L1 Monotherapy Research Articles

P0426 Lumeneye digital proctoscopy is safe, and streamlines management of immune checkpoint inhibitor-induced colitis

Abstract Background Immune checkpoint inhibitors (CPI) have transformed cancer outcomes, but trigger CPI-colitis in up to 46%, frequently incurring morbidity and CPI discontinuation. Diagnosis is via endoscopy, with >90% involving distal colonic inflammation. Timely diagnosis and treatment improve outcomes and reduce corticosteroid (cs) duration. The rising prevalence of CPI-colitis strains endoscopy services, risking delays in care. The Lumeneye, a cost-effective GI digital proctoscopy tool with biopsy capability, could streamline patient management pathways. Methods A prospective observational feasibility study was conducted at the Royal Marsden Hospital, UK. Patients with suspected CPI- colitis underwent Lumeneye proctoscopy with rectal biopsy sampling in an outpatient setting. Digital images were captured, and clinical data retrieved from electronic medical records. Patient comfort was evaluated using the Modified Gloucester Comfort Scale (MGCS) and, when applicable, compared to standard lower GI endoscopy performed within the previous 6 months. Clinical findings from Lumeneye and standard endoscopy were evaluated for concordance in patients who underwent both within 3 weeks. Results Forty Lumeneye procedures were performed on 37 patients (17 males and 20 females, median age 66 years). Cancers included melanoma (n=17), renal (n=4), lung (n=5), and “other” (n=11). CPI therapies included dual anti-CTLA-4/PD-1/L1 (n=14), and anti-PD-1/L1 monotherapy (n=23). The mean time from referral to examination was shorter for Lumeneye (5 days, IQR 3-7) compared to lower GI endoscopy (21 days, IQR 14-26; p<0.001). The mean procedure time or Lumeneye was 6 (IQR 4-8) minutes. Lumeneye was associated with a lower MGCS score compared to lower GI endoscopy (2 -minimal discomfort vs 3-mild discomfort, p<0.001). Endoscopic findings revealed normal mucosa in 19 patients; the remainder showed varying degrees of oedema, erythema, and erosions (Figure 1). In 5 cases, views were suboptimal. Concordance between Lumeneye and standard endoscopy was observed in 10/13 patients (83%), with histological agreement in 11/13 (85%). In 11 cases, normal mucosal findings informed the rationale for rapid cs taper and administration of topical cs (Clipper). In 3 cases, Lumeneye expedited the diagnosis of severe CPI-colitis, leading to timely anti-TNFa escalation. In one case, suspected melanoma deposits in the rectum prompted investigation of metastatic disease. Conclusion Examination of patients with CPI-colitis in the physician’s office using Lumeneye was safe, well tolerated and reduced the burden on endoscopy services. Lumeneye streamlined the patient pathway by facilitating early, accurate diagnosis and allowing timely escalation or de-escalation of immunosuppressive therapy.

P0410 Clinical outcomes of endoscopically confirmed immune checkpoint inhibitor-induced colitis: A multicentre retrospective study

Abstract Background Immune checkpoint inhibitors (CPIs) have transformed cancer outcomes, but frequently trigger CPI-induced colitis (CPI-c) leading to significant morbidity and prolonged immunosuppression. This study characterises CPI-c patients (pts) using robust definitions. Additionally, the impact of macroscopic inflammation (endoscopic and histological evidence) compared to microscopic inflammation (histological only) on clinical outcomes remains unclear. Methods Retrospective outcome data were obtained from consecutive CPI-c pts from 2 U.K centres. Pts with diarrhoea and histological ± endoscopic colonic inflammation were included. Factors associated with macroscopic inflammation were analysed using Chi squared tests and multivariable logistic regression. Results Of 161 pts (55% male, median age 64), cancers included melanoma (50%), renal (18%), lung (16%) and others (16%). CPI therapies included anti-PD-1/L1 monotherapy (41%), dual anti-CTLA-4/PD-1 (47%) and chemoimmunotherapy (6%). Toxicity onset was earlier with dual anti-PD-(L)1/CTLA-4 therapy vs. anti PD-(L)1 monotherapy (47 vs.150 days, p < 0.001). The average bowel frequency was 8x/day (range 2-20); 115 (71%) had nocturnal symptoms; 28 (17%) had bloody stool and 63% required hospitalisation. 89 pts (54%) were corticosteroid (cs) refractory, requiring biologics (infliximab (IFX), 73; vedolizumab, 13). 41/73 (56%) responded to IFX, and 5/13 (38%) to vedolizumab. Three underwent colectomy for refractory colitis. Macroscopic inflammation occurred in 78%, while 22% had microscopic inflammation. Time to endoscopy did not differ between groups. Among macroscopic cases, 91 (70%) had mild (Mayo 1), while 30% had moderate or severe inflammation (Mayo 2-3). CTCAE grade did not correlate with endoscopic severity. In the regression analysis, male sex (OR 3.25 p<0.01) and dual anti-CTLA-4/PD-1 (OR 2.63 p<0.01) predicted macroscopic inflammation. Age, cancer, CTCAE grade, duration of diarrhoea, concurrent CMV colitis, number of cs tapers, duration of cs therapy, hospitalisation and recurrence of colitis were not predictive. Macroscopic inflammation correlated with higher faecal calprotectin (FC) levels (889 vs 414, p=0.02) and biologic escalation (52.7% vs 30.6%, p<0.05). 30% received CPI re-challenge, with colitis relapse in 13/45 (29%). No relapses exceeded initial CTCAE or endoscopic severity. Conclusion This study represents one of the largest real-world cohorts of robustly defined CPI-c pts. Pts with macroscopic inflammation have a more aggressive clinical course, marked by higher FC levels and greater need for biologic escalation, emphasising the need for heightened monitoring in this group. Reassuringly, CPI re-challenge did not lead to more severe colitis relapses than the initial episode.

