Grade Immune-related Adverse Events Research Articles

Neoadjuvant immune checkpoint inhibitors for patients with resectable stage III/IV melanoma: A nationwide real-life study in France (NEOMEL).

9578 Background: Several studies have shown the efficacy of neoadjuvant treatment (NT) with immune checkpoint inhibitors (ICI) for resectable stage III/IV melanoma. However, real-life data are lacking. Methods: NEOMEL is a national multicenter retrospective study assessing the efficacy and tolerability of NT with ICI (NT-ICI) for resectable metastatic melanoma in a real-life setting. Data were obtained in patients (pts) with resectable stage III/IV melanoma who initiated NT-ICI (at least one infusion). Primary endpoint was pathologic complete response (pCR) (i.e no residual tumor) rate. Secondary endpoints were pathologic response (pR) according to INMC, radiologic response (RECIST), safety profile (CTCAE) and survival outcomes. Results: A total of 166 pts with resectable stage III/IV melanoma were included. Median age was 67 years (range, 24-96). Most pts had primary cutaneous melanoma (n=157, 89%), stage IIIB-D disease (n=156, 94%); a BRAF V600-mutant melanoma was observed in 47% (n=78); 8% (n=14) pts had received a previous systemic treatment. The median number of infusions of NT-ICI was 3 (range, 1-5). ICI regimens were anti-PD-1 monotherapy (n=122, 73%) or nivolumab + ipilimumab (NIVO + IPI) (n=44, 27%). Median follow-up was 6.5 months (range, 1-85). Overall, 143 pts (86%) underwent surgery. A pCR was observed in 44% of pts (n=63/143), including 52% (n=51/99) treated with anti-PD-1 monotherapy, and 27% (n=12/44) treated with NIVO + IPI. Of note, 78 pts (54%) were treated with 3 infusions of pembrolizumab (PBZ) (according to SWOG 1801 protocol) and had a pCR in 45% (n=35). A pR was assessed according to INMC criteria in 58% of pts (n=83/143): 51% of pCR (n=42), 8% of near-pCR (n=7) corresponding to a major pR of 59% (n=49/83), 16% of pathologic partial response (n=13) and 25% of pathologic non-response (n=21). Twenty-three pts (14%) did not undergo surgery because of progressive disease (n=10), clinical and radiologic responses (8 complete responses, 1 partial response, 1 stable disease), toxicity (n=2) or patient’s choice (n=1). Radiologic overall response rate according to RECIST (data available after NT in 49% of pts) was 54% (n = 44/82). All grade immune-related adverse events (irAEs) of NT-ICI occurred in 31% (n=51) of pts, including grade 3-4 irAEs in 10% (n=17) and one grade 5 irAE (pneumonitis with PBZ). Severe irAEs (grade 3 or more) were observed in 4% (n=4/99) of pts treated with anti-PD1 monotherapy and 32% (n=14/44) of pts treated with NIVO + IPI. Adjuvant treatment was started for 120 pts (84%). At last follow-up, 26 pts (18%) have had recurrence after surgery, including 3 pts with a pCR and 23 pts with a non-pCR to NT-ICI. Survival data are not yet available. Conclusions: NT-ICI for advanced melanoma demonstrated its efficacy with high rates of pCR in a real-life setting and an acceptable safety profile, particularly NT anti-PD1 monotherapy.

Tislelizumab plus sitravatinib as adjuvant therapy for patients with hepatocellular carcinoma at high risk of recurrence after surgical resection: Preliminary analysis of a multi-center, non-randomized, open-label phase 2 study.

