Cycle Of Immune Checkpoint Inhibitors Research Articles

Tislelizumab-induced cytokine release syndrome: the first case report and review of the literature.

Cytokine release syndrome (CRS) is an uncommon but deadly side effect of immune checkpoint inhibitors (ICIs). ICIs are presently an increasingly important therapy option for malignant tumors, but there are limited treatments available for CRS. We present a case of a 72-year-old man who received one cycle of ICI coupled with cisplatin and albumin-binding paclitaxel therapy for a locally advanced right lung adenocarcinoma. Following an abrupt onset of dyspnea, the patient underwent a quick physical examination, blood tests and was diagnosed with CRS. After prompt initiation of glucocorticoid pulse treatment, the symptoms relieved. The case illustrates the management of severe CRS following ICI therapy while highlighting the uncommon and potentially fatal immune-related side effects.

Detrimental effect of an early exposure to antibiotics on the outcomes of immunotherapy in a multi-tumor cohort of patients.

Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape of many solid tumors. Modulation of the intestinal microbiota by antibiotics (Abx) has been suggested to impact on ICI outcomes. Retrospective analysis of 475 patients with advanced solid tumors treated with ICI from 2015 to 2022. For each patient, the use of Abx was recorded from 1 month before ICI initiation until disease progression or death. The impact of Abx on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. Kaplan-Meier and log-rank tests were used to compare survival outcomes. In total 475 patients with advanced solid tumors were evaluated. Median age was 67.5 years and performance status (PS) was 0-1 in 84.6%. 66.5% of patients received Abx during treatment with ICI, mainly beta-lactams (53.8%) and quinolones (35.9%). The early exposure to Abx (from 60 days before to 42 days after the first cycle of ICI) was associated with a lower ORR (27.4% vs 39.4%; P < .01), a lower DCR (37.3% vs 57.4%; P < .001), lower PFS (16.8 m vs 27.8 m; HR 0.66; P < .001]) and lower OS (2.5 m vs 6.6 m; HR 0.68; P = .001]). The negative impact of Abx on OS and PFS was confirmed by a multivariable analysis. This effect was not observed among patients receiving Abx after 6 weeks from ICI initiation. Our results validate the hypothesis of a detrimental effect of an early exposure to Abxon the efficacy of ICI in a multi-tumor cohort of patients.

Enhancing outcomes in extensive-stage small cell lung cancer brain metastases: a retrospective study on the synergistic effects of immune checkpoint inhibitor, brain radiotherapy, and chemotherapy.

Brain metastasis is a frequent complication in small cell lung cancer (SCLC), and there is an urgent need for new treatment modalities, given the limited success of traditional approaches. This study evaluates the combined efficacy and safety of brain radiotherapy (BRT), chemotherapy, and immune checkpoint inhibitors (ICIs) in the treatment of brain metastases in patients with extensive-stage SCLC (ES-SCLC). Additionally, it seeks to identify prognostic factors in these cases. A retrospective analysis was performed on 187 patients with ES-SCLC and brain metastases treated at Zhejiang Cancer Hospital from January 2017 to October 2023. Patients were divided into three groups based on their initial treatment: BRT alone, ICI alone, and a combined ICI + BRT approach, with chemotherapy included in all regimens. Variables such as age, number of brain metastases, symptoms, comorbidities, Karnofsky Performance Status (KPS) scores, smoking history, Graded Prognostic Assessment (GPA) scores, survival time, and treatment-related adverse events (TRAEs), including hematologic and hepatic toxicities were evaluated. Prognostic factors were assessed using univariate and multivariate analyses via Cox's proportional hazards model. The study also compared outcomes and TRAEs between patients undergoing synchronous treatment (ICI and BRT within four weeks) versus those with asynchronous therapy (more than four weeks apart). Median overall survival (OS) times differed significantly across the groups: 11.6 months for BRT, 11.6 months for ICI, and 20.9 months for ICI + BRT (P<0.001). The ICI + BRT group also exhibited notably better progression-free survival (PFS) and intracranial PFS (iPFS), with medians of 12.6 and 14.9 months, respectively (P<0.001). This group demonstrated significantly improved systemic and intracranial objective response rates (ORR) and disease control rates (DCR). No significant differences in acute radiation injury rates were observed between the BRT and ICI + BRT groups. Multivariate analysis identified several factors influencing OS, including treatment regimen, number of chemotherapy and ICI cycles, presence of bone and multiple brain metastases, and antiangiogenesis therapies and extracranial radiotherapy. Both atezolizumab and serplulimab ICIs, in combination with various radiotherapy regimens [whole BRT (WBRT), WBRT with boost], were effective. Notably, asynchronous ICI and BRT treatment demonstrated advantages in PFS and iPFS over concurrent therapy, with no significant differences in other therapeutic indices or TRAE incidence rates. For ES-SCLC patients with synchronous brain metastases, combined ICI and BRT, alongside chemotherapy, surpasses the efficacy of either treatment alone with manageable TRAEs. Importantly, asynchronous ICI and BRT therapy showed superior outcomes compared to synchronous treatment modalities.

