors (83.7%). Forty-two patients (21.3%) developed a new irAE after starting immunotherapy, while 29 had an AD flare (14.7%). Patients with inflammatory bowel disease (IBD) had the highest rate of AD flare (31.7%), while patients with hypothyroidism had the highest incidence of new irAEs at 39.2%. Patients with IBD had more severe adverse events however with a median CTCAE grade of 3.5. In our cohort, all patients that were diagnosed with a new irAE were treated with immunosuppressive therapy. AD flares were managed similarly. With regards to irAE manifestations, colitis was the most common presentation in our cohort; at least 24 patients (23.2%) excluding those patients with a diagnosis of (IBD and microscopic colitis) had this type of complication. This was followed by pneumonitis in 9 patients (4.5%) and transaminitis in 7 patients (3.5%). Conclusion: Studies on the correlation between prior AD and immunotherapy are still lacking. Our findings suggest that patients with GI and rheumatologic ADs had higher incidence of AD flare up than new irAE development, while patients with thyroid and neurologic ADs appeared to have higher incidence of new irAEs compared to AD flare. Patients with prior AD experiencing a flare or a new irAE after immunotherapy tend to require more aggressive immunosuppressive treatment for symptom control. Thorough evaluation of baseline disease status, the appropriate medical management prior to ICI, and early recognition of inflammatory exacerbation could be key factors to ensure long-term success with treating and improving outcomes of these patients. Table 1. - Summary of irAE characteristics per Autoimmune Disease system, N=197 Autoimmune Disease per system Active AD status before ICI, N (%) On medical Rx before ICI, N (%) Flare up after ICI, N (%) Type of ICI Peak CTCAE grade of flare up (median, IQR) Required IMS for flare up, N (% of those that had flare) New irAE in different organ from AD, N (%) Peak CTCAE of irAE (median, IQR) IMS required for irAE, N (% of those that had irAE) Hematological ITP (N=2) 0 (0) 0 (0) 0 (0) PD1/L1=2 (100) N/A N/A 0 (0) N/A N/A Endocrine Hypothyroidism (N=51) 0 (0) 51 (100) 2 (3.9) Combined= 9 (17.6); PD1/L1=42 (82.3) Grade 2 in 1 (50) 0 (0) 20 (39.2) 2(1-3) 20 (100) Neurological MS-TM-GBS (N=27) 27 (100) 3 (11.1) 2 (7.4) Combined= 1 (3.8); PD1/L1= 21 (77.7); CTLA-4=5 (18.5) N/A 2 (100) 5 (18.5) 1(1-1.5) 5 (100) Rheumatological Rheumatoid A (N=58) 0 (0) 58 (100) 15 (25.8) Combined= 1 (1.7); PD1/L1= 57 (98.2); N/A 15 (100) 12 (20.6) 2.5(2-3) 9 (75) Gastroenterological (N=30) 0 (0) 30 (100) 10 (33.3) Combined=3 (10); PD1/L1=27 (90) N/A 10 (100) 5 (16.6) N/A 5 (100) Microscopic Colitis (N=10) 0 (0) 3(30) 8 (80) PD1/L1=10 (100) N/A 8 (100) 1 (10) N/A 1 (100) Celiac Disease (N=1) 0 (0) 0 (0) 0 (0) PD1/L1=1 (100) N/A N/A 0 (0) N/A N/A IBD (N=19) 1 (5.2) 10 (52.6) 6 (31.7) Combined=3 (15.7); PD1/L1=16 (84.2) N/A 6 (100) 4 (21) 3.5(3-4) 4 (100) Footnote: IMS=immunosuppressant. ITP=Immune Thrombocytopenic Purpura. MS=Multiple Sclerosis. TM= Transverse Myelitis. GBS=Guillain Barre Syndrome. IBD=Inflammatory Bowel Disease.*all the patients had baseline low activity at the time of ICI initiation. Flare up occurred when the symptoms progressed from baseline activity.

The Inpatient Immunotherapy Outcomes study: A multicenter retrospective study of patients treated with immune checkpoint inhibitors in the inpatient setting.

