Incidence Of Immune-related Adverse Events Research Articles

Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients Aged ≥ 75 Years With Non–small-cell Lung Cancer (NSCLC): An Italian, Multicenter, Retrospective Study

IntroductionNon–small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged ≥ 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy. Material and MethodsInclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age ≥ 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events. ResultsEighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P = .008). No difference in survival was found between patients younger and older than 80 years. ConclusionsIn the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials.

Real-life experience with nivolumab monotherapy in patients with advanced lung cancer: Efficacy and immune-related adverse events at Jiangsu Cancer Hospital, Nanjing, China

ObjectiveImmune-related adverse events (irAEs) associated with programmed death 1 (PD-1) inhibitor in advanced lung cancer, at home and abroad, have scarcely been reported. We thus aimed to understand the adverse events related to the therapy of nivolumab, a PD-1 inhibitor, in advanced lung cancer, and to provide more experience for the future use of this drug. Methods34 patients were included in this retrospective study in the Department of Oncology, Jiangsu Cancer Hospital from January 2016 to January 2019, and the adverse immune events were summarized. ResultsAfter treatment with nivolumab, irAEs including skin reaction, fatigue, loss of appetite, pneumonia, hypothyroidism, hyperthyroidism, elevated blood alanine aminotransferase (ALT), elevated amylase and decreased platelets and neutrophils were observed or detected, in which the incidences of more than 10% were pneumonia (23.5%), skin reaction (20.6%), fatigue (17.6%), loss of appetite (11.8%), and elevated blood ALT (11.8%). Most of the patients had grade I-II IrAEs, 2 patients with non-small cell lung cancer (NSCLC) developed grade III and IV immune pneumonia, and 1 patient with SCLC developed grade IV cardiotoxicity. The mean PFS of patients with advanced NSCLC was 195.81 ± 36.34 days [95%CI, 124.57~267.05 days] and their mean OS was 541.87 ± 110.80 days [95%CI, 324.70.44~759.03 days] (Fig. 2A and B). The objective response rate of patients with NSCLC was19.23% (5/26) and the disease control rate of those was 57.69% (15/26). ConclusionThough the incidence of immune-related adverse events of nivolumab monotherapy is relatively lower and most of them are in grade I-II, attention should be paid to a few serious adverse events that develop rapidly and even endanger life.

Impact of aging on immune-related adverse events generated by anti–programmed death (ligand)PD-(L)1 therapies

BackgroundAging is an important risk factor for cancers and is associated with poor prognosis. Weakness of the immune system, also called immunosenescence may occur with older age. The impact of aging on efficacy and safety of immune checkpoint blockers, such as anti-programmed death (ligand) PD-(L)1, remains undetermined. This study aims to evaluate the incidence of immune-related adverse events (irAEs) in patients aged 70 years or older than their younger counterparts. MethodsPatients with advanced solid tumors treated at Gustave Roussy with an anti–PD-(L)1 monotherapy between June 2014 and October 2017 were prospectively included within the dedicated irAEs pharmacovigilance registry REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie). The incidence of irAEs of grade ≥II was compared between patients aged ≥70 (old patients, OP) versus patients aged < 70 years (young patients, YP) using a chi-squared test. Survivals were estimated using the Kaplan-Meier method. ResultsAmong the 603 patients treated by anti-PD(L)1, 191 were ≥70 y.o (OP) and 424 < 70 y.o (YP). The median (range) age of OP and YP were respectively 77 (70–93) and 59 years old (17–69). A total of 165 irAEs occurred in these patients (103 grade II and 58 grade III–IV). The overall incidence of grade ≥II irAEs was higher in OP than in YP (33% versus 25%, p = 0.03). In addition, OP were more prone of having multiples irAEs compared with YP (p = 0.037). Skin toxicities were more frequent in OP than in YP (p = 0.007) but endocrine toxicities were less frequent in OP than in YP (p = 0.044). This higher level of irAEs seems to be responsible for a higher rate of treatment discontinuation in OP (p = 0.2). There was no statistical difference in median time to toxicity, exposure to steroids or survival between the two groups. ConclusionAlthough anti-PD-(L)1 immunotherapies remain an acceptable treatment option for older patients, prescribers should be aware that irAEs are more frequent in the elderly. Further translational studies are warranted to better understand the relationship between aging and irAEs.

Onset, duration, and clinical impact of immune-related adverse events in Hodgkin lymphoma.