Clinicogenomic predictors of outcomes in patients with hepatocellular carcinoma treated with immunotherapy.

Immune checkpoint inhibitor (ICI) combinations extend overall survival (OS) while anti-PD-1/L1 monotherapy is non-inferior to sorafenib in treatment-naïve, patients with advanced hepatocellular carcinoma (HCC). Clinicogenomic features are posited to influence patient outcomes. The primary objective of this retrospective study was to define the clinical, pathologic, and genomic factors associated with outcomes to ICI therapy in patients with HCC. Patients with histologically confirmed advanced HCC treated with ICI at Memorial Sloan Kettering Cancer Center from 2012 to 2022 were included. Association between clinical, pathological, and genomic characteristics were assessed with univariable and multivariable Cox regression model for progression-free survival (PFS) and OS. Two-hundred and forty-two patients were treated with ICI-based therapy. Patients were predominantly male (82%) with virally mediated HCC (53%) and Child Pugh A score (70%). Median follow-up was 28 months (0.5-78.4). Median PFS for those treated in 1st line, 2nd line and ≥ 3rd line was 4.9 (range: 2.9-6.2), 3.1 (2.3-4.0), and 2.5 (2.1-4.0) months, respectively. Median OS for those treated in 1st line, 2nd line, and ≥ 3rd line was 16 (11-22), 7.5 (6.4-11), and 6.4 (4.6-26) months, respectively. Poor liver function and performance status associated with worse PFS and OS, while viral hepatitis C was associated with favorable outcome. Genetic alterations were not associated with outcomes. Clinicopathologic factors were the major determinates of outcomes for patients with advanced HCC treated with ICI. Molecular profiling did not aid in stratification of ICI outcomes. Future studies should explore alternative biomarkers such as the level of immune activation or the pretreatment composition of the immune tumor microenvironment.

Surufatinib plus PD-1/L1 inhibitors as maintenance therapy following first line (1L) platinum-based chemotherapy combined with PD-1/L1 inhibitors in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC).

e15109 Background: Pts with ES-SCLC have a poor prognosis. PD-1/L1 inhibitors combined with chemotherapy as 1L treatment has been demonstrated to improve the survival. Yet, pts are prone to progression after chemo-immunotherapy followed by anti-PD-1/L1 monotherapy. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) combined with PD-1/L1 inhibitors in pts with ES-SCLC as 1L maintenance therapy. Methods: Key inclusion criteria were cytologically or pathologically confirmed ES-SCLC, ECOG PS 0-1, no disease progression after 4-6 cycles platinum-based chemotherapy combined with PD-1/L1 inhibitors. Enrolled pts received surufatinib (250mg, po, QD) plus PD-1/L1 inhibitors (same as that in prior 1L therapy: Durvalumab, Sintilimab, Toripalimab or Serplulimab) until disease progression or intolerable toxicity. The primary endpoint is progression free survival (PFS) per RECIST 1.1 by investigator. Results: From Sept 2022 to July 2023, 21 pts were enrolled. The median age was 62 years. 90.5% were male, 85.7% were former and current smokers and 52.4% had ECOG PS of 0, 11 pts completed 6 cycles of platinum-based chemotherapy combined with PD-1/L1 inhibitors, and 12 pts received durvalumab in 1L therapy. As of 20 Nov, 2023, the median follow-up duration was 9.2 months. Objective response rate (ORR) was 14.3% and DCR (disease control rate) was 71.4%. The mPFS of 1L maintenance therapy was 4.0 months (95%CI: 2.0-5.6). The mPFS from 1L treatment to disease progression was 8.7 months. mOS was not reached, with 3 mo- , 6 mo- and 9 mo- OS rate was 100%, 94.4% and 75.6%, respectively. 21 (100%) pts experienced treatment-emergent adverse events (TEAEs), and 8 (38.1%) pts experienced grade ≥3 TEAEs, most commonly with platelet count decreased, neutrophil count decreased and pneumonia. There was no treatment-related death. Conclusions: Surufatinib combined with PD-1/L1 inhibitors showed encouraging efficacy and tolerable safety profile as 1L maintenance therapy. Further OS follow-up is warranted. Clinical trial information: NCT05509699 .