Prognostic value of immuno-nutritional status in patients with cancer treated by immune checkpoint inhibitors.

226 Background: The treatment efficacy of immune checkpoint inhibitors (ICIs) may relate to tumor factors or host factors, such as systemic inflammation status or nutritional status. In this study, we investigated the prognostic value of immuno-nutritional status in cancer patients treated by ICIs, and develop nomogram models for predicting overall survival (OS). Methods: We used Chang Gung Research Database to retrospectively evaluate cancer patients who received ICIs during January 2015 to December 2021. Patients had double cancer or received only one cycle of ICI were excluded. All patients were divided into a training cohort and a validation cohort. The training cohort was used to analyze the risk factors and develop nomogram models. The models were validated by the validation cohort. The univariate analysis, stepwise multivariate analysis, receiver operator characteristics (ROC) analysis were used to find out the independent risk factors. The calibration plot were used to evaluate the reliability of the models. Results: All patients (3219 cases) could be categorized into lung cancer (22.1%), genitourinary cancer (14.9%), upper gastrointestinal tract cancer (8.1%), colorectal cancer (3.1%), hepatocellular carcinoma (24.6%), pancreatobiliary cancer (3.8%), head and neck cancer (12.9%), melanoma (4.0%), breast cancer (1.9%) and lymphoma (0.5%). 80.2% of patients received anti-PD1, 19.8% of patients received anti-PD-L1. In training cohort, the cut-off value was set for neutrophil-to-lymphocyte ratio (NLR), total lymphocyte count (TLC), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), prognostic nutrition index (PNI) and hemoglobin-albumin-lymphocyte-platelet (HALP) score. The above risk factors showed significant difference in median OS in validation cohort respectively (Table). The multivariate analysis demonstrated that NLR, PNI and HALP score were independent risk factors in predicting OS. The hazard ratio were 1,439 (95% CI 1.149-1.801), 0.689 (95% CI 0.549-0.865) and 0.784 (95% CI 0.626-0.982) respectively. Conclusions: We developed nomogram models to investigate the immuno-nutritional status and predict the OS of cancer patients who received ICIs therapy. High NLR, low PNI and low HALP score were associated with worse OS. [Table: see text]

Negative association of steroids with immunotherapy efficacy in a multi-tumor cohort: time and dose-dependent

Previous studies have suggested a negative impact of steroids on the efficacy of immune checkpoint inhibitors (ICI), but how this effect is modulated by the dosage and time of administration is yet to be clarified. We have performed a retrospective analysis of 475 patients with advanced solid tumors treated with ICI as monotherapy from 2015 to 2022. Data regarding immune-related adverse events (irAEs) and clinical outcomes were collected. For each patient, the daily steroid dose (in mg/kg of prednisone) was registered until disease progression or death. The impact of cumulative doses on response rates and survival outcomes was analyzed within different periods. The objective response rate (ORR) was significantly lower among patients exposed to steroids within 30 days before the first cycle of ICI (C1) (20.3% vs. 36.7%, p < 0.01) and within the first 90 days of treatment (25.7% vs. 37.7%, p = 0.01). This negative association was confirmed by multivariable analysis. Higher mean steroid doses were observed among non-responders, and cumulative doses were inversely correlated with the disease control rate (DCR) around ICI initiation. Remarkably, poorer outcomes were observed even in patients belonging to the lowest dose quartile compared to the steroid-naïve population. The exposure to steroids after 6 months of ICI was not associated with worse survival outcomes. Our results suggest that the potential impact of steroids on ICI efficacy may be time-dependent, prevailing around ICI initiation, and dose-dependent, with modulation of neutrophil-to-lymphocyte ratio as a possible underlying mechanism.

Outcomes of adjuvant immune checkpoint inhibitor therapy in melanoma: a retrospective study

ABSTRACT Background Adjuvant treatment of malignant melanoma has improved the outcomes for patients. However, real-world data on efficacy and safety are limited. We investigated outcomes of melanoma patients treated with adjuvant immune checkpoint inhibitors (ICI) in the Ghent University Hospital. Methods Patients with melanoma (stage III-IV), who received at least one cycle of ICI as adjuvant treatment between 2018 and 2021 were included in this retrospective cohort study. Primary outcomes were recurrence-free (RFS) and overall survival (OS). Other outcomes of interest were relapse patterns and safety. Results 59 patients were included, with a median follow-up of 36 months. Disease recurrence or death of any cause was observed in 25/59 (42.4%) of the patients. The median RFS was 56.0 months (95%CI 36.1–75.9 months). At 48 months, RFS and OS were 55.9% and 84%, respectively. 9/23 (39%) recurrences were locoregional and 14/23 (60.9%) patients developed distant metastasis as first recurrence, including 2 (3.4%) with brain metastasis. Median time to recurrence was 9 months (range 2–56 months). 35/59 (59.3%) completed one year of adjuvant treatment, 12/59 (20.3%) stopped because of recurrence and 10/59 (16.9% because of toxicity. Immune-related adverse events wereseen in 29/59 (49.4%) patients, 10/59 (16.9%) developed grade 3-4 toxicity. Conclusion This study confirms the real-world efficacy and safety of adjuvant ICI for melanoma, achieving RFS and OS comparableto the pivotal clinical trials. About 40% of patients develop arelapse, mainly during the adjuvant treatment. The outcomes ofpatients progressing during adjuvant ICI are poor, emphasizing the need of prospective and real-world studies on optimal management after progression on (neo)adjuvant treatment.

Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis

Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. Among 91 eligible patients, with a median (IQR) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years 0.72, 95% CI 0.53-0.99, p= 0.044) and ICI washout time (aHR per 1 week 0.92, 95% CI 0.86-0.99, p= 0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p= 0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8] vs. 8.0 [9.0]; p= 0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p= 0.032). Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitor use prior to liver transplantation suggest acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without immune checkpoint inhibitor exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies.

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 &gt;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]

Development of a novel risk stratification model for immune-related adverse events for patients with advanced melanoma and non-small cell lung cancer treated with immune checkpoint inhibitors.

2649 Background: Immune checkpoint inhibitors (ICI) transformed treatment paradigm across cancers. There remain few reliable, clinically accessible predictors of ICI-induced immune related adverse events (irAEs). We derive a novel risk stratification model for irAEs using baseline patient, tumor and treatment variables in a large cohort of patients with advanced melanoma (AM) or non-small cell lung cancer (NSCLC) treated with ICI. Methods: We conducted a multi-centre retrospective observational cohort study of consecutive patients with AM or NSCLC receiving ≥ 1 cycle of single-agent or combination ICI, in any line, 2015 - 2023, in Alberta, Canada. Clinically significant irAEs, defined as those requiring treatment delay or systemic steroids/steroid sparing agents, were identified as outcome of interest. The association between irAEs, overall survival (OS), and time to next treatment (TTNT) was assessed with Cox Proportional Hazards regression. Stepwise logistic regression was used to select and weight baseline variables associated with development of irAEs to derive a predictive risk score. Model validation was carried out on 500 iterations of bootstrapped samples. Harrel’s C-index was calculated and internally validated to ascertain the model’s discriminatory performance. Results: 1,292 total patients were included, 519 (218/489 [44.6%] AM and 301/803 [37.5%] NSCLC) developing a clinically significant irAE. Using a subset of 801 patients with available baseline characteristics, the following variables were identified and weighted for creation of risk model (risk score attributed): tumor type (NSCLC) (+1), age &gt;60 (+1), ECOG ≥1 (-1), BMI ≥ 25 (+1), ICI after first line (-1), combination ICI (+4), &gt;10 cycles of ICI (+2), albumin level &lt; LLN (+2), adrenal metastasis (+1), multiple sites of metastasis (-1). Patients were stratified into 3 irAE risk groups based on combined score: low (n = 230, risk score ≤ 0), intermediate (n = 412, risk score 1-2), high (n = 159, risk score ≥3). The risk model performed well with an optimism-corrected c-index of 0.707 in internal validation, and strong association with odds of irAE occurrence (Table). The development of irAE was associated with an improvement in OS (HR 0.48, 95% CI 0.41-0.44, p&lt;0.001), with a median OS of 34.3 (95% CI 28.8-39.6) months compared to 12.0 (95% CI 10.6-14.3) months for those who did not develop an irAE. Similar robust stratification was also seen with TTNT. Conclusions: We presented and internally validated, a simple risk stratification tool that utilizes readily available baseline patient, tumor, and treatment characteristics to robustly stratify risk of irAE development. [Table: see text]

Long term outcomes of patients with advanced/unresectable melanoma treated with immune checkpoint inhibitors.