e16239 Background: Adjuvant therapy has the potential to prevent or delay recurrence after curative-intent hepatectomy for hepatocellular carcinoma (HCC) patients. IMbrave 050 trial demonstrated improved recurrence-free survival (RFS) for HCC patients at high risk of recurrence when treated with atezolizumab plus bevacizumab, underscoring the promising potential of checkpoint inhibitor-based combination therapy as a strategy in the adjuvant setting. The aim of this study was to evaluate the efficacy and safety of tislelizumab (a PD-1 inhibitor) plus sitravatinib (a selective tyrosine kinase inhibitor) as adjuvant therapy in HCC patients at high risk of recurrence after curative-intent hepatectomy. Here, we reported the preliminary analysis results. Methods: HCC patients confirmed by histopathology or cytology, who had undergone a curative resection and with one or more of the high-risk factors for recurrence, including: a solitary tumor>5 cm, a solitary tumor>2cm and ≤5cm with microvascular invasion, or 2~3 lesions, were eligible. Enrolled patients received tislelizumab (200mg, IV, Q3W) and sitravatinib (100mg, PO, QD), with a maximum treatment duration of one year. The primary endpoint was 2-year RFS rate. Secondary endpoints include RFS, time to recurrence, overall survival (OS), 1-year RFS rate, 1-year and 2-year OS rate, and safety. Results: A total of 22 patients were enrolled, with hepatitis B being the most common (86.4%) etiology, and 36.4% with microvascular invasion. Most patients were at BCLC stage A (86.4%), while stage 0 and stage B accounted for 4.5 and 9.1%, respectively. Till the data cut-off date on Nov. 30th, 2023, the median follow-up duration was 6.0 months (range 0.7-16.2); 2 patients relapsed and 1 patient died. The 1-year RFS rate was 81.3% and the longest RFS (censored) was over 12.5 months. Safety profile indicated that 21 patients (95.5%) experienced treatment-related adverse events (TRAEs), and 8 (36.4%) experienced grade ≥3 TRAEs. Most common (≥10%) grade ≥3 TRAEs were hypertension (13.6%) and palmar-plantar erythrodysesthesia (13.6%). Any grade immune-related adverse events (irAEs) were observed in 12 patients (54.5%) and 3 (13.6%) experienced grade ≥ 3 irAEs. AE leading to tislelizumab delay was observed in 2 patients (9.1%) and sitravatinb delay in 16 patients (72.7%). Dose reduction of sitravatinib occurred in 81.8% of patients due to AE. One patient died due to treatment-related pulmonary infection and biliary fistula. Conclusions: For patients with HCC at high risk of recurrence after curative-intent resection, tislelizumab plus sitravatinib showed preliminarily positive signal in controlling recurrence and had managable safety profile as adjuvant therapy. Further follow-up is needed to validate these findings with more mature data. Clinical trial information: NCT05407519 .

Efficacy of immune checkpoint inhibitors in patients with HIV-associated unresectable HCC (uHCC): Propensity-score matched analyses from two international consortia.

442 Background: HIV-associated HCC is an incompletely characterized disease with poor prognosis. People living with HIV (PWH) are commonly excluded from clinical trials, leading to a paucity of high-level evidence for optimal management. Whether ICIs are tolerated and effective in HIV-associated uHCC remains unclear. Methods: Using data from the CATCH-IT consortium and from a global dataset recruiting patients with HCC from 14 centers in 3 continents, we selected patients with HIV-associated uHCC treated with ICIs and compared their outcomes with a matched cohort of HIV negative (HIV-) patients. Primary endpoints were overall (OS) and progression-free survival (PFS). Propensity score matching (PSM) between the two groups was performed for the following variables: age, sex, HCC aetiology, Child-Pugh class (CP-C), ECOG-PS, BCLC stage, alpha-fetoprotein (AFP) levels, treatment line, portal vein tumor thrombosis (PVTT), and extrahepatic spread (EHS). Restricted mean survival time (RMST) difference analyses stratified by HIV status were performed for OS and PFS at 3, 6 and 9 months. Results: We accrued 46 PWH and 400 HIV-, treated mostly in the first-line setting (58.7% vs. 43.7%) with either atezolizumab plus bevacizumab (28.3% vs 17.5%) or anti-PD-1 monotherapy. Median age at ICI start was 62 (38-76) and 64 (18-87); viral hepatitis (HCV: 58.7%; HBV: 34.8%) were the prevalent aetiologies in PWH, non-viral (46%) was the most common in HIV-; most patients had BCLC-C HCC (84.8% and 82.3%). In PWH, median CD4 count was 345 cells/mm3 (IQR: 200-465); viral load was undetectable in 45 patients, all were established on combined anti-retroviral therapy. Following PSM, 44 PWH and 117 HIV- were included. Median OS was 7.5 months (95%CI: 5.2-NR) in PWH and 10.8 months (95%CI: 7.3-19.5) in HIV- (HR: 0.89; 95%CI: 0.56-1.42; p=0.58). Presence of PVTT, AFP>400 ng/mL, and ECOG-PS=1 but not HIV status were associated with worse OS in uni- and multivariable models. Median PFS was 2.8 months (95%CI: 2.6-4.8) for PWH vs 3.0 months (95%CI: 2.4-5.3) for HIV- (HR: 0.83-95%CI:0.56-1.24 ;p=0.38); HIV status was not associated with worse PFS. RMST confirmed no OS or PFS differences based on HIV status. In matched cohorts, neither ORR (21% vs. 19.1%, p=0.97) nor DCR (44.7% vs. 55.4%, p=0.19) were associated with HIV status. All grade immune-related adverse events (irAEs) were more frequent in HIV (44.0% vs 21.7%, p=0.003), with similar incidence of grade ≥3 irAEs (22.2% vs 13.0%). PWH had lower incidence of dermatological toxicities (4.3% vs 22%, p=0.003) and a trend towards lower incidence of hepatotoxicity (6.5% vs 18%, p=0.059). Conclusions: This study provides practice-informing evidence to support the use of ICIs in PWH and uHCC. Our findings encourage the inclusion of patients with well-controlled HIV in prospective clinical trials.

