Immune Checkpoint Inhibitors Exposure Research Articles

Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns

With the widespread use of immune checkpoint inhibitors (ICIs), concerns about their pregnancy outcomes through maternal exposure have emerged, and clinical comparative data are lacking. To assess the risk of pregnancy-, fetal-, and/or newborn-related adverse outcomes associated with exposure to ICIs compared with exposure to other anticancer agents. In this cohort study, all reports mentioning a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) used for a cancer indication registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. Anticancer agents, including ICIs, used during pregnancy for a cancer indication. Immune checkpoint inhibitors included blockers of programmed cell death 1 (PD1) or its ligand (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4). The main outcome was the reporting odds ratio (ROR) for maternal, fetal, or newborn complications in patients treated with ICIs vs any other anticancer drug. Adverse events, categorized into 45 individual maternofetal adverse outcomes, were directly mapped to Medical Dictionary for Regulatory Activities preferred terms in VigiBase. A total of 3558 reports (ICI: 91 [2.6%]; other anticancer drugs: 3467 [97.4%]) were included in the analysis. In the ICI group, most reports were from the US (60 [65.9%]), and the mean (SD) patient age was 28.9 (10.2) years; in 24 of 55 reports with data on cancer type (43.6%), patients were treated for melanoma. The molecules involved in the ICI group were anti-PD1 (58 reports [63.7%]), anti-PD1 plus anti-CTLA4 (15 [16.5%]), anti-CTLA4 (13 [14.3%]), anti-PD-L1 (4 [4.4%]), and anti-PD1 plus anti-lymphocyte activation gene 3 (1 [1.1%]). An ICI was used in combination with a non-ICI anticancer agent in 10 participants (11.0%). Compared with other anticancer drugs, none of the 45 adverse outcomes identified were overreported in the group exposed to ICIs. However, preterm birth was significantly overreported for the anti-PD1 plus anti-CTLA4 combination compared with other anticancer drugs (12 of 15 [80.0%] vs 793 of 3452 [23.0%]; ROR, 13.87; 95% CI, 3.90-49.28; P < .001) but not for anti-PD-L1 or anti-CTLA4 monotherapy. Three reports of possibly immune-related maternofetal events were identified: 1 case of maternal antiphospholipid syndrome leading to spontaneous abortion, 1 case of pneumonitis leading to neonatal respiratory distress syndrome and death, and 1 case of transient congenital hypothyroidism. In this cohort study of 91 individuals exposed to ICIs during pregnancy, ICI exposure was not associated with overreporting of specific adverse pregnancy, fetal, and/or newborn outcomes compared with other anticancer treatments. However, due to possible rare immune-related neonatal adverse events, ICI use in pregnant women should be avoided when possible, especially the anti-PD1 plus anti-CTLA4 combination.

Engraftment Syndrome Incidence after Immune Checkpoint Inhibitor Therapy in Pts with Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation: A Single Institutional Review

Introduction: After receiving frontline chemotherapy for classical Hodgkin lymphoma, up to 30% of patients (pts) relapse. Salvage chemotherapy and autologous stem cell transplantation (ASCT) are the standard of care. Immune Checkpoint inhibitors (ICIs) have become essential to salvage therapy with improved complete response (CR) rates. However, ICIs have been linked to an increased risk of engraftment syndrome (ES), reported in as many as 68-78% of cases (Moskowitz et al. 2021; Park et al. 2021), while others have reported lower rates 3-12% (Bryan et al. 2023; Mei et al. 2022). The variability is connected to the definition of ES. The more stringent Spitzers criteria require 3 major (non-infectious fever (NIF), skin rash, pulmonary edema, or hypoxia) or 2 major and 1 minor criteria within 96 hours of engraftment, while the more lenient Maiolino criteria require a NIF with skin rash, pulmonary infiltrates, or diarrhea. Early diagnosis of ES and early intervention with corticosteroids is important to minimize toxicity during the ASCT. Here, we evaluate ES incidence at our institution during ASCT with or without the inclusion of ICI during salvage therapy. Method: The institutional database was queried for pts with relapsed/refractory cHL who underwent ASCT between 2018 and 2023. ES is broadly defined as the presence of non-infectious fever with skin rash, diarrhea, or pulmonary infiltrates (Maiolino Criteria) or clinical suspicion requiring corticosteroids. Results: A total of 47 pts underwent ASCT during this period and were included in the final analysis. Twenty-nine pts received ICI during salvage therapy (72%). Regarding basic patient characteristics: the median age at ASCT was 31 [19-72], 27 pts were female (57.5%), 35 pts were white (74.5%), the most common subtype was nodular sclerosis (n=42; 89.4%), with 23 pts (50%) initially presenting with advanced-stage disease. The most common initial therapy was ABVD (n=42, 89.4%), with one patient being treated with an ICI-based therapy on clinical trial (SWOG 1826). Thirty pts (63.8%) had a CR after frontline treatment and 16 pts with primary refractory disease. For the CR pts, the median time to progression was 159 [13-3864] days. Thirty-five pts achieved a CR after salvage therapy (74.5%), 25 receiving ICI (71.4%), most commonly pembrolizumab. Regarding conditioning regimens, the most used and our institutional standard is total lymphoma irradiation (TLI) followed by high-dose chemotherapy (CCV) (n=34; 72.3%), which we have reported having high and durable response rates (10-yr PFS 68.5% and OS 68.0%). (Paudel et al. 2019) The median time to neutrophil engraftment is 10 days [7-30]. The rate of post-ASCT relapse was higher in the chemotherapy-only conditioning group (31%) compared to TLI-CCV (3.3%). All pts who received TLI-CCV are still alive, with two deaths in the chemotherapy only conditioning group (Total OS 95.7%). Out of 47 evaluable pts, no pts qualified with a diagnosis of ES using the stringent Spitzers criteria. However, 17 received corticosteroids using the broader diagnosis criteria for ES (36%). Looking specifically at pts who received ICI (n=29), 14 pts had ES (48.3%), while of the 18 pts who did not receive ICI, 3 had ES (16.7%). Of the pts who did develop ES (n=17), 16 pts received TLI-CCV (94%), the median time to onset was 9 [2-11] days, the median time to resolution was 6 [2-19] days, the median time to neutrophil engraftment was 10 [8-12] days. When evaluating pts who received TLI-CCV conditioning, 24 pts received ICI during treatment before ASCT, with 13 pts having ES (54.2%). By comparison, 3 (33%) of the 9 ICI-naïve pts who received TLI-CCV were diagnosed with ES. The incidence of ES with or without ICI exposure was not statistically significant (p = 0.2549). Overall, the median time to ES onset is 9 days, and the duration of 6 days. There was no recorded mortality from ES. Only 3 pts relapsed post-ASCT (8.8%), with two receiving ICIs. Even with the small number of pts in this retrospective study, there was an increase in ES incidence between the use of ICI during salvage therapy (p=0.0279). Conclusions: In this single-institution retrospective analysis, we found that the addition of ICI during salvage therapy increased the incidence of a broadly defined ES, with an increase in corticosteroid use. ES must be recognized early and treated with corticosteroids aggressively.