e21518 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced/unresectable melanoma. There is a need for long term follow up of patients (pts) treated with ICIs in the real world to evaluate durability of response and facilitate follow-up care. Methods: Pts ≥ 18 years (y) old with advanced/unresectable melanoma who received ≥ 1 cycle of ICI at BC Cancer between 2012 and 2022 were identified using the BC Cancer Registry and pharmacy databases. Best overall response of complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) was obtained from CT and PET reports. Oligo-progression that was successfully treated with local therapy was not considered true progression. Results: In total 530 pts were identified. The median follow up for alive pts was 65 months (m) (range 1.4 – 150 m); the median age was 66 y (range 21 – 98). The majority were male (63%) and Caucasian (91%), with ECOG performance status 0 (38%) or 1 (48%). Primary tumour origin was cutaneous (n = 390, 74%), mucosal (n = 36, 7%), ocular (n = 47, 9%) or unknown (n = 57, 11%). BRAF V600 mutations (mut) were identified in 35% of pts (40% cutaneous/unknown). Pts either received PD-1 inhibitor alone (PD-1i) (n = 242, 46%), combination ipilimumab and nivolumab (ipi/nivo) (n = 136, 26%), ipilimumab alone (ipi) (n = 83, 16%) or sequential use of ipi and PD-1i (sequential) (n = 69, 13%). Overall survival (OS) was superior in cutaneous/unknown (5 y 34.5%) compared with mucosal (5 y 28%) and ocular (5 y 5%) primaries (p &lt; 0.001). Excluding ocular cases for the ensuing analyses, by treatment group (ipi/nivo, PD-1i, ipi, sequential) the 5 y OS was 43%, 36%, 37% and 10%, respectively (p &lt; 0.001). Pair-wise comparison of ipi/nivo vs PD-1i favored ipi/nivo (OS p = 0.059) despite a greater proportion of pts with M1d disease (24% vs 15%; p = 0.012). The benefit of ipi/nivo was more pronounced in pts &lt; 65 y (5 y OS 45% vs 36%; p = 0.07), but less clear in pts ≥ 65 y (5 y OS 40% vs 36%; p = 0.385). An OS benefit was observed with ipi/nivo in pts with BRAF wild-type disease (5 y 47.5% vs 33%, p = 0.018 (cutaneous/unknown only, p = 0.021) but not in patients with BRAFmut positive disease (5 y 38% vs 41.5%, p = 0.989). Those treated with ipi/nivo vs PD-1i had numerically higher rates of CR (37% vs 26%), though pts who achieved a CR with either ipi/nivo or PD-1i had a similar 5 y OS (88% vs 96%; p = 0.285). To minimize guarantee-time bias, a 1 y landmark analysis was performed for those treated with ipi/nivo and PD-1i, excluding pts that died during the first year. 5 y OS differed significantly by response (CR, PR, SD, PD) to both ipi/nivo (86%, 36.5%, 42%, 8%; p &lt; 0.001) and PD-1i (90.5%, 35%, 16%, 19%; p &lt; 0.001). Conclusions: Overall, pts treated with ipi/nivo have the best long-term outcomes. However, outcomes are similar in pts treated with PD-1i who have a CR. Further, in older pts and pts with BRAFmut positive disease the benefit of ipi/nivo over PD-1i is less clear.

Immune-related adverse events in patients treated with immunotherapy according to corticosteroid exposure.

e14709 Background: Patients with cancer require treatment with corticosteroids for multiple reasons, including prevention of chemotherapy-related side effects. Although corticosteroid use has been associated with lower efficacy of immune checkpoint inhibitors (ICI) in some studies, whether corticosteroid exposure affects the presence and severity of immune-related adverse events (irAEs) remains unclear. Methods: Retrospective single-center study of patients diagnosed with solid tumors treated with ICI. Eligible patients were those who received at least one cycle of ICI and had at least 1 month of follow-up post-ICI initiation. Patient data were extracted from electronic medical records. Comparisons between groups were made based on steroid exposure (defined as the administration of &gt;10 mg of prednisone or its equivalent for &gt;10 days within a 30-day period or at any point during ICI treatment, excluding steroid treatment for irAEs). Associations between variables were assessed using independent samples T-test, Chi-square, and Fisher’s exact tests. Results: We included 135 patients (mean age 61 years, SD 13); 72 (54%) were male. Forty-two (31%) had been exposed to steroids (mean prednisone equivalent of 427 mg, SD 298). Most patients received ICI as palliative treatment for advanced disease (105/135; 78%), primarily as first-line therapy (79/105; 75%). Patients exposed to corticosteroids were more likely to have received ICI with chemotherapy (76% vs 1%, p&lt;0.001), were younger (56 vs. 63 years, p=0.009), more likely to be female (62% vs. 39, p=0.014), and had lower median Charlson Comorbidity Index scores (2 vs. 3, p=0.026). Steroid-exposed patients were more likely to have employed ICI in the neoadjuvant or adjuvant settings (36 vs. 16%, p=0.024) or as third or subsequent line therapy (26 vs. 8%, p=0.044). There were no statistically significant differences in the frequency of irAEs of any grade based on steroid exposure (31% vs 41%, p=0.252). However, patients who were exposed to steroids were significantly less likely to delay or suspend ICI (10% vs. 32%, p=0.005). No other parameters were associated with the rate or severity of irAEs. Conclusions: Our findings suggest that corticosteroid exposure does not increase the frequency of irAEs in patients treated with ICI, but it is associated with a reduced likelihood of discontinuing ICI due to irAEs. These observations suggest that corticosteroids may play a beneficial role in managing patients undergoing immunotherapy, particularly in sustaining treatment continuity despite irAEs. This study underscores the need for further investigation into optimal steroid use strategies to enhance patient outcomes with immunotherapy, especially in situations when they are commonly prescribed, such as premedication for chemotherapy.

Comparing rates of immune checkpoint inhibitor toxicity in different treatment settings (neoadjuvant, adjuvant, and palliative) in non-small cell lung cancer (NSCLC): A meta-analysis of phase III clinical trials.