Phase II clinical trial of camrelizumab combined with famitinib for advanced acral and mucosal melanoma.

9550 Background: Acral and mucosal melanoma were rarely seen in Caucasians but common in Asians. Previous studies revealed that acral and mucosal melanoma are more aggressive than cutaneous melanoma with a high unmet need for effective treatments. Camrelizumab plus anti-angiogenic agents have shown promising antitumor activity in previously untreated melanoma. Famitinib, a selective multiple-target tyrosine kinase inhibitor that exhibits both anti-angiogenesis and antiproliferative effects via targeting VEGFR-2, PDGFR, c-kit, FGFR and so on, combined with camrelizumab had been proven effective in multiple cancers. This study aimed to assess the antitumor activity and safety of camrelizumab plus famitinib in both immunotherapy naïve and experienced advanced mucosal or acral melanoma. Methods: This single-center, open-label phase II study recruited patients (pts) with advanced acral and mucosal melanoma. Pts who were immune checkpoint inhibitors (ICI) treatment naïve were in cohort 1, while pts experienced ICI in cohort 2. In both cohorts, pts received camrelizumab (200 mg i.v. q3w) and famitinib (20 mg po qd) until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per RECIST1.1. Secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. This analysis focused on cohort 2. Results: As of January 12, 2023, 18 pts (9 mucosal and 9 acral histology subtypes) were enrolled in cohort 2. The median age of all pts was 58 yrs (ranged 38-71 yrs); 9 pts (50.0%) were female; prevalence of mutations: BRAF (11.1%), C-KIT or NRAS (16.7% each); 38.9% received ≥2 prior treatments. All pts progressed after anti-PD-1/L1 monotherapy (27.8%) or combinational therapy (66.7%), except one progressed after 4-1BB mAb monotherapy. The combination drugs included anti-LAG-3/CTLA-4 antibodies (38.9%), oncolytic viruses (11.1%), c-kit inhibitors, chemotherapy and anti-angiogenic agents (5.6% each). The median follow-up was 7.3 months (ranged 4.6-14.7 months). At the data cutoff, 5 pts remained on treatment. 17 pts were evaluable. The ORR and DCR were 17.6% and 64.7%, including two pts with confirmed PR, and one with unconfirmed PR, all of which were acral subtype. The median PFS was 6.0 months. The median OS was not reached. Of 18 pts, the incidence of treatment-related adverse events (TRAEs) was 88.9%. The most common grade 3 TRAEs was neutrophil count decreased (11.1%). No grade 4 TRAEs and no treatment-related deaths occurred. Conclusions: Camrelizumab plus famitinib showed promising antitumor activity in ICI-experienced advanced acral and mucosal melanoma pts, and was generally well tolerated. Clinical trial information: NCT05051865 .

Sclerosing mesenteritis following immune checkpoint inhibitor therapy.

Sclerosing mesenteritis (SM), a fibroinflammatory process of the mesentery, can rarely occur after immune checkpoint inhibitor (ICI) therapy; however, its clinical significance and optimal management are unclear. We aimed to assess the characteristics and disease course of patients who developed SM following ICI therapy at a single tertiary cancer center. We retrospectively identified 12 eligible adult cancer patients between 05/2011 and 05/2022. Patients' clinical data were evaluated and summarized. The median patient age was 71.5years. The most common cancer types were gastrointestinal, hematologic, and skin. Eight patients (67%) received anti-PD-1/L1 monotherapy, 2 (17%) received anti-CTLA-4 monotherapy, and 2 (17%) received combination therapy. SM occurred after a median duration of 8.6months from the first ICI dose. Most patients (75%) were asymptomatic on diagnosis. Three patients (25%) reported abdominal pain, nausea, and fever and received inpatient care and corticosteroid treatment with symptom resolution. No patients experienced SM recurrence after the completion of corticosteroids. Seven patients (58%) experienced resolution of SM on imaging. Seven patients (58%) resumed ICI therapy after the diagnosis of SM. SM represents an immune-related adverse event that may occur after initiation of ICI therapy. The clinical significance and optimal management of SM following ICI therapy remains uncertain. While most cases were asymptomatic and did not require active management or ICI termination, medical intervention was needed in select symptomatic cases. Further large-scale studies are needed to clarify the association of SM with ICI therapy.