Arterial inflammation induced by immune checkpoint inhibitors assessed on 18F-FDG PET-CT scans in stage III/IV melanoma patients

Abstract Background In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, as they lead to a substantial improvement in the prognosis of cancer patients. In high-grade melanoma patients, ICIs have doubled the three-year survival rate. However, ICIs may not only increase the immune response to tumor cells, but also to non-tumor cells, potentially inducing pro-atherogenic effects that can result in increased vascular inflammation and subsequent cardiovascular events. Purpose The objective of this study is to assess differences in vascular inflammation in the large arteries, as detected by 18F-FDG PET-CT scans, between stage III/IV melanoma patients receiving ICI therapy compared to stage III/IV melanoma patients not treated with ICIs. Methods The study population consisted of a cohort stage III/IV melanoma patients who underwent PET-CT scans at baseline, defined as &amp;lt; 1 year after diagnosis of stage III/IV melanoma and at T1 and T2, 6 months and 18 months after the baseline scan respectively. Patients with a history of cardiovascular events, treated with statins or corticosteroids (prednisolone &amp;gt; 10 mg per day) were excluded. Vascular inflammation was evaluated in the following eight arterial segments: the left and right carotid artery, ascending aorta, aortic arch, thoracic descending aorta, abdominal aorta and the left and right iliac artery. For each segment, the maximum standardized uptake value (SUV) for 18F-FDG uptake was derived and target-to-background ratio (TBR) was calculated from the ratio of the maximum SUV of the segment and the mean SUV of the superior and inferior vena cava. Vascular inflammation was defined as the total TBR per patient, calculated by sum of the TBR values of the eight arterial segments. The study endpoint was the difference in the increase in total TBR between patients treated with ICIs (exposure group) and patients without ICI treatment (control group). Results A total of 70 stage III/IV melanoma patients of whom 46 received ICIs and 24 did not receive ICI therapy were analyzed in this study. The median age at diagnosis was 61 years [IQR: 49-69] and 37 patients (52.9%) were female. The exposure group had a median ICI treatment of 9 [6-13] cycles. The results showed a significant difference in the TBR between the baseline PET-CT scan and T1 between the two groups. The control group showed a decrease in TBR by -0.33 [95% CI: -0.66 – 0.01], whereas the exposure group showed an increase in TBR by 0.17 [-0.14 – 0.49] (p = 0.045). No differences in TBR were found between T1 and T2. Conclusion The present study demonstrated that in stage III/IV melanoma patients treated with ICIs, there was a significant increase in vascular inflammation assessed by PET-CT in the large arteries during the first six months after treatment initiation, as compared to a control group without ICI treatment.∆TBR on PET-CT between baseline and T1∆TBR on PET-CT between T1 and T2

Salvage lenvatinib/everolimus combination therapy after immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor for metastatic renal cell carcinoma.

The optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking. We retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan-Meier method. The median age was 64 (range 31-84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5-7.6) and the median OS was 9 months (95% CI, 7.6-12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18-7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08-3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. LE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies.

Predictors for the development of neurological immune-related adverse events of immune checkpoint inhibitors and impact on mortality.

Little is known about risk factors for developing neurological immunological adverse events (neuro-irAEs) from immune checkpoint inhibitors (ICIs). We report the incidence, predictors for development, impact on mortality of neuro-irAEs, and impact of ICIs on pre-existing neurological conditions in a large clinical cohort. Patients who received ICIs between January 2011 and December 2018 were identified from a tertiary cancer center registry. Descriptive statistics were used to summarize patient, cancer, and treatment data. Odds ratios from univariable and multivariable logistic regression models were calculated to identify potential predictors for developing a neuro-irAE. Impact of neuro-irAEs on overall survival was estimated by Kaplan-Meier and Cox proportional hazard models. Overall frequency of neurological irAEs was 2.3%. Peripheral nervous system complications were most frequent (53.6%). Melanoma, younger age, prior chemotherapy, prior resection, CTLA-4 ICIs exposure, and combination PD-1 and CTLA-4 ICIs exposure had significantly higher odds for developing a neuro-irAE (p < 0.05) in univariate but not multivariate models. Those with a neuro-irAE were less likely to die at 3 years compared to those without a neuro-irAE (69% vs. 55%, p = 0.004) in univariate but not multivariate model. Flare of pre-existing neurological condition after exposure to ICIs was present (15.4%, 2 of 13 patients) but manageable. One patient was rechallenged with ICIs without recurrent flare. Neuro-irAEs are not associated with increase in overall mortality. Potential predictors for the development of neuro-irAEs are younger age, melanoma, prior chemotherapy and resection, CTLA-4, or combination ICIs exposure.