8645 Background: Immunotherapy has created a paradigm shift in the treatment of NSCLC. There is growing interest in the utility of immunotherapy alone or in combination with chemotherapy for NSCLC in the peri-operative setting with practice changing results demonstrated in several pivotal phase III clinical trials. Nevertheless, immune related adverse events (irAEs) are the main barrier in the care of patients treated with immune checkpoint inhibitors (ICIs) with grade ≥ 3 irAEs seen in 10-15% of patients. The present meta-analysis aims to compare rates of irAEs across different treatment settings in NSCLC to aid in individual patient treatment decisions. Methods: We extracted data from selected published phase III clinical trials which have led to the approval of PD-1/PDL-1 ICIs in the neoadjuvant, adjuvant, peri-operative and in the palliative setting. We excluded trials which did not have supplemental data on irAEs included with published results and trials of CTLA-4 inhibitors. A sensitivity analysis was performed to assess whether number of cycles correlated with toxicity rates. Results: Pooled data from 15 published phase III NSCLC clinical trials including 5918 patients were included. This included 1 neoadjuvant, 2 peri-operative, 3 adjuvant, and 9 palliative studies. One of the peri-operative trials included data on irAEs which occurred during the neoadjuvant/surgery phase only and this data was pooled within the neoadjuvant group. The ICI drugs included nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab +/- chemotherapy. This included a total of 2523 stage 1B-3C and 3395 stage IV patients. We found a 9.5% rate of grade 3-5 and 35.8% rate of all grade irAEs in palliative trials (n=3395). In contrast, neoadjuvant ICI (n=572) had a 3.5% rate of grade 3-5 and 16.8% of all grades irAEs. Peri-operative ICI (n=797) had a 5.4% rate of grade 3-5 and 24.47% all grades irAEs. Adjuvant ICI (n=1550) had a 7% rate of grade 3-5 and 38.52% rate of all grade irAEs. The relative risk (RR) between the palliative and the neoadjuvant setting of a grade 3-5 irAE is 2.35 (95% CI:1.54 to 3.59; p = 0.0001) and the RR of any irAE is 2.03 (95% CI: 1.69 to 2.43; p=0.0001). The following median number of ICI cycles was seen: neoadjuvant = 3.5, adjuvant = 18, peri-operative = 18, palliative = 10. Lower number of cycles did correlate with lower toxicity in the neoadjuvant setting but this was not seen in other treatment settings. Conclusions: Neoadjuvant, peri-operative and adjuvant ICI’s are associated with a lower rate of irAEs than that seen in palliative trials. A neoadjuvant-only approach is associated with the lowest rates of irAEs and this may be due to the lower number of cycles received. These findings have implications for individual patient treatment decisions and support the use of neoadjuvant immunotherapy in NSCLC.

Toxicity of weight-based vs. flat dosing for immune checkpoint inhibitors in patients with low weight: Retrospective analysis from a tertiary care center.

e14616 Background: Immune checkpoint inhibitors (ICI) have come to the forefront of cancer therapy. Barring Ipilimumab, all other ICIs are dosed at flat doses for ease of administration. Pharmacokinetic studies have shown a wide range of peak and trough concentrations for flat doses. However, for underweight patients (&lt;50 Kg), when one looks at weight-based dosing, it may seem that flat dose may deliver excessive amounts of the drug within a short period of time, which in turn may cause an immune-related adverse event (irAE). We conducted a retrospective study comparing the toxicities and outcomes of weight based and flat doses in underweight patients treated with ICI. Methods: This is a retrospective study of patients receiving ICI for any cancer-related indication. Patients receiving chemotherapy with pembrolizumab, nivolumab and/or ipilimumab were included. Patients on other ICI were excluded. All grade toxicities were recorded, and Odds ratio (OR) was calculated using the Z-test. Results: 313 patients were included where 255 (81.5%) were females, median age 66 years (range 19-93), and 225 (72%) were White. Lung cancer was the most common histology (n-170, 54%) followed by H&amp;N (n-34, 11%) and GI cancers (n- 27, 9%). The median weight was 47 Kgs (range: 31-50). 252 patients (80.5%) received flat dose ICI and 61 patients (19.5%) received weight-based ICI, most of whom (n-45, 74%) received prior to 2018. Median ICI cycles was 4 (2-9) vs. 5 (3-10). Single agent PDL-1 inhibitor was prescribed to 205 patients (65%) of which 120 received pembrolizumab (59%) and 85 received nivolumab (41%), and 89 patients (28%) received ICI in combination with chemo or targeted therapy. 94 patients (30%) experienced all grade toxicities. Thyroid dysfunction (n-47, 15%) and colitis (n-24, 8%) were the most common. There was a non-significant trend towards lower toxicity in weight-based dosing: 13 (21.3%) vs. 81 (32.1%), OR =0.57, 95% CI (0.29 - 1.11) p =0.10, and a trend toward less hospitalization or need for treatment for iRAE: 8 (13.1%) vs. 55 (21.8%), OR =0.54, 95% CI (0.24 - 1.20) p=0.13. Significantly higher toxicity was recorded when chemotherapy-ICI or TT-ICI combinations: 56 (24.8%) vs. 38 (43.7%) OR = 0.42, 95% CI (0.25 - 0.71) p= 0.001. There was no difference in death or needing hospice care rates: 43 (70.5%) vs 169 (67.1%), OR= 1.17 (95% CI, 0.64 - 2.16) p= 0.61. Conclusions: Compared to standard flat dosing, weight-based dosing of ICI was associated with a trend towards lower iRAE in patients &lt; 50 Kgs without a difference in survival. These results urge the oncology community to consider the potential financial toxicity savings if weight-based dosing of ICI is adopted more broadly in underweight patients without negatively impacting outcomes, large scale and prospective studies are needed to support this hypothesis.