300 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the care of patients (pts) with cancer. However, median time to response is 2-6 months and many pts derive no benefit from ICIs. Pts are often admitted to the hospital with complications of advanced disease or its treatment, and many have prognoses limited to months. Several recent studies have demonstrated a limited benefit of anticancer therapy at end of life. ICIs are also associated with significant financial toxicity for both pts and the health care system. The role of ICI therapy in the inpatient (IP) setting is unclear. To begin to address this gap in knowledge, we conducted the Inpatient Immunotherapy Outcomes Study (IIOS) to describe characteristics and outcomes of pts who received IP ICIs. Methods: IIOS is a multicenter, retrospective study of pts treated with PD-(L)1 and CTLA-4 inhibitors during IP hospitalization between 2012-2021 at 4 large academic institutions: Mount Sinai Hospital, Yale-New Haven Hospital, University of Pennsylvania, and Georgetown University Hospital. Manual data collection was performed using each institution’s EMR and was approved by each institution’s IRB. Descriptive statistics were used to characterize the population and demonstrate pt outcomes. Results: A total of 159 pts received IPI ICI. Median age was 61 years. 54.7% of pts were white and 17.6% were Black; 12.6% were Hispanic. Thoracic/head and neck malignancies were most common (26.4%), followed by gastrointestinal (19.5%) and hematologic malignancies (17.6%). Most pts (73%) initiated ICIs in the IP setting while 27% continued an outpatient ICI regimen. 129 pts (81.1%) had stage IV solid malignancies at the time of ICI initiation in any setting; median prior lines of systemic therapy was 1 (range, 0-11). The most commonly administered IP ICI was pembrolizumab (49.1%) followed by nivolumab (34.0%), with ICIs administered with non-curative intent in 91.8% of pts. In 44.7% of pts, the ICI given did not have an FDA approval for that cancer type and stage at the time of administration. PD-L1 expression was available on tumors from 60 pts, 32 (53.3%) of whom had expression of 50% or higher. 112 pts (70.4%) had no documented clinical or imaging-based response to ICI therapy. Discharge disposition included home (47.2%), IP death (27%), rehabilitation centers (15.1%), and hospice (10.1%). Median days between first IP ICI dose and death was 47 (95% CI, 33-68). Conclusions: This is the largest multi-institutional effort to understand pt outcomes following IP ICI administration. Preliminary data, as outlined above, is concerning for poor clinical outcomes which should give clinicians pause when considering IP ICI use. Further analysis is ongoing to determine predictors of overall survival and discharge to home.

Eosinophil as a biomarker for diagnosis, prediction, and prognosis evaluation of severe checkpoint inhibitor pneumonitis.

IntroductionCheckpoint inhibitor pneumonitis (CIP) is a common serious adverse event caused by immune checkpoint inhibitors (ICIs), and severe CIP can be life-threatening. We aimed to investigate the role of peripheral blood cells in diagnosis, prediction, and prognosis evaluation for all and severe CIP.Materials and methodsPatients with lung cancer receiving ICIs were enrolled in this retrospective study. Baseline was defined as the time of ICI initiation, endpoint was defined as the time of clinical diagnosis of CIP or the last ICI treatment, and follow-up point was defined as 1 week after CIP. Eosinophil percentages at baseline, endpoint, and follow-up point were shortened to “E bas”, “E end and “E fol”, respectively.ResultsAmong 430 patients included, the incidence of CIP was 15.6%, and severe CIP was 3.7%. The E end/E bas value was lower in patients with CIP (p = 0.001), especially severe CIP (p = 0.036). Receiver operating characteristic curves revealed that E end/E bas could serve as a biomarker to diagnose CIP (p = 0.004) and severe CIP (p < 0.001). For severe CIP, the eosinophil percentage declined before the symptoms appeared and CT diagnosis. The eosinophil percentage significantly elevated at the follow-up point in the recovery group but not in the non-recovery group. The CIP patients with E fol/E bas ≥1.0 had significantly prolonged overall survival (p = 0.024) and after-CIP survival (AS) (p = 0.043). The same results were found in severe CIP but without a statistical difference.ConclusionsEosinophil percentage was associated with the diagnosis, prediction, and prognosis of CIP and severe CIP.

Impact of performance status on survival outcomes and health care utilization in patients with advanced non–small cell lung cancer treated with immune checkpoint inhibitors.