Safety of immune checkpoint inhibitors after proton beam therapy in head and neck mucosal melanoma: a case series.

Proton beam therapy (PBT) has shown promising efficacy in treating locally advanced head and neck mucosal melanoma despite its poor prognosis. Although PBT may improve the efficacy of subsequent immune checkpoint inhibitors (ICIs), the safety of ICIs in patients who have previously received PBT has not been established. Hence, this study evaluated the safety of ICIs in patients who had recurrent mucosal melanoma after PBT. Between April 2013 and June 2022, we retrospectively reviewed the medical records of patients diagnosed with cutaneous or mucosal melanoma at the National Cancer Center Hospital East. Seven patients were treated with ICIs after their head and neck mucosal melanoma (HNMM) recurred after PBT. Four of the seven patients experienced grade immune-related adverse events (irAEs). Due to irAE in the irradiation field, two patients had grade 3 hypopituitarism. Other grade 3 or higher irAEs included an increase in serum alanine aminotransferase in two patients and gastritis in one, and two patients discontinued ICI due to the irAEs. All irAEs were resolved with appropriate management. Although administering ICIs after PBT may increase the risk of irAEs, especially in the irradiation field, they appear manageable. These findings could help in the development of a treatment strategy for locally advanced HNMM that includes PBT and subsequent ICIs.

Results of MOLTO, a multicenter, open label, phase II clinical trial evaluating venetoclax, atezolizumab and obinutuzumab combination in Richter syndrome.

7502 Background: Chemoimmunotherapy is the standard first line of patients (pts) with diffuse large B-cell lymphoma (DLBCL) variant of Richter syndrome (RS). Response rate and duration are unsatisfactory. The biology of RS (high rate of DNA damage response pathway defects, high tumor mutation burden coupled with the expression of the PD1/PDL1 axis) prompts investigation of non-chemo combinations leveraging agents that circumvent TP53 abnormalities and trigger anti tumor immune response. MOLTO is a multicenter international ph 2 study (NCT04082897) evaluating activity and safety of atezolizumab (humanized monoclonal antibody blocking PD-L1), venetoclax (BCL2 inhibitor) and obinutuzumab (anti-CD20 MoAb) combination in untreated DLBCL-RS. Methods: Treatment consisted of 35 cycles with obinutuzumab (1000 mg C1-8), atezolizumab (1200 mg C1-18) and venetoclax (400 mg/d C1-35), q21. Primary endpoint was ORR ≥67% at C6. RS diagnosis was centrally revised. RS mutation profile was tested on pre-treatment cell free DNA. Minimal residual disease (MRD) was tested by 12 colors flow cytometry and NGS on peripheral blood mononuclear cells and plasma. Results: 28 planned pts were enrolled from Oct 2019 to Oct 2022 (Table). Three were not evaluable for primary endpoint due to G5 infection (n=1) or early withdrawn (n=2). As per intention-to-treat ORR was 67.9% (19/28) thus meeting primary endpoint. CR rate was 28.6%. No clinical characteristics influenced C6-ORR. After a median follow-up of 11.6 mo, 11/19 pts (57.9%) are in continuous remission (8 on active therapy, 2 received allogenic transplant, 1 discontinued due to MDS) among them, 6 for ≥24 mo. Of the remaining 8 pts, 7 progressed after a median of 14 cycles, 1 died from sepsis at C9 in remission. Median duration of response, PFS and OS were 11.7, 16.2 and 31.6 mo, respectively. Out of the 13 patients who progressed, 4 received a salvage therapy and are alive at a median follow-up of 24.3 mo. Bulky disease and ECOG PS >1 affected PFS. Rate of unmeasurable MRD, impact of mutations and chronic lymphocytic leukemia-RS clonal relation on outcomes will be presented at the meeting. Overall 43 G3-4 adverse events (AE) were recorded in 17 pts (60.7%), mostly hematological (51.2%). Any grade immune-related AEs were reported in 6 pts (G3-4 in 2), none led to discontinuation. No tumor lysis syndrome observed. Infections ≥G3 occurred in 6 pts, including 2 G5. One pt developed MDS. Conclusions: Atezolizumab, obinutuzumab and venetoclax combination is active in pts with untreated DLBCL-RS. This regimen led to durable remissions, longer than 2 yrs in one third of responders. Clinical trial information: NCT04082897 . [Table: see text]