Continuous immunotherapy beyond progression in clinical practice for small cell lung cancer.

In non-small-cell lung cancer, continuous immune-checkpoint inhibitors (ICIs) beyond progression are often used in clinical practice. On the other hand, there is almost no data on whether the concept of continuous ICIs beyond progression can be adopted in small-cell lung cancer (SCLC). We describe the effectiveness of continuous ICIs beyond progression in SCLC. Medical courses of SCLC patients treated with chemo-immunotherapy were retrospectively reviewed at our hospital. The study included 36 patients with a median age of 73 years (range 46-83 years) who introduced chemo-immunotherapy between September 2019 and December 2022. Atezolizumab and durvalumab in combination with platinum plus etoposide were administered in 24 and 12 patients, respectively. The overall response rate was 67% and the disease control rate was 86%. The median progression-free survival and time to treatment failure (TTF) were 5.1 and 10.3 months, respectively. The median cycle of ICIs was 5 (range 1-42). The median overall survival was 13.6 months. ICIs were administered beyond progression in 14 (39%) patients: five were treated again with chemo-immunotherapy and local ablative radiotherapy, four with local ablative radiotherapy and continuous ICIs, three with chemo-immunotherapy, and two with continuous ICIs alone. TTF exceeded 12 months in 12 (86%) of the 14 cases, six of which were still on ICIs. Adverse events ≥grade 3 were observed in 21 (58%) patients. A notable TTF suggested a benefit of continuous ICIs beyond progression. The concept could be suitably adopted and provide a favorable prognosis in selected cases of SCLC that were previously regarded as an aggressive malignancy.

Immune checkpoint inhibitors combined with or without radio(chemo)therapy for locally advanced or recurrent/metastatic esophageal squamous cell carcinoma

ObjectiveThis study was designed to investigate the efficacy and prognostic factors for immune checkpoint inhibitors (ICIs) combined with or without radio(chemo)therapy and to evaluate their toxicity in patients with locally advanced or recurrent/metastatic esophageal squamous cell carcinoma (LA/RM ESCC).MethodsIn this study, 198 patients with locally advanced or recurrent/metastatic (LA/RM) ESCC who received ICIs combined with or without radiotherapy/chemotherapy in the Department of Radiotherapy of the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS) and progression free survival (PFS). The factors affecting treatment response and the occurrences of treatment-related adverse events (trAEs) were analyzed.ResultsThe median OS and PFS were 30.4 months (95% confidence interval [CI] 15.1–45.7 months) and 15.3 months (95% CI 12.8–17.8 months), respectively. Univariate and multivariate analysis showed that the number of ICI cycles, the intervention of radiotherapy and dysphagia were independent factors affecting OS (Hazard ratio [HR] = 0.39, 2.043 and 0.365, respectively; P = 0.018, 0.001 and 0.032, respectively). The intervention of radiotherapy was an independent factor for PFS (hazard ratio [HR] = 18.149, P = 0.013). The median OS and PFS for patients who had complete response and partial response (Objective response, ORR) were 50.8 months (95% CI 25.8–75.7 months) and 20.5 months (95% CI 14.1–27.0), respectively, which were significantly higher than those in the non-ORR group (OSnon-ORR:17.5 months, 95% CI 14.0–21.0; χ2 = 13.881, P < 0.001; PFSnon-ORR: 12.1 months, 95% CI 10.1–14.1, χ2 = 10.676, P = 0.001). The intervention of radiotherapy could improve treatment response (χ2 = 47.725, P = 0.000). In entire study population, 83 patients (41.9%) had ≥ grade 2 trAEs.ConclusionsICIs combined with radiotherapy/chemotherapy are safe and effective in LA/RM ESCC patients. Intervention of radiotherapy, the number of immunotherapy cycles and occurrence of dysphagia affecting the overall survival of LR/RM ESCC patients. Intervention of radiotherapy was an independent prognosis factor for OS and PFS and associated with better treatment response.