9053 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm of non-small cell lung cancer (NSCLC). Despite the high prevalence of patients with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS ≥2) in real-world practice, landmark studies have typically excluded this patient group from enrolment. The primary objective of this study was to evaluate the impact of ECOG PS on clinical outcomes and health care utilization in a large cohort of NSCLC patients treated with ICI in real-world practice. Methods: Using the Alberta Immunotherapy Database, we identified consecutive patients who received at least one dose of Pembrolizumab or Nivolumab for the treatment of advanced NSCLC between 1/1/2010 and 12/30/2019. The data cut-off date was 10/1/2020. Baseline clinical, pathological, and laboratory-based data were collected retrospectively. The primary outcome was median overall survival (mOS), as stratified by ECOG PS. The secondary outcomes were median time-to-treatment failure (mTTF) and metrics of health care utilization, including emergency department (ED) visits, hospitalizations, and death in hospital. Kaplan-Meier survival curves were used to determine survival outcomes, and compared with the log-rank test. The association between ECOG PS and healthcare utilization were represented with risk ratios and evaluated using chi-square tests. Results: A total of 790 patients were included. Median follow-up time was 20.6 months. 29.2% (n = 231) had PS ≥2 at the time of ICI initiation. As compared with the favorable PS group (PS &lt; 2), patients with PS ≥2 had significantly lower mOS - 3.3 months (95% CI 2.5-4.0) versus 13.4 months (95% CI 11.7-16.0) (HR, 3.0; 95% CI 2.5-3.6, p &lt; 0.0001), and mTTF – 1.4 months (95% CI 0.9-1.8) versus 4.9 months (95% CI 4.4-5.6) (HR, 2.2; 95% CI 1.9-2.6, p &lt; 0.0001). 3- and 12-month survival rates were also significantly lower in the PS ≥2 group as compared with the PS &lt; 2 group (52.8% versus 86.4% and 13.4% versus 41.0%, p &lt; 0.0001 for both comparisons). Patients with PS ≥2 were also significantly more likely to present to the ED (RR 1.6; 95% CI, 1.3-2.0, p &lt; 0.001) and be admitted to hospital (RR 2.3; 95% CI 1.7-3.0, p &lt; 0.0001) within the first month after treatment initiation. These patients were also significantly more likely to die in hospital during their first admission (RR 2.7; 95% CI 1.8-4.1, p &lt; 0.0001), as well as at any point during treatment (RR 2.2; 95% CI 1.60-3.0, p &lt; 0.0001). Conclusions: NSCLC patients with poor ECOG PS at the time of ICI initiation had significantly worse survival outcomes and were significantly more likely to utilize health care services than those with favorable ECOG PS. The large proportion of patients with poor ECOG PS further justifies the urgent need for randomized trials evaluating the efficacy of ICI in this high-risk population.

The impact of pembrolizumab on patients with pre-existing autoimmune diseases.

2660 Background: Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape across a range of solid and hematologic malignancies. With the mechanistic activation of the adaptive immune response and known unique development of immune-related adverse effects (irAE), there is a theoretical risk of causing detrimental effects on patients with pre-existing autoimmune diseases (AID). However, this patient population was excluded from many clinical trials, and there is limited and conflicting retrospective data speculating upon the impacts of using ICI therapy in patients with AID. This study aims to report the impact of pembrolizumab in patients with AID. Methods: Patients who received pembrolizumab for treatment of any type of cancer between 1/1/2017-8/1/2021 were retrospectively reviewed, and patients with AID (rheumatologic or non-rheumatologic) were identified. Data including age, gender, race, ECOG, and primary cancer diagnosis were collected. AID was characterized by type, activity (symptomatic vs. asymptomatic at ICI initiation), and immunosuppressive treatment (IST) use. Outcomes included flare of AID, irAE, and ICI discontinuation. Results: Out of 810 patients, 12 with pre-existing AID were found and being treated for non-small cell lung cancer (NSCLC) (58% N=7), renal cell carcinoma (RCC) (16.6% N=2), colorectal cancer (CRC) (8% N=1), head and neck cancer (8% N=1), and cervical cancer (8% N=1). Around 67% of these patients were females with a median age of 65 years (50-77). Median ECOG was 1 (0-2). 9 patients (75%) had rheumatologic disease (5 rheumatoid arthritis (RA), 1 systemic lupus erythematosus (SLE), 2 psoriatic arthritis, and 1 systemic sclerosis (SS)). 3 patients (25%) had non-rheumatologic AID (1 multiple sclerosis (MS), 1 autoimmune hepatitis, and 1 Evan’s syndrome). All patients were asymptomatic prior to initiation of therapy. At the time of ICI initiation, 11 patients (92%) were on therapy, including steroids, methotrexate, and other IST. Due to concern for severe flare, pembrolizumab was discontinued in 3 (25%) MS, RA, and SS patients treated for RCC, CRC, and NSCLC, respectively. 3 patients (25%) developed irAE unrelated to their AID (pneumonitis, dermatitis, arthritis, gastritis) and received steroids. 4 patients (33.3%) had documented flares while on pembrolizumab requiring escalation of their ongoing therapy, and 1 NSCLC patient had a severe exacerbation of SS requiring cyclophosphamide and rituximab infusions. Conclusions: This analysis adds to the limited available literature that patients with an AID and on IST appear to have minimal AID-associated flares requiring intervention and tolerate pembrolizumab with a similar rate of irAE compared to patients without AID. Additional larger studies are needed to assess the efficacy of treatment in this population.