Exocrine Pancreatic Insufficiency Induced by Immune Checkpoint Inhibitors.

Scant data describe exocrine pancreatic insufficiency (EPI) secondary to immune checkpoint inhibitor (ICI) use. The goal of this study is to describe the incidence, risk factors, and clinical characteristics of patients with ICI-related EPI. A single center, retrospective case-control study was performed of all ICI-treated patients at Memorial Sloan Kettering Cancer Center between January 2011 and July 2020. ICI-related EPI patients had steatorrhea with or without abdominal discomfort or weight loss, started pancrelipase after initiation of ICI, and demonstrated symptomatic improvement with pancrelipase. Controls were matched 2:1 by age, race, sex, cancer type, and year of ICI start. Of 12 905 ICI-treated patients, 23 patients developed ICI-related EPI and were matched to 46 controls. The incidence rate of EPI was 1.18 cases per 1000 person-years and the median onset of EPI was 390 days after the first dose of ICI. All 23 (100%) EPI cases had steatorrhea that improved with pancrelipase, 12 (52.2%) had weight loss, and 9 (39.1%) had abdominal discomfort; none had changes of chronic pancreatitis on imaging. Nine (39%) EPI patients had episodes of clinical acute pancreatitis preceding the onset of EPI, compared to 1 (2%) control (OR 18.0 (2.5-789.0), P < .001). Finally, the EPI group exhibited higher proportions of new or worsening hyperglycemia after ICI exposure compared with the control group (9 (39.1%) vs. 3 (6.5%), P < .01). ICI-related EPI is a rare but clinically significant event that should be considered in patients with late onset diarrhea after ICI treatment and often is associated with development of hyperglycemia and diabetes.

Clinical and genomic predictors of response and toxicity to sotorasib in a real-world cohort of patients with advanced KRAS G12C-mutant non-small cell lung cancer.

9083 Background: With the accelerated approval of the KRAS G12C inhibitor sotorasib for patients with advanced KRAS G12C-mutant non-small cell lung cancer (NSCLC), there is a new need to explore efficacy and identify clinical and genomic factors associated with activity and toxicity among patients treated in routine clinical practice. Methods: Patients(pts) treated with sotorasib outside of the clinical trial setting at three institutions (MSK, Columbia, NYU) were examined to identify factors associated with real-world PFS (rwPFS), overall survival (OS), real-world (rw) response, and clinically significant toxicity (CTCAE v5.0 grade 3 or higher treatment-related adverse events [G3+ TRAE]). TP53, STK11, and KEAP1 status were assessed by targeted NGS. Response and rwPFS were determined by investigator assessment of radiology reports. rwPFS and OS were estimated by Kaplan-Meier methods; log-rank tests were used for univariate group comparisons and Mantel-Haenszel method was used to determine hazard ratios (HRs). Fisher’s exact test was used to determine associations between categorical variables. Results: 105 pts with advanced KRAS G12C-mutant NSCLC treated with sotorasib were identified. The response rate for patients treated was 28%, with median rwPFS of 5.3 months, and median OS of 12.6 months. KEAP1 co-mutations were associated with shorter rwPFS and OS (rwPFS HR 3.19, P = 0.004; OS HR 4.10, P = 0.003); no significant differences in rwPFS or OS were observed among pts with or without TP53 co-mutations (rwPFS HR 1.10, P = 0.731; OS HR 1.19, P = 0.631) or STK11 co-mutations (rwPFS HR 1.66, P = 0.098; OS HR 1.73, P = 0.168). Dual STK11/ KEAP1 co-mutation status was associated with shorter OS compared to STK11 wild-type (WT)/ KEAP1 mutant (MUT) status (OS HR 4.04, P = 0.033) and STK11 MUT/ KEAP1 WT status (OS HR 5.41, P = 0.012). 16/105 (15%) pts experienced G3+ TRAEs. 15/16 (94%) patients with G3+ TRAE had previously been treated with immune checkpoint inhibitor (ICI). Among pts with prior ICI exposure (n = 86), last exposure within 12 weeks of sotorasib initiation was associated with G3+ sotorasib TRAEs ( P &lt; 0.001) and TRAE-related sotorasib discontinuation ( P = 0.014); there was no association between prior irAE during ICI therapy and G3+ sotorasib TRAEs ( P = 0.757). In total, 15/53 (28%) pts with last ICI exposure within 12 weeks of sotorasib initiation experienced G3+ TRAEs, most commonly hepatotoxicity. No cases of G3+ TRAEs were observed in 33 pts with last ICI exposure &gt; 12 weeks prior to sotorasib treatment. Conclusions: Among patients treated with sotorasib in routine clinical practice, KEAP1 co-mutations were associated with poor outcomes. Severe toxicity was almost exclusively associated with recent ICI exposure. These observations may help further guide sequencing of sotorasib and may help inform the next generation of KRAS G12C clinical trials.