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

Introduction: Chemoimmunotherapy is the standard first line treatment of diffuse large B-cell lymphoma (DLBCL) variant of Richter syndrome (RS). However, response rate and duration are unsatisfactory. The biology of RS (high rate of DNA damage response pathway defects, high tumor mutation burden coupled with the expression of the PD1/PDL1 axis) prompts investigation of non-chemo combinations leveraging agents that circumvent TP53 abnormalities and trigger anti-tumor immune response. MOLTO is a multicenter international phase 2 study (NCT04082897) evaluating activity and safety of atezolizumab (humanized monoclonal antibody blocking PD-L1), venetoclax (BCL2 inhibitor) and obinutuzumab (anti-CD20 MoAb) combination in untreated DLBCL-RS. Methods: Treatment consisted of 35 q21 cycles with obinutuzumab (1000 mg C1–8), atezolizumab (1200 mg C1–18) and venetoclax (400 mg/d C1–35). Primary endpoint was ORR ≥67% at C6. RS diagnosis was centrally revised. RS mutation profile was tested on pre-treatment cell free DNA. Minimal residual disease (MRD) was tested by 8 colors flow cytometry and NGS on peripheral blood mononuclear cells and plasma. Results: Overall 28 planned pts were enrolled from October 2019 to October 2022 (Table 1). Three were not evaluable for primary endpoint due to G5 infection (n = 1) or early withdrawn (n = 2). As per intention-to-treatment ORR was 67.9% (19/28) thus meeting primary endpoint. CR rate was 28.6% (8/28). No clinical characteristics influenced ORR at C6. After a median follow-up of 11.6 months, 11/19 pts (57.9%) are in continuous remission (8 on active therapy, 2 received allogenic transplant, 1 discontinued due to MDS), among them 6 for ≥24 months. Of the remaining 8 pts, 7 progressed after a median of 14 cycles, 1 died from sepsis at C9 in remission. Median duration of response was 11.7 months, median PFS was 16.2 months and median OS 31.6 months. Out of the 13 pts who progressed, 4 received a salvage therapy and are alive at a median follow-up of 24.3 months. Bulky disease and ECOG PS >1 affected PFS. Rate of unmeasurable MRD and impact of mutations and chronic lymphocytic leukemia-RS clonal relation on outcomes will be presented at the meeting. A total of 43 G3–4 adverse events (AE) occurred in 17 pts (60.7%), mostly hematological (51.2%). Any grade immune-related AEs was reported in 6 pts (G3–4 in 2), none led to discontinuation. No tumor lysis was observed. Infections ≥G3 occurred in 6 pts, including 2 G5. One pt developed MDS. Conclusions: Atezolizumab, obinutuzumab and venetoclax combination is active in pts with untreated DLBCL-RS. This regimen led to durable remissions, longer than 2 years in one third of responders. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Roche Keywords: combination therapies, immunotherapy, molecular targeted therapies Conflicts of interests pertinent to the abstract A. M. Frustaci Other remuneration: Abbvie, AstraZeneca, Janssen, Beigene; advisory boards, travel grants, speaker invitations

Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium.

Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS. Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Predicting immune-related adverse events using a simplified frailty score in cancer patients treated with checkpoint inhibitors: A retrospective cohort study.

Checkpoint inhibitors (CPIs) are in widespread clinical use. Little is known about which patients are at risk for developing toxicity. It is essential being able to identify patients with higher risk of experiencing immune-related adverse events (IRAEs) before initiation of CPI treatment to optimize treatment decisions and follow-up strategy. The aim of this study was to investigate whether a simplified frailty score based on performance status (PS), age, and comorbidity expressed as Charlson comorbidity index (CCI) could predict development of IRAEs. We performed a retrospective cohort study at three Swedish centers. All patients (n = 596) treated with PD-L1 or PD-1 inhibitor for advanced cancer between January 2017 and December 2021 were included. In total, 361 patients (60.6%) were classified as nonfrail and 235 (39.4%) as frail. The most common cancer type was non-small cell lung cancer (n = 203; 34.1%) followed by malignant melanoma (n = 195; 32.7%). Any grade of IRAE occurred in 138 (58.7%) frail and in 155 (42.9%) non-frail patients (OR: 1.58; 95% CI: 1.09-2.28). Age, CCI, and PS did not independently predict the occurrence of IRAEs. Multiple IRAEs occurred in 53 (22.6%) frail and in 45 (12.5%) nonfrail patients (OR: 1.62; 95% CI: 1.00-2.64). In conclusion, the simplified frailty score predicted all grade IRAEs and multiple IRAEs in multivariate analyses whereas age, CCI, or PS did not separately predict development of IRAEs suggesting that this easy-to-use score may be of value in clinical decision making but a large prospective study is needed to assess its true value.