Melanoma Metastases to the Adrenal Gland Are Highly Resistant to Immune Checkpoint Inhibitors.

Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands. We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti-PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis. Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells. In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland-directed therapies or surgical resection.

Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events

PurposeAs gut microbiota composition is an important determinant of response to immune checkpoint inhibitors (ICIs), we examined the effect of various co-medications known for their interaction with microbiota, when given at ICI initiation. Patients and methodsWe identified patients with advanced cancer treated with ICI between May 2015 and September 2017 in our institution. Co-medications given within 1 month before or 1 month after the first administration of ICI were reviewed from medical records. Survival data were analysed with univariable Cox regression, and the combined effect of multiple factors was assessed with factor analysis of mixed data (FAMD). The impact of co-medications on immune-related adverse events (irAEs) occurrence was also assessed. ResultsA total of 635 patients were included. Psychotropic drugs (41%), proton pump inhibitors (PPIs; 38%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs; 32%), glucocorticoids (26%), antibiotics (24%), statins (21%) and morphine (20%) were the most prescribed co-medications. Baseline use of antibiotics, glucocorticoids >10 mg/day, PPIs, psychotropic drugs, morphine and insulin was associated with significantly shortened overall survival and decreased tumour response, whereas coadministration of statins, ACEs and/or ARBs, non-steroidal anti-inflammatory drugs, aspirin and oral antidiabetic drugs did not impact patient outcomes. Treatments that altered the response to ICI were also associated with a decreased incidence of irAEs. FAMD revealed the respective weight of each factor or co-medication on the oncological outcomes. ConclusionCo-medications must be carefully assessed at the time of ICI initiation and clinicians aware of their possible deleterious effect, notably for PPIs, glucocorticoids, antibiotics and psychotropic drugs.

Bone modifying agents and skeletal related events in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

e18593 Background: Bone metastases and skeletal related events (SREs) are a common cause of morbidity among patients with metastatic non-small cell lung cancer (mNSCLC). SREs include pathologic bone fractures, spinal cord compression, orthopedic surgery/stabilization, and palliative radiation to bone. Bone modifying agents (BMA) such as bisphosphonates and RANK ligand inhibitors are often used for mNSCLC patients with bone metastases to reduce the incidence of SRE. Data on the associations between BMA use and overall survival (OS) and the development of SRE among patients with mNSCLC treated with immune checkpoint inhibitors (ICI) is limited. Methods: We conducted a retrospective study of patients with mNSCLC treated with first line pembrolizumab or pembrolizumab plus chemotherapy at The Ohio State University from 2017-2020. The associations between SRE and categorical variables were studied using Fisher’s exact test and with continuous variables using the Kruskal-Wallis test. The association between BMA and risk of osseous progression was studied using Fisher’s exact test. The association between BMA and OS was examined using a Cox proportional hazard model. Median OS was estimated using the Kaplan-Meier method with 95% CI. OS was calculated from date of ICI initiation to death from any cause or last follow up. Results: We identified a cohort of 228 patients: 107 (47%) treated with pembrolizumab and 121 (53%) treated with pembrolizumab plus chemotherapy; 48 (21%) had squamous histology and 179 (79%) had nonsquamous histology (1 had NSCLC histology not specified); median age 62.6 years; median OS was 26.8 months (95% CI: 17.2 – 34.5 months). A total of 95/228 (42%) patients had bone metastases at time of ICI initiation; 45/95 (42%) had treatment with BMA and 50/95 (58%) were not treated with BMA. Among patients with bone metastases at time of ICI, 45 (42%) developed SRE after ICI initiation and BMA use was not associated with risk of SRE (p = 1). BMA use was not significantly associated with risk of osseous progression (p = 0.21). For patients with baseline bone metastases prior to ICI, the use of BMA was not associated with OS (p = 0.24); the type of BMA used (bisphosphonate vs RANK ligand inhibitor) was also not associated with OS (p = 0.13). Conclusions: In patients with metastatic NSCLC treated with first line pembrolizumab alone or with chemotherapy, bone modifying agents were not associated with OS, decreased risk of osseous progression, or development of SRE in patients with baseline bone metastases prior to ICI initiation. The type of BMA used was also not associated with survival. Further studies evaluating the utility and impact of BMA use in this patient population are needed.