Antibiotic Treatment is an Independent Poor Risk Factor in NSCLC But Not in Melanoma Patients Who had Received Anti-PD-1/L1 Monotherapy

BackgroundAntibiotic treatment may reduce the efficacy of cancer immunotherapy by disrupting gut microbiome. We aimed to study the association of antibiotics and survival outcomes in advanced cutaneous melanoma and non–small-cell lung cancer (NSCLC) patients who had received anti-PD-1/L1 monotherapy. Patients and MethodsA total of 222 melanoma and 199 NSCLC patients had received anti-PD-1/L1 monotherapy in 5 Finnish hospitals between January 2014 and December 2020. Clinical characteristics, antibiotic and corticosteroid treatment, and survival outcomes were retrospectively collected from hospital and national medical records. ResultsThere were 32% of melanoma and 31% of NSCLC patients who had received antibiotic treatment (ABT) 3 months before to 1 month after the first anti-PD-1/L1 antibody infusion. In survival analyses, early antibiotic treatment was associated with inferior overall survival (OS) (ABT 19.2 [17.6-43.7] vs. no ABT 35.6 [29.3-NA] months, P = .033) but not with inferior progression-free survival (PFS) (ABT 5.8 [3.0-12.6] vs. no ABT 10.2 [7.7-15.3] months, P = .3) in melanoma patients and with inferior OS (ABT 8.6 [6.4-12.3] vs. no ABT 18.5 [15.1-21.6] months, P < .001) and PFS (ABT 2.8 [2.1-4.5] vs. no ABT 5.6 [4.4-8.0] months, P = .0081) in NSCLC patients. In multivariable analyses, ABT was not an independent risk-factor for inferior OS and PFS in melanoma but was associated with inferior OS (hazard ratio [HR] 2.12 [1.37-3.28]) and PFS (HR 1.65 [1.10-2.47]) in NSCLC after adjusted for other risk factors. ConclusionsEarly ABT was an independent poor risk factor in NSCLC patients who had received anti-PD-1/L1 monotherapy but not in melanoma patients. The weight of ABT as a poor risk factor might depend on other prognostic factors in different cancers.

Efficacy and predictive biomarkers of immunotherapy in Epstein-Barr virus-associated gastric cancer

BackgroundEpstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is a distinct molecular subtype of GC with a favorable prognosis. However, the exact effects and potential mechanisms of EBV infection on immune...

Clinical Characteristics and Outcomes of Oral Mucositis Associated With Immune Checkpoint Inhibitors in Patients With Cancer.

Immune checkpoint inhibitor (ICI) therapy predisposes patients to immune-related adverse events (irAEs). Data are limited regarding the incidence, management, and outcomes of one such irAE: mucositis. In this study, we evaluated the clinical characteristics, disease course, treatment, and outcomes of ICI-mediated mucositis. This was a retrospective, single-center study of patients who received ICI therapy and developed oral mucositis at The University of Texas MD Anderson Cancer Center from January 2009 to September 2019. Inclusion criteria included age ≥18 years, a diagnosis of oral mucositis and/or stomatitis based on ICD-9 and ICD-10 codes, and therapy using CTLA-4 or PD-1/L1 inhibitors alone or combined with other agents. We identified 152 patients with a mean age of 60 years, 51% of whom were men. Of the sample patients, 73% had stage IV cancer, with melanoma the most common (28%). Median time from ICI initiation to mucositis was 91 days. The most common clinical presentation of mucositis was odynophagia and/or oral pain (89%), 91% developed CTCAE grade 1-2 mucositis, and 78% received anti-PD-1/L1 monotherapy. Compared with anti-PD-1/L1-based therapy, anti-CTLA-4-based therapy was more frequently associated with earlier onset of mucositis (73 vs 96 days; P=.077) and a lower rate of symptom resolution (76% vs 92%; P=.029); 24% of patients required immunosuppressive therapy, which was associated with longer symptom duration (84 vs 34 days; P=.002) and higher mucositis recurrence rate (61% vs 32%; P=.006). ICI interruption was associated with worse survival (P=.037). Mucositis recurrence, immunosuppressant use, and presence of other irAEs did not affect survival. For ICI-mediated mucositis, a diagnosis of exclusion has not been well recognized and is understudied. Although the clinical symptoms of mucositis are mostly mild, approximately 25% of patients require immunosuppression. Mucositis recurrence can occur in approximately 39% patients. Our results showed that ICI interruption compromises overall survival.