A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC

IntroductionAlthough immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC. MethodsThis is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)–resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI. ResultsRecruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15–1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events. ConclusionsImmune checkpoint inhibition is ineffective in EGFR TKI–resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.

130P Autoantibodies as potential biomarkers of high grade immune-related adverse events (irAEs) in metastatic melanoma patients treated with check point inhibitors (ICIs)

The majority of patients treated with ICIs develop irAEs. It is currently not possible to predict the development of irAEs using biomarkers. Here we evaluated the IgG autoantibodies (AAbs) profiles in pre-treatment sera of metastatic melanoma patients treated with ICIs to identify AAbs that are associated with high-grade irAEs.

Factors associated with immunotherapy respond and survival in advanced non-small cell lung cancer patients

ObjectivesThis study aimed to explore factors associated with immunotherapy respond and survival in advanced non-small cell lung cancer (aNSCLC) patients treated with immune checkpoint inhibitors (ICIs). MethodsA total of 101 patients with aNSCLC receiving ICIs were included. The association between clinical factors and multiple endpoints including objective response rate (ORR), disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) were investigated by multivariate analyses. ResultsMultivariate logistic analyses revealed that clinical stage, lactate dehydrogena (LDH), and any grade immune-related adverse events (irAEs) were independent predictors of ORR, while LDH and ICIs treatment type were independent predictors of DCR. In Multivariate Cox analysis, Eastern Cooperative Oncology Group performance status (ECOG PS), LDH, albumin (Alb), platelet to lymphocyte ratio (PLR), and any grade irAEs were independent factors for OS. Similarly, clinical stage, LDH, Alb, and any grade irAEs were independent factors for PFS. Pre-treatment prognostic score was established based on clinical stage, ECOG PS, LDH, Alb and PLR to classify patients into three groups: the good group (0–1 score), the intermediate group (2 scores) and the poor group (3-4 scores). The immunotherapy response was significantly different in various prognostic groups. Subset analyses showed pre-treatment prognostic score ≥ 3 tended to have a strong negative impact on survival among patients with programmed cell death-ligand 1 (PD-L1) expression ≥ 50%. ConclusionsPre-treatment prognostic score based on clinical stage, ECOG PS, LDH, Alb and PLR may help to identify aNSCLC patients who may benefit from ICIs.

Risk factors for immune-related adverse events from anti-PD-1 or anti-PD-L1 treatment in an Asian cohort of nonsmall cell lung cancer patients.

Immune-related adverse events (IrAEs) of immune checkpoint inhibitors (ICIs) can be serious and unpredictable. We examine the incidence rate and risk factors for IrAEs in an Asian cohort of nonsmall cell lung cancer (NSCLC) patients treated with immunotherapy. Between June 2014 and August 2020, we retrospectively analysed IrAEs in NSCLC patients treated with anti-PD-1 or anti-PD-L1 inhibitors at the National University Cancer Institute, Singapore. A Poisson regression model was used to estimate the effect of risk factors on incidence rate of any grade IrAEs. One hundred and forty-one patients were enrolled. Median age was 63. Majority were male (67%) with Eastern Cooperative Oncology Group (ECOG) PS 0-1 (77%). More than half (56%) received pembrolizumab. Eleven percent harboured epidermal growth factor receptor (EGFR) mutation. Eighteen percent received concomitant chemotherapy. Median number of cycles was 4, and median duration of treatment was 2.1months. IrAEs were seen in 71 (50.4%) patients, with an incidence rate of 99 events per 1000 person-months. Fatigue (25%), rash (10.5%) and pneumonitis (7.9%) were the most common IrAEs. Twenty out of 152 IrAEs (13.2%) were Grade 3 or higher in severity: most common being pneumonitis (5.3%), fatigue (3.3%) and transaminitis (1.3%). Multivariable analysis demonstrated that concomitant chemotherapy use, higher BMI and presence of EGFR mutation are significant predictors for IrAEs (P < .0001; P=.016; P=.007). Our findings can help guide risk stratification and monitoring of IrAEs among NSCLC patients on immunotherapy.

Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases.

Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described. We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan-Meier and Cox proportional hazard analyses were performed. A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 vs. 10months, p = 0.004), systemic TTF (15 vs. 4months, p < 0.001) and intracranial TTF (14 vs. 5months, p = 0.001), relative to patients without IRAEs. Presence of IRAEs and high PD-L1 (≥ 50%), but not absent/moderate PD-L1 (0-49%), had a positive association for OS, systemic TTF, and intracranial TTF. Following multivariable analysis, IRAE experienced on pembrolizumab was an independent predictor of OS, systemic TTF, and intracranial TTF. In our series of patients with NSCLC and brain metastases treated with pembrolizumab, IRAE presence was associated with a significant increase in OS, systemic TTF, and intracranial TTF. Future studies with increased cohorts will clarify how IRAEs should be interpreted among molecular subtypes.

Effect of performance status on survival with pembrolizumab monotherapy in advanced non-small cell lung cancer (NSCLC).

9533 Background: Pembrolizumab (P) is now widely used as standard of care (SOC) in advanced NSCLC. We sought to identify prognostic factors influencing survival with it in a real-world setting. Methods: We conducted a retrospective cohort study of with advanced NSCLC patients who initiated treatment with SOC P monotherapy at our center from 2/11/16 to 10/15/19 (data cutoff 1/15/20). Patient demographic, clinicopathologic, therapeutic and outcomes data were extracted. Survival time was defined from start of P. Cox proportional hazards and logistic regression were utilized. Results: Of 74 patients with median follow up of 83.9 weeks, 30 (40.5%) were alive at cutoff. Patient characteristics at start of therapy were: 36 (48.6%) female, median age 68.5 yr (range 33-87), 10 (13.5%) with symptomatic brain metastases; 54 (72.9%) treatment-naïve, 29 (39.2%) with ECOG performance status (PS) ≥2. Tumor characteristics were: 53 (71.6%) with PD-L1 tumor proportion score (TPS) ≥50%, median PD-L1 TPS 75% (range 1-100), tumor mutational burden (TMB) tested in only 37 (50%) patients, median TMB 8 mut/mB (range 1-62). Any grade immune-related adverse events (irAE) occurred in 33 (44.6%) patients, while 16 (21.6%) received systemic steroids. Median survival was 43.3 wks (95% CI 29-104.1). Multivariable regression showed ECOG PS of ≥2 as the strongest risk factor for death (Table). We next evaluated differences in characteristics of patients who were alive vs dead within 12 wks of starting P, by which initial response assessments are completed in routine practice. ECOG PS was the only significantly different baseline variable, even after multivariable adjustment (p = 0.002). Conclusions: ECOG PS of ≥2 is a poor prognostic risk factor associated with P monotherapy in advanced NSCLC. Though comprising a clinically significant subset of patients in real-world, they were not included in landmark trials (KEYNOTE-024 &amp; 042). Prospective evaluation is warranted. [Table: see text]

Assessing the effect of immunosuppressive agents for immune-related adverse event management on tumor response.

3066 Background: High grade immune-related adverse events (irAEs) to cancer immune checkpoint inhibitors (ICI) require considerable immunosuppression (IS) with high-dose steroids and steroid-sparing IS (SSIS) for steroid-dependent cases. T lymphocyte-specific IS has generally been avoided or used with significant caution due to the fear that these agents may negatively impact ICI efficacy. We sought to determine whether T cell-specific IS agents, such as calcineurin inhibitors (CNIs), have an adverse effect on tumor control when compared to other immunomodulatory drugs (IMDs). Methods: We retrospectively analyzed clinical annotations of adult patients treated with ICIs for malignancy from 1/1/2000-12/31/2019, highlighting patients who were managed with SSIS, specifically those most commonly used for autoimmune disease therapy. Topical IS use was excluded. Patients were categorized as tumor responders or non-responders, and irAEs were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Progression-free survival (PFS) was assessed via Kaplan-Meier curve. Results: 1331 unique individuals were prescribed ≥1 ICIs, with 526 prescribed systemic steroids (39.5%) and 90 (6.8%) patients prescribed SSIS agents, 25 patients with &gt;1 SSIS: mycophenolate (39), methotrexate (26), leflunomide (5), azathioprine (3), rituximab (24), tocilizumab (3), infliximab (8), etanercept (1), adalimumab (1), golimumab (1) and CNIs (18): cyclosporine, tacrolimus. IMDs hydroxychloroquine (6) and sulfasalazine (5) were also prescribed. The objective response rate was 50.0% in the CNI group compared to 45.5% in the IMD cohort and 45.4% in the irAE group (CTCAE grade matched) with steroids alone without any SSIS. Median PFS were compared between CNI cohort (5.4 months, range 1.3-34 months) to IMD (1.1 months, range 0.4-6.4, p=0.02) and steroid alone (2.4 months, range 0.69-17.7, p=0.48). Multiple regression analysis identified irAE presence as an independent correlates to tumor response (p=0.02). Conclusions: T cell-specific IS should not be excluded from irAE treatment algorithm as we observed that PFS was comparable to immunomodulators and similar efficacy was observed compared to steroids alone. Rapid identification and management of irAEs can help mitigate morbidity but there are virtually no reliable clinical trials to guide irAE management with SSIS. These findings support the need for larger, prospective evaluation of immunosuppression use for high grade irAE therapy.