Baseline Modified Glasgow Prognostic Score Associated with Survival in Metastatic Urothelial Carcinoma Treated with Immune Checkpoint Inhibitors.

The modified Glasgow prognostic score (mGPS), a clinical tool that incorporates albumin and C-reactive protein, has proven useful in the prognostication of multiple cancers. Several immune checkpoint inhibitors (ICIs) have been approved for the treatment of metastatic urothelial cell carcinoma (mUC), but a prognostic biomarker is needed. We investigated the impact of mGPS on survival outcomes in patients with mUC receiving ICIs. We retrospectively reviewed patients with mUC treated with ICIs (programmed cell death protein 1 or programmed cell death ligand 1 inhibitors) at Winship Cancer Institute from 2015 to 2018. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical or radiographic progression, respectively. mGPS was defined as a summary score with one point given for C-reactive protein >10 mg/L and/or albumin <3.5 g/dL. Univariate (UVA) and multivariate (MVA) analyses were carried out using Cox proportional hazard model. These outcomes were also assessed by Kaplan-Meier analysis. A total of 53 patients were included with a median follow-up 27.1 months. The median age was 70 years, with 84.9% male and 20.8% Black. Baseline mGPS was 0 in 43.4%, 1 in 28.3% and 2 in 28.3%. Increased mGPS at the time of ICI initiation was associated with poorer OS and PFS in UVA, MVA, and Kaplan-Meier analyses. The mGPS may be a useful prognostic tool in patients with mUC when treatment with ICI is under consideration. These results warrant a larger study for validation. The ideal prognostic tool for use in a busy clinical practice is easy-to-use, cost-effective, and capable of accurately predicting clinical outcomes. There is currently no universally accepted risk score in metastatic urothelial cell carcinoma (mUC), particularly in the immunotherapy era. The modified Glasgow prognostic score (mGPS) incorporates albumin and C-reactive protein and may reflect underlying chronic inflammation, a known risk factor for resistance to immune checkpoint inhibitors (ICIs). This study found that baseline mGPS is associated with survival outcomes in patients with mUC treated with ICIs and may help clinicians to prognosticate for their patients beginning immunotherapy.

P09.13 Bone Metastases and Overall Survival in Patients with Metastatic Non-Small Cell Lung Cancer Treated with Pembrolizumab

Bone metastases (BM) and skeletal-related events (SRE) are a common cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data on the impact of BM on overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI) is limited. Here we report the incidence, impact on survival, and risk factors for SRE in patients with mNSCLC treated with first-line pembrolizumab monotherapy or pembrolizumab plus chemotherapy. We conducted a retrospective study of patients with mNSCLC treated with first-line pembrolizumab or pembrolizumab plus chemotherapy at our institution from 2017-2020. The associations between SRE and categorical variables were studied using Fisher’s exact test and with continuous variables using the Kruskal-Wallis test. Kaplan-Meier plots were used to visualize survival curves. The association between baseline BM and OS was examined using a Cox proportional hazard model. OS was calculated from date of ICI initiation to death from any cause or last follow-up. We identified a cohort of 202 patients: 93 (46%) treated with pembrolizumab and 109 (54%) treated with pembrolizumab plus chemotherapy; 39 (19%) had squamous histology and 163 (81%) had nonsquamous histology; median age 62.7; median OS 33.7 months (95% CI: 17.2 – NR). In our cohort, 87 (43%) patients had BM at time of ICI initiation and 47 (23%) developed SRE after ICI initiation. Patients who developed SRE were more likely to have baseline BM than those without SRE (91.5% vs 28.4%, p<0.001). Development of BM during treatment with ICI and performance status were also significantly associated with SRE (p<0.001 and p=0.006, respectively). Patients with BM at time of ICI, or development of new or progression of existing BM while on ICI, had shorter survival than those without (Figure 1a and Figure 1b, respectively). In multivariate survival analysis, the hazard of death for patients with baseline BM was 2.85 times those without (HR=2.85, 95% CI: 1.53, 5.29, p-value=0.0009) after controlling for age, BMI, performance status, histology, PD-L1 expression, smoking, and SRE. The use of bone-modifying agents (BMA) was not associated with OS, osseous progression, or risk of SRE. The presence of BM at time of ICI was associated with shorter survival after controlling for multiple clinical characteristics. These patients represent a high-risk cohort for worse outcomes when treated with ICI alone or in combination with chemotherapy. In our cohort BMA were not associated with increased OS or decreased risk of osseous progression or SRE.