Immune checkpoint inhibitor-related thrombocytopenia: incidence, risk factors and effect on survival

IntroductionImmune checkpoint inhibitors (ICI) are associated with unique immune-related adverse events (irAEs). Immune-related thrombocytopenia (irTCP) is an understudied and poorly understood toxicity; little data are available regarding either risk of irTCP or the effect of irTCP on clinical outcomes of patients treated with ICI.MethodsWe conducted a retrospective review of sequential cancer patients treated with ICI between 2011 and 2017 at our institution. All patients who received ICI alone or in combination with other systemic therapy in any line of treatment were included; those with thrombocytopenia ≥ grade 3 at baseline were excluded. We calculated the incidence of ≥ grade 3 irTCP and overall survival (OS). Patient factors associated with irTCP were assessed.ResultsWe identified 1,038 patients that met eligibility criteria. Overall, 89 (8.6%) patients developed grade ≥ 3 thrombocytopenia; eighteen were attributed to ICI (1.73% overall). Patients who developed grade ≥ 3 irTCP had worse overall survival compared to those whose thrombocytopenia was unrelated to ICI (4.17 vs. 10.8 month; HR. 1.94, 95% CI 1.13, 3.33; log-rank p = 0.0164). Patients with grade ≥ 3 irTCP also had worse survival compared to those without thrombocytopenia (4.17 vs. 13.31 months; HR 2.22, 95% CI 1.36, 3.62; log-rank p = 0.001). The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy (p = 0.059) and was not associated with cancer type, smoking status, age, gender, race, or line of therapy.ConclusionsUnlike other irAEs, we found that irTCP was associated with worse overall survival. The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy.

S218 Characteristics, Treatment, and Outcome of Diverticulitis Related to Immune Checkpoint Inhibitors in Patients With Malignancies

Introduction: Immune checkpoint inhibitors (ICIs) are an efficacious treatment for various malignancies. In addition to immune related adverse events (irAEs), there is growing evidence that ICIs might induce colonic diverticulitis. The aim of this study was to assess the clinical spectrum and management of diverticulitis among cancer patients after ICI treatment. Methods: A retrospective chart review was conducted on cancer patients who were exposed to ICIs between January 2010 and June 2020. Patients were divided into two groups: those who developed diverticulitis after ICI treatment (cases) and those who had diverticulitis before ICI treatment (controls). Patient clinical characters, treatment, and outcomes were compared between the two groups. Results: Among 502 cancer patients with a diagnosis of diverticulitis in the study window, 77 eligible patients were included in our final analysis where-in: 63 patients with a diverticulitis event after ICI and 14 as controls with diverticulitis only before ICI. Among 63 cases after ICI exposure, 46 had an initial episode, and 17 had recurrent episodes from pre-ICI era. Diverticulitis occurred after a median of 129 days (range: 32-277) after ICI initiation with anti-PD1/L1 monotherapy more frequently (75%). Clinical characteristics overlapped with traditional acute diverticulitis, with 93% of patients achieving symptom resolution with oral antibiotics alone. Diverticulitis complication rate in this ICI cohort is higher than traditional diverticulitis (23.8% vs 12%). Those with complicated ICI related diverticulitis more frequently needed hospitalization (87% vs 48%, P=0.015) and surgery/interventional radiology procedures (27% vs 0%, P=0.002), and had worse overall survival (P=0.022). Regarding recurrence after the first diverticulitis episode post ICI therapy, history of diverticulitis does not appear to contribute to more severe disease course. Immunosuppressants (e.g., corticosteroids) were rarely required unless concurrent ICI colitis was identified. Conclusion: Diverticulitis appeared to be more frequent after ICI therapy, particularly anti-PD-1/L1 therapy. Clinical presentation, evaluation, and management is similar to traditional diverticulitis, although it has higher complication rates requiring surgical intervention and impairing overall survival.

Differential Dermatologic Adverse Events Associated With Checkpoint Inhibitor Monotherapy and Combination Therapy: A Meta-Analysis of Randomized Control Trials.

Background: As immune checkpoint inhibitors (ICIs) transition to the forefront of cancer treatment, a better understanding of immune related adverse events (IRAEs) is essential to promote safe clinical practice. Dermatologic adverse events are the most common IRAEs and can lead to drug withdrawal and decreased quality of life. This meta-analysis aimed to investigate the risk of the most prevalent dermatologic adverse events (pruritus and rash) among various ICI treatment regimens.Methods: A systematic search of electronic databases was performed to identify qualified randomized controlled trials (RCTs). Data for any grade and high grade pruritus and rash were extracted for meta-analysis. Two reviewers independently assessed methodological quality. The relative risk summary and 95% confidence interval were calculated.Results: 50 RCTs involving 29941 patients were analyzed. The risk of pruritus (2.15 and 4.21 relative risk respectively) and rash (1.61 and 3.89 relative risk respectively) developing from CTLA-4 or PD-1/-L1 inhibitor were increased compared to placebo, but this effect was not dose-dependent. PD-1/-L1 plus CTLA-4 inhibitor was associated with increased risk of pruritus (1.76 and 0.98 relative risk respectively) and rash (1.72 and 1.37 relative risk respectively) compared to either monotherapy. Compared with CTLA-4 inhibitor, PD-1/-L1 inhibitor had a significantly decreased risk of pruritus and rash in both monotherapy and combination therapy (0.65 and 0.29 relative risk respectively). No significant difference was found between PD-1/-L1 inhibitor combined with chemotherapy and PD-1/-L1 monotherapy in any grade and high grade rash (0.84 and 1.43 relative risk respectively). In subgroup analyses, PD-1 inhibitor was associated with reduced risk of pruritus and rash compared to PD-L1 inhibitor.Conclusion: Our meta-analysis demonstrates a better safety profile for PD-1/-L1 inhibitor compared to CTLA-4 inhibitor in terms of pruritus and rash among both monotherapy and multiple combination therapies. PD-L1 inhibitor may contribute to an increased risk of pruritus and rash compared to PD-1 inhibitor.