Clostridium difficile infection and immune mediated diarrhea and colitis in patients with cancer on immune checkpoint inhibitors.

e14683 Background: Immune checkpoint inhibitors (ICIs) have altered the landscape of cancer treatment. ICIs are associated with immune mediated diarrhea and colitis (IMDC) which can be challenging to diagnose and differentiate from other etiologies of diarrhea. Clostridium difficile infection (CDI) is a common cause of diarrhea in patients with cancer and can have similar symptoms. In a similar study, CDI was found to be relatively common in ICI-treated cancer patients and especially those with IMDC requiring immunosuppressants. Our study evaluates the incidence of CDI and IMDC in patients with ICI exposure and compares clinical characteristics between the two to determine risk factors that may predispose patients to CDI or IMDC. Methods: This is a retrospective, single-center study of cancer patients on an ICI from 1/1/2011 to 4/7/2022 who were tested for Clostridium difficile with stool nucleic acid amplification tests during or after treatment with an ICI. Patients were determined to have CDI if clinically suspected and had to have a positive stool GDH Ag along with positive C. difficile toxins A &amp; B or a positive stool C. difficile toxin B gene. Patients with positive GDH Ag in the stool but with negative toxins A&amp;B were determined to be colonized. The diagnosis of IMDC was based on the clinical presentation and had to be made by the treating oncologist. Results: 375 patients met our study criteria and got CDI testing at any point during or after ICI exposure. 27 patients tested positive for CDI, whereas 24 were colonized. 105 patients were determined to have IMDC and 97/105 received treatment with steroids or immunosuppressants. Among patients determined to have IMDC, 6 were colonized for clostridium difficile. There were no patients with IMDC who were also positive for clostridium difficile. 71 patients were on a dual ICI regimen whereas 304 patients were on a single ICI. In patients on the dual ICI regimen, 67.6% were diagnosed with IMDC when compared to patients on a single ICI regimen where 18.8% of patients were diagnosed with IMDC (p&lt;0.0001). The absolute lymphocyte count on the day of CDI testing was 1.185 ± 0.066 in the IMDC group when compared to 0.948 ± 0.044 in the non-IMDC group (p=0.003). The mean duration of diarrhea was longer in the IMDC group at 16.905 ± 1.211 days when compared to the CDI group at 9.852 ± 2.387 days (p= 0.0094). Smoking status, sex, history of autoimmunity, and history of prior immune related adverse events did not impact incidence of IMDC or CDI. Conclusions: IMDC was a common cause of diarrhea in patients with ICI exposure who were tested for CDI. We did not find IMDC to be a risk factor for CDI. IMDC has a longer duration of diarrhea and colitis symptoms when compared to CDI. The absolute lymphocyte count on symptom onset is higher in patients with IMDC when compared to patients with CDI and may be useful in identifying patients with IMDC earlier.

Are severe immune-related adverse events more likely in patients with pre-existing autoimmune disease?

e14599 Background: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system to treat malignancy. As a consequence of this activation, ICIs may cause autoimmunity in healthy tissues, termed “immune-related Adverse Events” (irAEs). The literature reports a wide range in irAE incidence (10-80%), with a higher incidence in patients exposed to combination therapy. ICI treatment of patients with pre-existing autoimmune disease presents a dilemma for oncologists because of concern that immune activation will lead to more frequent or severe irAEs. As a result, these patients have been excluded from ICI clinical trials. Prior studies suggested that approximately 40% of patients with pre-existing autoimmune disease experience an autoimmune exacerbation during ICI treatment, but more data are needed on the incidence and severity of irAEs in other tissues. Methods: This retrospective case-control study included adult patients who received an FDA-approved ICI for treatment of a solid malignancy (excluding non-melanoma skin cancer) from 2015-2021 at an academic medical center. Cases were patients with pre-existing autoimmune disease. Controls without pre-existing autoimmunity were matched 2:1 based on age, sex, ICI class, and cancer type. Severe IrAEs were defined as grade three or higher by CTCAE definitions and occurring after ICI exposure. ICD-9 and 10 codes were used to identify patients with subsequent data extraction by manual chart review. Results: Of 3,130 adult cancer patients treated with ICIs, 28 cases were identified with pre-existing autoimmune disease: antiphospholipid syndrome (n=1), inflammatory polyarthritis (n=3), juvenile arthritis (n=1), multiple sclerosis (n=3), psoriatic arthritis (n=3), rheumatoid arthritis (n=14), and type I diabetes (n=3). Six out of 28 cases (21.4%) developed severe irAEs, including three (50%) who received anti-PD1/PDL1 monotherapy and three (50%) who received ICI combination therapy. One case experienced a grade five irAE (death) attributed to ICI-colitis; the remaining five patients (83.3%) successfully recovered with suspension of ICI therapy and treatment with immunosuppressive medications. By comparison, 9/56 (16.1%) controls developed severe irAEs. The odds of developing a severe irAE were not significantly different in patients with pre-existing autoimmunity compared to controls (OR 1.42, 95% CI 0.42-4.68, p=ns). Subgroup analysis of 23 cases and 46 controls treated with anti-PD1/PDL1 monotherapy also found no difference in the odds of severe irAE development (OR 0.84, 0.22-3.70, p=ns). Conclusions: Our data suggest that the majority of solid tumor patients with pre-existing autoimmune disease can safely receive ICI monotherapy and combination therapy. Severe (grade 3 or higher) irAEs were infrequent, often treatable, and did not occur more frequently than in patients without pre-existing autoimmunity.