#3880 REDUCED EGFR IS ASSOCIATED WITH IMPROVED SURVIVAL IN PATIENTS WITH RENAL CANCER WHO RECEIVED TARGETED SYSTEMIC ANTI-CANCER THERAPY

Abstract Background and Aims Treatment with vascular endothelial growth factor signalling pathway inhibitors (VSPI) and immune checkpoint inhibitors (ICI) has transformed outcomes in advanced renal cancer. A significant proportion of people with renal cancer have co-existing chronic kidney disease (CKD) and concerns persist about the usage of these agents in patients with CKD. We sought to analyse the effect of reduced kidney function on the survival of patients with renal cancer treated with VSPI or ICI. Methods The ChemoCare and NHS West of Scotland SafeHaven databases were linked (data collection spanning 2008–2020), to identify adults from the Greater Glasgow and Clyde Health board who had received either a VSPI or ICI as an anti-cancer therapy. We included participants with two available serum creatinine values (at least 3 months apart) before the date of initiation of treatment. The estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI (2009), the average of the two eGFR results (at least 3 months apart) was included in the analyses. Proteinuria was defined as any positive urine albumin: creatinine (&amp;gt;3 mg/mmol) or protein:creatinine (&amp;gt;15 mg/mmol) ratio before treatment. Factors associated with all-cause mortality were analysed using Cox proportional hazards models with R Software. Results We identified 349 patients with renal cancer who received at least one cycle of ICI and/or VSPI. Sufficient serum creatinine results were available for analysis in 337 of these patients. The average age at first treatment was 63.0 (IQR 55-71) years, 62.5% were male and the median BMI was 28.2kg/m2 (IQR 23.9-31.6). Proteinuria results were recorded in 125 patients and 149 patients had nephrectomy prior to treatment. The majority of patients received VSPI (88.7%). Over a median follow-up of 335 days (IQR 131 days – 840 days), 281 patients died (Table 1). On univariable analysis, lower baseline eGFR (per 10mL/min/1.73 m2 decline in eGFR: HR 0.89, CI 0.84-0.95, p = &amp;lt;0.001) and prior nephrectomy (HR 0.65, CI 0.52-0.83, p= &amp;lt;0.001) were associated with a higher hazards of death. Age (HR 0.99, CI 0.98-1.00, p = 0.245), sex (HR 0.93, CI 0.74-1.18, p = 0.570), BMI (HR 0.99, CI 0.96-1.03, P = .775) and treatment class (HR 0.76, CI 0.51-1.14, p = 0.253) were not associated with higher hazards of death. After adjustment for age, sex and prior nephrectomy, lower eGFR was associated with lower hazards of death (per 10mL/min/1.73 m2 decline in eGFR: HR 0.91, CI 0.84-0.97, p= 0.007). In a sensitivity analysis in people who had complete eGFR and proteinuria data available, the presence of proteinuria was associated with greater hazards of death (HR 1.63, CI 1.05-2.12, p= 0.029) after adjustment for age, sex, eGFR and nephrectomy (Figure 1). Conclusion Lower baseline eGFR before treatment was associated with reduced hazards of death. This finding was not fully explained by the association of prior nephrectomy with better cancer outcomes. This suggests that other factors may contribute to these discrepancies, such as underlying selection bias of patients for treatment, or bias from the marker used to estimate GFR in this group of patients. The presence of proteinuria was associated with an increased hazards of death and maybe a better marker of renal-associated risk in this group than eGFR and warrants further investigation.

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]

Efficacy and safety of radiation therapy combined with anti-angiogenic agentsand immunotherapy for MSS/pMMR metastatic colorectal cancer: A real-world study.