Abstract 383: Efficacy of immune checkpoint inhibitors in lung cancer patients with EGFR P719A mutation: A case report

Abstract Background: Results from previous studies indicated that lung cancer patients harboring EGFR sensitizing mutations may receive unfavorable outcomes from immunotherapy. The present study aims to investigate the efficacy of inhibitors of programmed cell death protein-1in lung cancer patients with driver oncogene EGFR P719A mutations and strong positive PD-L1 expression in one special case. Methods: Tissue samples were subjected to NGS in our College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for driver oncogene mutations and PD-L1 expression. Results: A 52-year-old male never-smoker who complained of a persistent cough was examined by computed tomography (CT), which revealed a 39 mm wide tumor in the upper region of the right lobe of the lung in May 2019. Tumor biopsy pathology revealed that the patient had a stage IIIB (T2N3M0) adenocarcinoma. NGS performed on a formalin-fixed, paraffin-embedded tumor specimen to identify genomic aberrations. The tumor was positive for EGFR, EGFR P719A mutation. The PD-L1 expression have been tested by FDA-approved 22C3 antibodies, and PD-L1 expression level of 95%. The patients received anti-PD-1 combination treatment. He has reached partial response (PR) after 4 cycle treatment. After ten months, he has the opportunity to receive the operation. The following anti-PD-1/L1 monotherapy is still ongoing until now. Conclusion: Our real-world study supported that NSCLC patients harboring sensitizing oncogenic mutations may potentially benefit from anti-PD-1/L1 especially for those with positive indicators of immunotherapy with strong positive PD-L1 expression. Citation Format: Fuyu Gong, Kai Zheng. Efficacy of immune checkpoint inhibitors in lung cancer patients with EGFR P719A mutation: A case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 383.

Association of Chronic Immune-Mediated Diarrhea and Colitis With Favorable Cancer Response.

Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes. We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis. In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018). Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.

Using the tumor microenvironment to identify predictors of immunotoxicity to checkpoint inhibitors.

2545 Background: While Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, the benefits have come at the cost of serious side effects known as immune-related adverse events (irAEs). Approaches that can predict patients’ susceptibility to irAEs are key to their early detection and management. In the present study, we investigate the association between irAEs reported during ICI therapy across multiple cancer types and markers of tumor immune response. Our primary objective is to explore potential biomarkers for assessing patients’ risk of irAEs. Methods: 472 patients were evaluated who had tumor immune profiling performed paraffin embedded formalin fixed archival tumor biopsy samples using Omniseq Immune Report Card (IRC) and subsequently underwent ICI therapy. The IRC consisted of enumeration of tumor infiltrating lymphocytes (TILs) by immunohistochemistry (IHC) and TIL-associated genes by RNA-Seq, PD-L1 expression by IHC, and tumor mutational burden (TMB) by DNA-Seq. irAE type and grade were determined based on retrospective chart review. Fisher’s exact test was used to determined statistically significant associations between immune markers and irAE development. Results: Patients with lung (55%), ovarian (9%), and melanoma (5%) cancers constituted the majority of the cases. The median age of patients was 61, with 56% being female and 44% male. Most patients underwent treatment with (94%). irAEs developed in 36% of patients, with 2% of patients developing high-grade irAEs (Grade 3 or 4). Skin (11%), thyroid (10%), and GI (9%), were the most commonly affected organ systems. Increased TILs were associated with increased risk for any irAE (p = 0.04). A stronger association was noted in patients who underwent anti-PD-1/L1 monotherapy (p = 0.01) and/or in cases of lung cancer (p = 0.01). Interestingly, subanalyses by gender showed a statistically significant correlation between increased TILs and risk for any irAE in males (p = 0.006) but not in females (p = 0.63). High PD-L1 (defined as &gt; 70% by IHC) was also significantly associated with increased risk for any irAE (p = 0.03). Subanalyses by gender and age again showed a similar association in females (p = 0.0002) and/or patients &lt; 65 years (p = 0.04). high TMB and any irAE in female patients (p = 0.01) and in breast cancer cases (p = 0.03). On multivariate analysis, TILs by IHC appeared to be the strongest predictor of irAEs (p = 0.03). Conclusions: The tumor immune microenvironment (TME) has been shown to influence response to ICI, yet its association with irAEs has not been well studied. Our analysis sheds light on potential TME predictors for irAE in patients receiving ICI therapy. Further studies are needed to deepen our understanding of immune toxicity and to develop tools for identifying patients who are at risk.