Multidisciplinary team management for high grade immune-related adverse events (irAEs): A single center experience.

e15076 Background: Immune checkpoint inhibitors (ICIs) are increasingly used in the management of cancer. High grade irAEs are uncommon but can be severe and require hospital admission. There is an urgent need for early identification and triage of patients with irAEs in order to improve their management and outcomes. Methods: We established Immunotherapy toxicity (ITOX) team as the first in nation inpatient service at DFCI and Brigham and Women's Hospital (BWH) along with our partners at Massachusetts General Hospital (MGH) that is specifically devoted to mitigating irAEs. The ITOX service is consistent of 2 PAs and a medical oncology attending with an expertise in immunotherapy. The service utilizes algorithms that are modified from the ASCO and NCCN guidelines by our medical subspecialty experts at BWH. The service uses a multi-disciplinary approach with around the hour consulting service from experts in the field including GI, pulmonary, endocrinology and others. We leveraged EPIC to triage patients who are admitted to BWH and have ever received or currently on immune checkpoint inhibitors (ICIs). The daily list generated by EPIC is then curated manually by a PA to identify patients with potential irAEs. Results: A total of 138 patients with high grade irAEs were admitted to BWH between June 2018 and June 2019. Seventy percent of the 201 irAEs- related admissions were to ITOX service (70% accuracy in triaging). Most common irAEs was colitis (31%), pneumonitis (28%) and hepatitis (13%) which is consistent with the most common reported irAEs due to ICIs. Eighty five percent of the patients had grade 3 irAEs and 15% were admitted with life threatening grade 4 adverse events. About half of the patient had received ICI monotherapy; 33% received combination of ICI and non-ICI (chemotherapy or targeted therapy) and 17% received combination of ICIs. Most patients responded to steroids and only 9% had steroid-refractory irAEs requiring other immunosuppressive agents. The average length of stay for irAEs-related admission was 11 days with readmission rate of 26% within a year. Over 50 patients consented for tissue and blood biospecimen collection at the time of toxicity. Conclusions: We demonstrated the feasibility of empowering EMR to accurately triage patients with suspected irAEs to the ITOX service that is supported by institution developed guidelines and specialists. Our model is adaptable in major academic centers and can have major impact on quality improvement and future research studies that can be conducted in this unique setting.

Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ Programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: A multicentre analysis of immune-related adverse events

BackgroundSeveral studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients. Patients and methodsWe conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI. ResultsOne thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21–92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6–46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5–14.9 for overweight, and 16.6 (95%CI: 10.3–26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4–22.3], p < 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3–18.2], p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients. ConclusionsConsidering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.

Management of rheumatic complications of immune checkpoint inhibitor therapy - an oncological perspective.

Immune checkpoint inhibitors (CPIs) are an effective treatment for many cancers but cause diverse immune-related adverse events (IrAEs). Rheumatological IrAEs include arthralgia, arthritis, tenosynovitis, myositis, polymyalgia rheumatica and sicca syndrome. CPI use can unmask RA as well as causing flares of prior autoimmune or connective tissue disease. Oncologists categorize and grade IrAEs using the Common Terminology Criteria for Adverse Events and manage them according to international guidelines. However, rheumatological events are unfamiliar territory: oncologists need to work with rheumatologists to elicit and assess symptoms, signs, results of imaging and autoantibody testing and to determine the use of steroids and DMARDs. Myositis may overlap with myasthenic crisis and myocarditis and can be life-threatening. Treatment should be offered on balance of risk and benefit, including whether to continue CPI treatment and recognizing the uncertainty over whether glucocorticoids and DMARDs might compromise cancer control.

Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection

sBackgroundPatients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations.MethodsWe performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018.ResultsWe identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation.ConclusionsOur retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI–based clinical trials or treatment.