Salvage lenvatinib/everolimus (LE) combination therapy after immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) for metastatic renal cell carcinoma (mRCC).

e16520 Background: The optimal treatment for mRCC patients (pts) who have progressed after both ICI and TKI remains uncertain. LE is frequently used as a salvage treatment due to different antitumor mechanisms, but efficacy and toxicity data in this setting are limited. Methods: We retrospectively reviewed charts from two academic centers for 71 adult mRCC pts who received LE after prior ICI and TKI exposure. Collected data included patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details using CTCAEv5. Outcomes were objective response rate (ORR) per RECIST 1.1, median time to treatment failure (mTTF), and toxicity. Descriptive statistics, Cox proportional hazards model and Kaplan-Meier method were utilized. Results: The median age was 64 (range: 31–84). Most pts had clear cell histology (84.5%) and had undergone nephrectomy (75%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). Pts received a median of 3 (range 1-10) prior therapy lines (L) and 42 pts had sequential ICI and TKI, while 29 received ICI/TKI combination therapy. Average ORR was 26.8%, but numerically better when given earlier (2L/3L vs. ≥4L: 28.6% vs. 22%). The mTTF was 5.5 months (m) (95% confidence interval [CI], 3.5–7.6 m), which was not significantly changed by sequential or combinational ICI/TKI treatment exposure. In multivariable Cox analyses, int/poor IMDC risk was associated with a significantly worse TTF compared to favorable risk (HR, 2.2, 95% CI, 1.1-4.1; mTTF: 4.5 vs 12.9 m), and so was ≥4L treatment compared to 2L/3L treatment (HR, 3.2, 95% CI, 1.3-7.6; mTTF: 4.5 vs. 6.6 m). In 57 pts with int/poor IMDC risk, ≥4L treatment was associated with a significantly worse TTF (HR, 2.3, 95% CI, 1.2-4.5; mTTF: 3.6 vs. 6.6 m), while prior nephrectomy was associated with a significantly better TTF (HR, 0.46, 95% CI, 0.22-0.97; mTTF: 5.4 vs. 3.1 m) compared to those without nephrectomy. Of the 71 pts, 64% had ≥ grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. Conclusions: LE therapy is feasible but has modest efficacy following ICI/TKI treatment. Pts with favorable risk, prior nephrectomy or early salvage may have a better treatment response. These observations need to be confirmed in prospective studies.

Association between symptoms and health-related quality of life in patients with cancer with prior or ongoing immune checkpoint inhibitor therapy exposure.

e24085 Background: There is a growing appreciation that patients exposed to immune checkpoint inhibitors (ICI) may experience long-term symptoms that impact health-related quality of life (HRQoL). We conducted an app-based, electronic patient reported outcomes (ePRO) study to explore the relationship between the symptom experience and HRQoL in a population of patients with cancer exposed to ICI therapy. Methods: Eligible patients had a history of advanced skin cancer or kidney cancer treated with ICI (adjuvant or metastatic) with ongoing, clinician-assessed disease control. Patients may have completed a course of ICI or continued on therapy if ≥ 6 months had passed since initiation. We conducted a single-center, observational, prospective cohort study where participants completed ePRO assessments via smartphone (ImmunoWave) measuring eleven symptoms (PRO-CTCAE) and HRQoL (PROMIS-29) weekly for 12 weeks. We used generalized estimating equations to assess the changes in PROMIS scores over study and to test the association of PRO-CTCAE symptoms with PROMIS scores and subdomains. Results: Forty-seven patients (77% melanoma, 15% renal cell carcinoma, 8% non-melanoma skin cancer) consented to the study. 70% were on active therapy while 30% had completed therapy. Most (62%) were treated in the metastatic setting. 43 patients who completed questionnaires were included in the analysis. Among subdomains of HRQoL at the study population level, social function was observed to have a significant linear trend (p = 0.013) and potentially meaningful (3.9 points overall) increase over the 12 weeks. Other subdomains were felt to have no clinically meaningful change at the population level over the 12 wk study period. Several PRO-CTCAE symptoms were significantly associated with health-related quality of life (PROMIS) subdomains (Table). Joint pain was significantly associated with fatigue (B = 1.006, p = 0.045), pain interference (B = 2.579, p = 0.002) and physical function (B = -1.532, p = 0.042). Itch was associated with anxiety (B = 1.017, p = 0.007) and social function (B = -1.136, p = 0.030). Numbness and tingling was associated with fatigue (B = 0.891, p = 0.027) and sleep disturbance (B = 1.436, p &lt; 0.001). Conclusions: We observed high concordance between patient symptom report by PRO-CTCAE and corresponding PROMIS HRQoL subdomains. Addressing specific symptoms such as itch, numbness/tingling and joint pain in patients with current or prior ICI exposure could improve HRQoL. [Table: see text]

Incidence of venous thromboembolism with immune checkpoint inhibitors in a community setting: A single-center retrospective study.