S0185 Chronic Immune-Mediated Diarrhea and Colitis Is Associated With Favorable Cancer Outcomes

INTRODUCTION: Background Immune-mediated diarrhea and colitis (IMDC) is the second most common immune-related adverse effect related to immune checkpoint inhibitor (ICI) therapy. In this study, we aimed to identify risk factors for chronic IMDC and the prognostic value of chronic IMDC in terms of cancer outcome. METHODS: We retrospectively reviewed the charts of all patients with an established diagnosis of IMDC over a study period from January, 2018, through October, 2019, and grouped them, based on duration of disease, into acute (≤3 months) and chronic ( >3 months) IMDC categories. Patient demographics, clinical variables, and overall survival (OS) data were collected. A logistic regression model was used to assess the factors associated with chronic IMDC. The Kaplan-Meier and log-rank tests were used to estimate and compare OS differences between the two groups. RESULTS: Our sample was comprised of 88 patients, with 43 in the chronic IMDC, and 45 in the acute IMDC group. Median age was 65.5 years at the time of IMDC. Genitourinary cancer and melanoma accounted for 70% of malignancies in our cohort. PD-1/L1 monotherapy (52%) was more frequently used than CTLA-4 monotherapy (17%) or combination therapy (31%). Our analysis demonstrated that chronic IMDC was associated with PPI use (OR = 3.96, P = 0.026), long duration of IMDC symptoms (OR = 1.05, P < 0.001) and hospitalization (OR = 1.065, P = 0.043), histological feature of chronic active colitis (OR = 4.8, P = 0.025) or microscopic colitis (OR = 5.0, P = 0.045) and delayed introduction of SIT for IMDC (OR = 1.06, P = 0.047). Our results also demonstrated that chronic IMDC reflected a better cancer response to ICIs (30% vs. 51%, P = 0.002) and is accompanied by improved OS (P = 0.035). Similarly, we observed that high doses of SIT were associated with better OS (P = 0.018). CONCLUSION: Chronic IMDC can develop among patients with more aggressive IMDC disease course and chronic features on colon histology. It likely reflects a prolonged ICI effect, therefore is associated with a better cancer outcome and overall survival. Optimization of IMDC treatment target should be considered to improve treatment outcome in the future.Figure 1Figure 2.: Kaplan-Meier OS curve, stratified by patient. (A) OS duration between the chronic IMDC (>3 months) and acute IMDC groups (≤3 months). (B) OS duration in cases with 1–2 doses of SIT (infliximab or vedolizumab) vs. ≥3 doses of SIT.Table 1

Systematic review with meta-analysis: effectiveness of anti-inflammatory therapy in immune checkpoint inhibitor-induced enterocolitis.

Immune checkpoint inhibitors have revolutionised cancer treatment, but at the cost of off-target immune-mediated organ damage. This includes checkpoint inhibitor-induced enterocolitis which frequently requires hospitalisation and may be life-threatening. Empiric treatment typically includes corticosteroids and infliximab, although no large-scale studies have confirmed their effectiveness. To investigate the effectiveness of anti-inflammatory therapy in checkpoint inhibitor-induced enterocolitis METHODS: We performed a systematic review and meta-analysis of studies reporting clinical outcomes of checkpoint inhibitor-induced enterocolitis in adult cancer patients treated with anti-inflammatory agents. We searched Medline, EMBASE, and the Cochrane library through April and extracted the proportion of patients responding to anti-inflammatory therapy. Variation in effect size was studied using a random-effects meta-regression analysis, with checkpoint inhibitor agent and tumour type as the variables. Data were pooled from 1210 treated patients across 39 studies. Corticosteroids were effective in 59% (95% CI 54- 65) of patients, with response significantly more favourable in patients treated with anti-PD-1/L1 monotherapy, compared with anti-CTLA-4 containing regimens (78%, 95% CI 69-85 vs 56 %, 95% CI 49-63, P = 0.003), and more favourable in lung cancer patients compared with melanoma patients (88%, 95% CI 62-97 vs 55%, 95% CI 47-63, P = 0.04). Infliximab was effective in 81% (95% CI 73-87) of patients, and vedolizumab in 85% (95% CI 60-96). Corticosteroids, infliximab and vedolizumab, are effective in the treatment of checkpoint inhibitor-induced enterocolitis. Checkpoint inhibitor regimen and cancer type were significant moderators in response to corticosteroid therapy.