ES01.01 Chemotherapy is Strictly Additive to Immunotherapy

Historically, chemotherapy was the only systemic therapy for advanced NSCLC. Over the last decades, effective targeted therapy has been developed. EGFR is the prime target since 20 years now [1], and is followed by an increasing number of targetable rare oncogenic driver mutations. This decade, the phase I trial of nivolumab – including NSCLC patients – started recruitment on July 1, 2011 [2]. Since then, immunotherapy with immune checkpoint inhibition (ICI) has become the third pillar in our therapeutic armentarium, with a very rapid development for relapsed, and thereafter for untreated advanced NSCLC. Most patients with non-oncogene addicted advanced NSCLC will nowadays have both chemotherapy and ICI, either in a concurrent or sequential way. This raises the question whether their interaction is synergistic or additive, favoring the former versus the latter approach. We will look at this from the perspective of adverse events, mechanistic background, and clinical trial outcomes. There is not much overlap between the typical and common adverse events (AEs) of chemotherapy or ICI. The former are mostly bone marrow inhibition, nausea/vomiting, mucositis, hair loss and neuropathy. ICIs are well tolerated, with no or mild AEs in most patients, but may induce immune related AEs mostly in skin or endocrine organs, liver, lungs or kidneys. Hence, there is little difference in overall adverse event profiles when the chemotherapy+ICI (chemo+ICI) and chemotherapy+placebo (chemo+PL) arms from randomized trials are compared. In the Keynote-189 trial - an example with the anti-PD-1 agent pembrolizumab – overall grade 3 to 5 AEs were present in 67.2% and 65.8% of patients with chemo+ICI and chemo+PL, respectively [3]. Grade 3 to 5 immune-related AEs, as rated by investigators blinded to the assigned therapy, were 8.9% for chemo+ICI, while 4.5% for chemo+PL. AEs leading to discontinuation of all treatment were 13.8% and 7.9%, respectively. Hence, irAEs acted additive to the overall AE profile. The notable exception in this trial was renal toxicity. There was a low frequency of auto-immune nephritis (1.7%), but there was a 5.2% incidence of acute kidney injury in the chemo+ICI arm, compared to 0.5% in the control arm. In the IMpower-133 trial – an example with the anti-PD-L1 agent atezolizumab – overall grade 3 to 5 AEs were present in 67.2% and 63.8% of patients with chemo+ICI and chemo+PL, respectively [4]. All grade immune-related AEs, as rated by investigators blinded to the assigned therapy, were 39.9% for chemo+ICI, and 24.5% for chemo+PL. So, here again a rather additive pattern in AE profile is put forward. Chemotherapy has long time been regarded as immunosuppressive and incompatible with immunotherapy. To improve on the rather low response rate with ICI alone, recent trials focused on the combination of chemo+ICI, trying to exploit the immune modulatory (synergistic) effects of chemotherapy both on the tumor cells and immune cells. The details of this interaction are beyond the scope of this abstract, but a central one is immunogenic cell death (ICD) by chemotherapy. In contrast with necrotic/apoptotic cell death, ICD is characterized by immune-promoting features on dendritic cells and macrophages, by means of inducing calreticulin expression on tumor cells, release of adenosine triphosphate in the extracellular space and of high mobility group box 1 protein from the nucleus of the cancer cell. ICD, however, has been associated with only a limited number of chemotherapeutic agents used in clinical practice, such as doxorubicin, mitoxantrone, oxaliplatin and cyclophosphamide [5]. None of these agents is part of the modern chemotherapeutic armentarium for NSCLC. Recent phase III trials with chemo+ICI versus chemo+PL demonstrated a convincing benefit in response rate, progression-free survival (PFS) and overall survival (OS) with the combination (e.g. [3]). Of note, there are no randomized data comparing the combination of chemo+ICI in a concurrent versus a sequential way. Ideally, such a trial should have several arms: one with the concurrent use of chemo+ICI in all PD-L1 tumors; a sequential one with pembrolizumab followed by chemotherapy in PD-L1 ≥50% tumors; and one with the sequential use of a chemotherapy and then ICI in PD-L1 <50% tumors. The primary endpoint preferably should be PFS2 in a intention-to-treat analysis. In the absence of such data, there is no definitive evidence that one or the other strategy is superior, and we can only make speculations about this question. At the meeting, we will present suggested algorithms based on the comparison of PFS from several recent trials. Especially the PFS2 analysis of the Keynote-024 [6,7] and KN-189 [3,8] trials are helpful in this respect. Even if there are many caveats with this approach, it may be helpful to guide clinical practice between concurrent and sequential treatment strategies.