e14681 Background: Immune activation and inflammation caused by immune checkpoint inhibitors (ICIs) are critical pathobiological drivers for venous thromboembolism (VTE). There is a paucity of data about VTE risk in cancer patients receiving ICI. We aimed to describe the incidence of VTE in cancer patients receiving ICI in a community setting. Methods: We conducted a single center, retrospective cohort study at Saint Vincent Hospital. The study cohort was created using our center's pharmacy database of patients who received any of the five ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, or durvalumab) between Jan 2017 and Dec 2022. VTE events including deep venous thrombosis, splanchnic vein thrombosis, and pulmonary embolism, were identified by chart review. We used a self-controlled risk-interval design, with "control period" and "at-risk period" being 6 months before and after the initiation of ICI treatment respectively. VTE events were also analyzed for subgroups: Single-agent ICI therapy (IA), Dual ICI therapy (IB), and ICI + chemotherapy (IC). Descriptive statistics and cox regression were used for statistical analysis. Results: Study population included 170 patients, with 75, 14, and 81 patients in subgroups IA, IB, and IC respectively. The mean age of the patients was 69.51 ± 10.05 years with a majority being males (62.4%). The most common cancer observed was non-small cell lung cancer (43.5%) followed by small cell lung cancer (6.9%), and malignant melanoma (5.7%). Pembrolizumab (55.3%) was the most common ICI used and nivolumab + ipilimumab (7.64%) was the most common dual ICI used. We noted a 1.25-fold higher incidence of VTE post-ICI use (Incidence rate ratio [IRR]: 11.76 per 100 person-year) compared to pre-ICI use (IRR: 9.41 per 100 person-year) at 6 months. On subgroup analysis, Group IB had the highest risk for VTE at 6 months (IRR: 28.57 per 100 person-year), followed by group IC and IA (IRR: 14.12 and 8.0 per 100 person-year respectively). IRR decreased to 6.62 per 100 person-year at 12-month interval indicating increased VTE risk in the first 6 months of ICI exposure. Type of ICI, adjuvant chemotherapy or type of cancer was not able to predict VTE risk on multivariate analysis. Conclusions: ICI treatment was associated with an increased incidence of VTE in our study cohort with the highest risk among patients on dual ICI followed by ICI + chemotherapy and ICI monotherapy. Future prospective studies are needed to identify risk factors and biomarkers to improve risk stratification and risk-adapted thromboprophylaxis.[Table: see text]

Incidence, mortality, and risk factors of acute kidney injury after immune checkpoint inhibitors: Systematic review and meta-analysis of real-world evidence

BackgroundTo precisely quantify the incidence, mortality, and risk factors for acute kidney injury (AKI) following immune checkpoint inhibitor (ICI) treatment for cancer in real-world scenarios. MethodsComprehensive searches were performed on PubMed, EMBASE and the Cochrane library. Real-world observational studies reporting incidence, mortality and/or factors for AKI in ICI-treated patients were eligible. Odds ratio (OR) with 95% CI for potential predictors and hazard ratio (HR) with 95% CI for mortality risk associated with AKI were calculated using the random-effect model. ResultsEighteen articles comprising 12,111 patients receiving ICI were finally eligible. The pooled incidence was 16.0% (95% CI 11.2%-20.8%; n = 15) for AKI following ICI therapies overall and 3.5% (95% CI 2.1%-4.9%; n = 8) for ICI-induced AKI. Patients who developed AKI during ICI therapies had 51% increased risk of death compared with those without (HR 1.51, 95% CI 1.07–2.14). Regarding risk factors, statistically increased risk for AKI during ICI therapies was observed with preexisting chronic kidney diseases (OR 1.86, 1.25–2.78), diabetes (OR 1.26, 1.04–1.53), and concomitant extrarenal immune-related adverse events (OR 2.53, 1.79–3.56). Ipilimumab (OR 2.18, 1.43–3.32), combined ICI therapies (OR 1.80, 1.14–2.83) and concomitant use of proton pump inhibitors (OR 1.97, 1.56–2.49), renin‐angiotensin system inhibitors (OR 1.50, 1.05–2.14), diuretics (OR 1.69, 1.27–2.26) also significantly predicted the incident AKI. ConclusionsAKI episode is frequently observed during ICI exposure for cancer treatment, but ICI induced nephrotoxicity is only occasionally. Higher risk of AKI during ICI therapies was significantly associated with specific comorbidities, concomitant of certain drugs, ipilimumab and ICI combination therapies.

Waldenström macroglobulinemia with secondary pure red cell aplasia in a patient with metastatic castrate resistant prostate cancer receiving an immune checkpoint inhibitor: a case report

BackgroundHypoproliferative anemia is a frequently encountered adverse event in cancer patients receiving immune checkpoint inhibitors (ICI). Secondary pure red cell aplasia (PRCA) is a rare but recognized immune related adverse event. With the burgeoning use of ICIs, the association of secondary PRCA with an underlying lymphoproliferative disorder is often overlooked.Case presentationWe report a case of a 67-year-old non-Hispanic Caucasian male with metastatic castrate resistant prostate cancer, who developed severe transfusion dependent anemia with reticulocytopenia while receiving treatment with olaparib and pembrolizumab. His bone marrow findings demonstrated erythroid hypoplasia, in addition to a CD5-negative, CD10-negative monotypic B-cell population and a somatic MYD88L265P mutation. With a presence of an IgM-paraprotein, he was diagnosed with Waldenström macroglobulinemia (WM) with secondary PRCA and treated with 6 cycles of bendamustine and rituximab. He achieved a complete response with this regimen and was transfusion independent.ConclusionIn this case, underlying WM was uncovered through systematic investigation of anemia caused by ICI therapy. This report highlights the possibility of a lymphoproliferative disorder in patients with concerns for PRCA with prior ICI exposure. If identified, treating the underlying lymphoproliferative disorder is highly efficacious in the management of the secondary PRCA.