Anti-PD-1/L1 plus anti-angiogenesis therapy as second-line or later treatment in advanced lung adenocarcinoma

Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting. Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models. Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1months vs. 2.0months (HR 0.551 [95% confidence interval 0.337-0.902], P = 0.002) and median overall survival (OS) was 14.3months vs. 8.4months (HR 0.549 [95% CI 0.305-0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298-0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group. Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings.

Abstract 5536: ICOS hi CD4 T cells emerging on vopratelimab treatment have Th1 central memory characteristics and may contribute to durability of clinical responses

Abstract Background: Inducible T cell Co-stimulator (ICOS) is a costimulatory molecule expressed primarily on T lymphocytes that is upregulated upon cell activation. Vopratelimab (vopra) is a novel ICOS agonist antibody whose primary mechanism of action is the stimulation of primed CD4 T effector cells. Clinical responses in the Phase 1/2 ICONIC trial (NCT02904226) were associated with the emergence of ICOS hi CD4 T cells. In a separate study of PD-1/L1 monotherapy, this phenotype was not observed, demonstrating ICOS hi CD4 T cell emergence in ICONIC was due to vopra. Ex vivo stimulation of antigen-primed ICOS hi CD4 T cells by soluble vopra demonstrated induction of a polyfunctional cytokine response. Previous studies have shown that sustained ICOS upregulation was associated with clinical benefit in subjects treated with anti-CTLA-4 inhibitors, with preclinical data confirming a role for ICOS signaling in optimal anti-tumor activity. Vopra is currently being tested as a sequenced combination with ipilimumab (ipi) in the Phase 2 EMERGE trial (NCT03989362). Methods: Assessment of phenotype and function of ICOS hi CD4 T cells was conducted using serial collections of peripheral blood mononuclear cells (PBMCs) from a subset of evaluable subjects in the ICONIC trial. A mouse syngeneic tumor model was developed to assess the kinetics of ICOS hi emergence as well as determine functionality and combination efficacy. Biological activity was assessed through ex vivo functional assays, with phenotypic assessments by flow cytometry-based profiling and genomic analysis. Results: Phenotypic profiling of ICOS hi CD4 T cells demonstrated a T central memory phenotype with Th1 characteristics, and ICOS hi CD4 T cells increased as a % of the CD4 compartment longitudinally. Potent effector molecules, including perforin and granzyme, were significantly upregulated in isolated ICOS hi CD4 T cells relative to ICOS lo CD4 T cells from subjects. In a syngeneic tumor-bearing mouse system, ICOS hi CD4 T cells were induced in lymphoid organs following ipi treatment, with emergence detectable at day 3 and peaking at day 7 post-treatment, where up to 40% of CD4 T cells were ICOS hi. Relative to monotherapy, enhanced anti-tumor efficacy was observed in mice treated with combination ICOS agonist and ipilimumab. Conclusion: Emergence of a peripheral ICOS hi CD4 T cell population correlates with response to vopra treatment and occurs independent of anti-PD-1 activity. Transcriptional profiling of ICOS hi CD4 T cells further defined the phenotype as Tcm cells that express cytotoxic effector molecules, which may contribute to observed clinical benefit. Treatment with ipi in combination with an ICOS agonist resulted in enhanced efficacy in mice, and follow-up studies exploring sequential dosing are ongoing. Citation Format: Amadna Hanson, Abha Daneshwar, Heather Cohen, Yasmin Hashambhoy-Ramsay, Kristin O'Malley, Krithi Bala, Lara McGrath, Kristen Leone, Courtney Hart, Rachel McComb, Johan Baeck, Ellen Hooper, Elizabeth Trehu, Haley Laken, Monica Gostissa, Christopher Harvey. ICOS hi CD4 T cells emerging on vopratelimab treatment have Th1 central memory characteristics and may contribute to durability of clinical responses [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5536.

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

SummaryImmune checkpoint inhibitors (ICIs) improve clinical outcomes in patients suffering from different types of cancer. Liver toxicity is one of the immune-related adverse events associated with immunotherapy; although not common, its management is challenging as it is extremely heterogeneous in terms of presentation and severity. Differences in the development and evolution of ICI-related toxicity in healthy or cirrhotic livers have not yet been elucidated. Assessing causality is key to diagnosing ICI-induced liver toxicity; liver biopsies can assist not only in the differential diagnosis but also in assessing the severity of histological liver damage. The current classification of severity overestimates the grade of liver injury and needs to be revised to reflect the views of hepatologists. Spontaneous improvements in ICI-related liver toxicity have been reported, so corticosteroid therapy should probably be individualised not systematic. The reintroduction of ICIs in a patient with previous immune-mediated hepatitis may be possible, but the risk/benefit ratio should be considered, as the risk factors for hepatitis recurrence are currently unclear. The management of these patients, requiring a balance between efficacy, toxicity and specific treatments, necessitates multidisciplinary collaboration. The incidence of immune-related liver toxicity will continue to rise based on the increasing use of ICIs for most cancers, mandating improved understanding and management of this complication.