e15559 Background: The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) can reshape tumor microenvironment, and their effectiveness has been demonstrated in pattients with microsatellite stable (MSS) or mismatch repair profificient (pMMR) metastatic colorectal cancer (mCRC). Radiotherapy (RT) can induce tumor immunogenic cell death, increase infiltration of tumor-infiltrating T lymphocytes and enhance neoantigen expression. Whether the application of RT can further improve the prognosis of pts with MSS/pMMR mCRC receiving anti-vascular drugs and immunotherapy remains to be explored. Methods: We retrospectively identified data on mCRC pts who received anti-angiogenic targeted agents and ICIs after failure of standard therapy at our institution from January 2015 to September 2022. Pts either received RT (RT+TT+IT group) or did not (TT+IT group) during the course of the disease. Baseline characteristics of the groups were compared with the Chi-squared, Fisher's exact, or the independent sample t-test as appropriate. Progression-free survival (PFS) and overall survival (OS) were examined by the Kaplan-Meier method with a log-rank test. Univariate and multivariate Cox regression analysis was conducted to identify prognostic factors for PFS and OS. Results: Of the 89 pts who received anti-angiogenic targeted therapy in combination with ICIs, 43 (48.3%) received RT and 46 (51.7%) did not. All pts were MSS/pMMR. The objective response rate (ORR) of the RT+TT+IT and TT+IT groups was 18.6% (8/43) and 10.9% (5/46) and the disease control rate (DCR) was 83.7% (36/43) and 67.4% (31/46) (both p &gt; 0.05), respectively. The median PFS time was slightly higher in the RT+TT+IT group than in the TT+IT group (5.0 vs. 4.3 months, p = 0.065). In addition, the PFS of RT sequential/simultaneous TT+IT was superior to TT+IT sequential radiotherapy (RT→IT+TT vs. RT-IT+TT vs. IT+TT→RT: median 7.5 vs. 6.1 v.s 3.8 months, p = 0.004). The median OS of RT+TT+IT group was significantly better than that of TT+IT group (15.2 vs. 7.2 months, p = 0.026). Application of RT appeared to be most benefificial in pts aged 56 or younger, advanced stage of initial diagnosis, metastatic lesions involving ≥2 organs, primary lesion not resected, RAS mutations. Cox multivariate regression analysis showed that the number of anti-angiogenic agents plus ICIs cycles &gt; 4 was an independent prognostic factor for OS. No treatment-related deaths were reported, and radiation pneumonia occurred in one patient in the combined radiotherapy group in a manageable manner. Conclusions: The addition of RT during the course of disease can significantly improve the survival benefit of MSS/pMMR mCRC pts treated with anti-angiogenic drugs combined with ICIs posterior line therapy.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Over the last decades, a revolution has occurred in oncology with the development of immune checkpoint inhibitors (ICIs). Following tremendous successes in solid tumors, interest has risen to explore these inhibitors also in hematologic malignancies, especially lymphomas. Biomarkers for ICIs response and resistance include PD-L1 expression and other environmental factors, among which the gut microbiome (GM) is gaining increasing interest. Several studies have demonstrated a connection between GM compositional and functional patterns and ICIs efficacy in solid tumors, but no data in lymphomas have yet been published. We hypothesize that GM dynamics in lymphoma patients during ICIs therapy correlate with treatment response and toxicities. Methods: We enrolled 20 patients (15 with classical Hodgkin lymphoma [cHL] and 5 with primary mediastinal B-cell lymphoma [PMBCL]) treated with ICIs due to relapsed/refractory (R/R) disease. Feces were collected at baseline, before each therapy cycle and at response assessment, and profiled through Illumina sequencing. Sequencing data were processed using a bioinformatics pipeline combining PANDASEQ and QIIME 2. At each time point, patients compiled a 7-day weighted food intake record that was analyzed by MètaDieta (METEDA). All statistical analysis was performed in R (4.4.2). Results: The two groups of patients did not differ for baseline characteristics, thus both clinical outcomes and GM results are reported as pooled. Nineteen patients were refractory to last therapy, with a median of previous treatments of 3 (range 2–8). The median number of ICIs cycles was 14 (1–39). The overall response rate (ORR) was 30.5%, with a median progression-free survival of 11 months and a median disease survival not reached, at a median follow-up of 28.9 months. No association was found between clinical characteristics and response/survival outcomes. Three patients developed 6 hematological toxicities and 18 patients developed 58 extra-hematological toxicities; 4 patients had SAE, of which 2 were judged as drug related. As for GM (Figure 1), responding patients showed a peculiar enrichment of Lachnospira at baseline (p = 0.013). The relative abundance of this taxon negatively correlated with dietary intake of Omega-6 (p = 0.038). On the other hand, non-responders showed higher basal levels of Enterobacteriaceae (p = 0.041). These features were also maintained at the end of the treatment, even if only as trends (p < 0.1). Keywords: Diagnostic and Prognostic Biomarkers, Immunotherapy No conflicts of interests pertinent to the abstract.

The prognostic value of [18F]FDG PET/CT based response monitoring in metastatic melanoma patients undergoing immunotherapy: comparison of different metabolic criteria

PurposeTo investigate the prognostic value of [18F]FDG PET/CT as part of response monitoring in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs).MethodsSixty-seven patients underwent [18F]FDG PET/CT before start of treatment (baseline PET/CT), after two cycles (interim PET/CT) and after four cycles of ICIs administration (late PET/CT). Metabolic response evaluation was based on the conventional EORTC and PERCIST criteria, as well as the newly introduced, immunotherapy-modified PERCIMT, imPERCIST5 and iPERCIST criteria. Metabolic response to immunotherapy was classified according to four response groups (complete metabolic response [CMR], partial metabolic response [PMR], stable metabolic disease [SMD], progressive metabolic disease [PMD]), and further dichotomized by response rate (responders = [CMR] + [PMR] vs. non-responders = [PMD] + [SMD]), and disease control rate (disease control = [CMR] + [PMR] + [SMD] vs. [PMD]). The spleen-to-liver SUV ratios (SLRmean, SLRmax) and bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were also calculated. The results of PET/CT were correlated with patients’ overall survival (OS).ResultsMedian patient follow up [95% CI] was 61.5 months [45.3 – 66.7 months]. On interim PET/CT, the application of the novel PERCIMT demonstrated significantly longer survival for metabolic responders, while the rest criteria revealed no significant survival differences between the different response groups. Respectively on late PET/CT, both a trend for longer OS and significantly longer OS were observed in patients responding to ICIs with metabolic response and disease control after application of various criteria, both conventional and immunotherapy-modified. Moreover, patients with lower SLRmean values demonstrated significantly longer OS.ConclusionIn patients with metastatic melanoma PET/CT-based response assessment after four ICIs cycles is significantly associated with OS after application of different metabolic criteria. The prognostic performance of the modality is also high after the first two ICIs cycles, especially with employment of novel criteria. In addition, investigation of spleen glucose metabolism may provide further prognostic information.