Clinical Outcomes With Pembrolizumab-Based Therapies in Recurrent/Refractory NSCLC After Chemoradiation and Consolidative Durvalumab

BackgroundOften, patients with NSCLC experience recurrent/refractory (R/R) disease within 2 years of chemoradiation (CRT) and consolidative durvalumab. Despite prior immune checkpoint inhibitor exposure, immunotherapy with or without chemotherapy is typically initiated if a driver-oncogene is absent. However, there remains a paucity of data regarding the efficacy of immunotherapy in this patient population. Here, we present survival outcomes associated with pembrolizumab for R/R NSCLC. Materials and MethodsWe retrospectively assessed adults with NSCLC who received pembrolizumab for R/R disease between January 2016 to January 2023. Primary objective was to estimate OS and PFS in this cohort compared to historical outcomes. Secondary objective was to compare OS and PFS among subgroups. ResultsFifty patients were evaluated. Median follow-up time was 11.3 months (2.9-38.2). OS was 10.6 months (95% CI, 8.8-19.2); 1-year OS rate 49% (95% CI, 36 - 67%). PFS was 6.1 months (95% CI, 4.7-9.0); 1-year PFS rate 25% (95% CI, 15%-42%). Current smokers had significantly better median OS/PFS as compared to former smokers (NA vs. 10.5 and 9.9 vs. 6.0 months, respectively). The addition of chemotherapy demonstrated an OS benefit (median OS 12.9 vs. 6.0 months) but was not statistically significant. ConclusionPatients with R/R NSCLC represent a distinct cohort with inferior survival outcomes when compared to those with de novo stage IV disease treated with pembrolizumab-based regimens. Based on our findings, we recommend oncologists exercise caution when considering checkpoint inhibitor monotherapy in the front-line setting for R/R NSCLC, regardless of PD-L1 expression.

Obesity Measured via Body Mass Index May Be Associated with Increased Incidence but Not Worse Outcomes of Immune-Mediated Diarrhea and Colitis

Obesity defined by high body mass index (BMI) has traditionally been associated with gastrointestinal inflammatory processes but has recently been correlated with better survival in patients receiving immune checkpoint inhibitors (ICI). We sought to investigate the association between BMI and immune-mediated diarrhea and colitis (IMDC) outcomes and whether BMI reflects body fat content on abdominal imaging. This retrospective, single-center study included cancer patients with ICI exposure who developed IMDC and had BMI and abdominal computed tomography (CT) obtained within 30 days before initiating ICI from April 2011 to December 2019. BMI was categorized as &lt;25, ≥25 but &lt;30, and ≥30. Visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA: VFA+SFA), and visceral to subcutaneous fat (V/S) ratio were obtained from CT at the umbilical level. Our sample comprised 202 patients; 127 patients (62.9%) received CTLA-4 monotherapy or a combination, and 75 (37.1%) received PD-1/PD-L1 monotherapy. Higher BMIs ≥ 30 were associated with a higher incidence of IMDC than BMIs ≤ 25 (11.4% vs. 7.9%, respectively; p = 0.029). Higher grades of colitis (grade 3–4) correlated with lower BMI (p = 0.03). BMI level was not associated with other IMDC characteristics or did not influence overall survival (p = 0.83). BMI is strongly correlated with VFA, SFA, and TFA (p &lt; 0.0001). Higher BMI at ICI initiation was linked to a higher incidence of IMDC but did not appear to affect outcomes. BMI strongly correlated with body fat parameters measured by abdominal imaging, suggesting its reliability as an obesity index.

Cardiovascular Immunotoxicity Associated with Immune Checkpoint Inhibitors in Metastatic Melanoma

Checkpoint inhibitors, such as PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab), are widely used in metastatic melanoma, and most immune-related adverse events are known. Several cardiovascular AEs (CVAEs) associated with immune checkpoint inhibitor exposure have been reported in post-marketing surveillance studies and represent major issues for patients with melanoma during and after cancer treatment. Data on CVAES induced by immune checkpoint inhibitors in melanoma, especially incidence and risk factors, are lacking. A systematic review of the literature up to 31 August 2020 was performed in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov register according to prespecified selection criteria from inception to 7 April 2020. Statistics were performed on 3289 patients from five randomized clinical trials on melanoma. Patients with melanoma treated with immune checkpoint inhibitors had a significant risk of presenting dyslipidemia (Peto OR: 4.74, 95% CI: 2.16-10.41, p < 0.01, I2 = 0%, p = 0.94). The Peto OR was numerically significant for pericarditis, myocarditis, heart failure, myocardial infarction, cerebral ischemia, high pulmonary pressure, blood high pressure, arrhythmias, endocarditis, and conduction disturbances, but the confidence interval was not significant. The risk of CVAEs was not statistically different between melanoma treated with immune checkpoint inhibitors and other tumors treated with immune checkpoint inhibitors (range of p-value from 0.13 to 0.95). No interaction between follow-up length and CVAE reporting was found. Our study underlines that checkpoint inhibitors used for melanoma increase CVAEs, especially dyslipidemia, which could pave the way to chronic inflammatory processes, atherosclerosis, and, finally, ischemic cardiopathy. These cardiovascular adverse events could be acute or delayed, justifying the monitoring of lipidic biology and a baseline cardiology consultation.

Abstract 6644: Investigating the effect of immune checkpoint inhibitors (ICI) on ovarian function in young patients with melanoma

Abstract Immune related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) are well documented for nearly every organ system, except for the reproductive system. Mouse models have demonstrated that ICIs can decrease ovarian follicular reserve and impair oocyte maturation, which may have implications for fertility (PMID: 36008687). There are no studies investigating the effect of ICIs on fertility in humans. We sought to evaluate ovarian function in women treated with ICIs compared to untreated women by evaluating non-invasive surrogate markers of ovarian reserve, anti-müllerian hormone (AMH) and antral follicle counts (AFC). We enrolled women 18 - 40 years old diagnosed with stage III or IV melanoma. Participants underwent phlebotomy for AMH levels and a pelvic ultrasound to assess AFC. The medical record was retrospectively reviewed to obtain data on patient characteristics, treatments, and outcomes. A total of 14 patients with stage IIIA - IV melanoma participated. Six patients received ICI treatment before AMH and AFC testing while 8 had no prior ICI exposure. The ICI group ages ranged from 22-40 years with a median age of 31 years. The untreated group ages ranged from 25-39 years with a median age of 32 years. The time between starting an ICI and enrolling in the study ranged from 28 - 351 days. ICI regimens included ipilimumab/nivolumab, nivolumab, pembrolizumab, and atezolizumab (on a clinical trial). Four of these six patients experienced an irAE during their course, including: dermatitis, hepatitis, colitis, thyroid dysfunction, and adrenal insufficiency. Median AMH levels were lower for patients treated with ICIs (2.9 vs 4.0 ng/mL), as was median AFC (22.5 vs 23.5 ng/mL). Only three patients’ clinicians discussed fertility preservation. None of the patients underwent fertility preservation. Our study found lower AMH and AFC in women with melanoma who were treated with an ICI compared to untreated women. Although AMH and AFC are surrogate markers for ovarian reserve and fertility, and our study is a small cohort, these early results suggest that ICIs may impact ovarian function. Age is less likely to be a confounding factor as the median age of the treated group was younger than the untreated group. While these results are preliminary, when considered in conjunction with recent pre-clinical data showing changes within the ovaries after ICI treatment, fertility consultation should be considered for young women prior to ICI initiation. We are investigating associations between AMH, AFC, age, ICI exposure, and future pregnancies in an ongoing prospective study. Citation Format: Ashley Hickman, Katherine Smith, Zaraq Khan, Elizabeth Ann Enninga, Yulian Zhao, Elizabeth Cathcart-Rake, Haidong Dong, Lisa Kottschade, Svetomir Markovic, Heather Montane, Anastasios Dimou, Yiyi Yan. Investigating the effect of immune checkpoint inhibitors (ICI) on ovarian function in young patients with melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6644.

Association between immune checkpoint inhibitors and myocardial infarction in Asians: A population-based self-controlled case series.

While immune checkpoint inhibitors (ICIs) are associated with elevated cardiovascular risks, evidence of any association between ICIs and myocardial infarction (MI) was scarce, especially in Asians. Using prospectively collected population-based data, this self-controlled case series included patients prescribed an ICI between 1/1/2014 and 31/12/2020 in Hong Kong who had MI within January 1, 2013 to December 31, 2021. Incidence rate ratios (IRRs) for MI during and after ICI exposure were estimated, compared to the year before ICI initiation. Of 3684 identified ICI users, 24 had MI during the study period. MI incidence increased significantly in the first 90 days of exposure (IRR 3.59 [95% confidence interval: 1.31-9.83], p=0.013), but not days 91-180 (p=0.148) or ≥181 (p=0.591) of exposure, nor postexposure (p=0.923). Sensitivity analyses excluding patients with MI-related death and incorporating extended exposure periods produced consistent results separately. ICIs were associated with increased MI incidence in Asian Chinese patients during the first 90 days of use, but not later.

Immune-related adverse events after immune checkpoint inhibitor exposure in adult cancer patients with pre-existing autoimmune diseases.

Immune checkpoint inhibitor (ICI) therapy can predispose patients to immune-related adverse events (irAEs) and autoimmune disease (AD) flare-ups, but the characteristics of irAEs among patients with pre-existing ADs are largely unknown. We conducted this study to determine the clinical courses, irAEs, AD flares, treatment, and outcomes of patients with AD on ICIs. This was a retrospective study of adult cancer patients at a large cancer center who were diagnosed with ADs before undergoing ICI therapy. Patients' clinical courses, complications, treatments, and outcomes related to both ADs flares and irAEs were collected and analyzed. The study included 197 patients. Most (55.4%) were women. Melanoma comprised the highest proportion (28.4%) of malignancies, and most (83.8%) patients received PD-1/PD-L1 inhibitors. Fifty (25.3%) patients developed a new irAE after starting ICI therapy, while 29 (14.7%) patients had an AD flare-up. Patients with inflammatory bowel disease had the highest incidence of AD flare-ups (31.7%), while patients with Hashimoto hypothyroidism had the highest incidence of new irAEs (39.2%). Patients with inflammatory bowel disease had more severe adverse events. In our cohort, patients with a new diagnosis of irAE were treated with immunosuppressive therapy. AD flares were managed similarly. With regard to irAE manifestations, the most common presentations were colitis (24 [12.1%] patients), hepatic transaminase elevations (8 [4%] patients), and pneumonitis (7 [3.5%] patients). Our findings suggest that patients with gastrointestinal and rheumatologic ADs had a higher incidence of AD flare-ups, while patients with Hashimoto hypothyroidism and neurologic ADs had a higher incidence of new irAEs. Patients with prior ADs experiencing flare-ups or new irAEs after ICI therapy tend to require aggressive immunosuppressive treatment. Thorough evaluation of baseline disease status, appropriate medical management before ICI therapy, and early recognition of inflammatory exacerbation may help ensure long-term success in treating and improving outcomes in these patients.