95 Background: The incidence of immune-related adverse events (irAEs) in patients (pts) with Hodgkin lymphoma (HL) treated with PD-1 antibodies (ICI) is reported at 28 - 36%. However, clinically relevant information on irAE onset, duration, or impact on ability to continue therapy in HL is lacking. Additionally, these incidence rates reflect CTCAE definition and grading, and not ASCO Clinical Practice Guidelines irAE-specific criteria (Brahmer et al, JCO 2018). The objectives of this study were to evaluate the rate and severity of irAEs in HL pts using ASCO criteria, to characterize irAE time profile and to assess their impact on continued therapy. Methods: HL pts who received a PD-1 inhibitor for the treatment of HL at Mayo Clinic Rochester between January 1, 2011 and March 1, 2018 were identified. We conducted a detailed, longitudinal retrospective chart review with definition and grading of irAEs in accordance with ASCO guidelines. Results: Fifty-one pts were identified (35% women, median age at ICI initiation 35 years [range: 19-87]). Median duration of follow up from ICI start was 30 months (range: 1-70). Thirty-one pts (61%) had any irAE. Most common irAEs were inflammatory/bullous dermatoses (23.5%/5.9% any grade/grade3-4; median onset/duration of 81/57 days[d]), followed by thyroiditis (22%/0%; 86/84 d), colitis (14%/8%; 82/106 d), pneumonitis (14%/10%; 241/182 d), and hepatitis (14%/4%; 71/35 d). Fifteen pts (29%) required treatment with steroids. Among the total cohort, ICI was held for an irAE 28 times (50% of 56 total irAEs). Median treatment cycles held was 2.5 and ICI was permanently discontinued due to irAE in 18%. The most common irAE leading to treatment discontinuation was pneumonitis, followed by neuritis (5.9%/3.9%; 179/374 d), colitis, and rash. Conclusions: The rate of irAEs of 61% in this cohort as defined by ASCO consensus criteria was higher than reported in trials. Most irAEs were characterized by delayed onset of several months and prolonged duration, particularly pneumonitis and neuritis. Treatment discontinuation due to irAEs was infrequent overall. Further studies are needed to determine whether the development or duration of irAEs is predictive of treatment outcomes in HL.

Safety of Influenza Vaccine in Patients With Cancer Receiving Pembrolizumab.

There is a concern that influenza vaccination could increase the incidence of immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors. The aim of our study was to determine the safety of influenza vaccination in this patient population. We retrospectively identified patients who received at least 1 dose of pembrolizumab during any influenza season from September 2014 to August 2017 and reviewed medical records for irAEs. The primary endpoint was the incidence of irAEs. We used multivariable logistic regression and cumulative incidence curve with competing risks for comparison. Among 162 patients with cancer included in this study, 70 patients (43.2%) received at least 1 influenza vaccination. The vaccinated group was significantly older (P = .002) and received more cycles of pembrolizumab (P = .006). The incidence of any grade irAEs in the vaccinated group trended toward being lower (25.7% v 40.2%; P = .07) compared with the nonvaccinated group. Influenza vaccination was independently associated with fewer irAEs, with an odds ratio of 0.4 (95% CI, 0.2 to 0.9; P = .03) in multivariable analyses. The vaccinated group was less likely to have irAEs compared with the nonvaccinated group (24.7% v 34.4% at 12 months; P = .05), with death as a competing risk. The median irAE-free duration in the vaccinated group was longer than the nonvaccinated group (not reached v 28 months; P = .037). Influenza vaccination in patients with cancer receiving immune checkpoint inhibitor therapy was not associated with increased irAEs. This supports the safety of influenza vaccination in this patient population.

Risk of Toxicity After Initiating Immune Checkpoint Inhibitor Treatment in Patients With Rheumatoid Arthritis.

Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced cancer. Rheumatoid arthritis (RA) is associated with an increased risk of malignancies; however, patients with RA have been excluded from ICI trials. In this study, we evaluated risk of toxicity after initiation of ICI treatment in RA patients. We conducted a single-institution, medical records review analysis to assess the incidence of immune-related adverse events (irAEs) and autoimmune disease (AID) flares among patients with AIDs treated with ICIs from 2011 to 2018. A subgroup analysis for RA patients was performed with frequencies of irAEs and AID flares reported. Twenty-two patients with RA who were treated with ICI for malignancy were identified. At the time of ICI initiation, 86% had inactive RA disease activity. Immune-related adverse events occurred in 7 (32%) of patients, with 2 (9%) developing grade 3 (i.e., severe) irAEs. Immune checkpoint inhibitors were temporarily discontinued because of irAEs in 5 patients (23%), and permanently in 1 patient. Rheumatoid arthritis flares occurred in 12 patients (55%). Of those, 10 (83%) received oral corticosteroids with an adequate treatment response. Our analysis suggests that irAEs following ICI treatment are not increased among RA patients compared with other cancer patients. Heightened RA disease activity during ICI treatment is common, but most adverse events are manageable with oral corticosteroids, and few require permanent ICI discontinuation. A close collaboration between the oncologist and rheumatologist is advisable when considering ICIs in patients with RA.

Evaluating the role of FAMIly history of cancer and diagnosis of multiple neoplasms in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: the multicenter FAMI-L1 study

ABSTRACT Background: We investigate the role of family history of cancer (FHC) and diagnosis of metachronous and/or synchronous multiple neoplasms (MN), during anti-PD-1/PD-L1 immunotherapy. Design: This was a multicenter retrospective study of advanced cancer patients treated with anti-PD-1/PD-L1 immunotherapy. FHC was collected in lineal and collateral lines, and patients were categorized as follows: FHC-high (in case of cancer diagnoses in both the lineal and collateral family lines), FHC-low (in case of cancer diagnoses in only one family line), and FHC-negative. Patients were also categorized according to the diagnosis of MN as follows: MN-high (>2 malignancies), MN-low (two malignancies), and MN-negative. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of immune-related adverse events (irAEs) of any grade were evaluated. Results: 822 consecutive patients were evaluated. 458 patients (55.7%) were FHC-negative, 289 (35.2%) were FHC-low, and 75 (9.1%) FHC-high, respectively. 29 (3.5%) had a diagnosis of synchronous MN and 94 (11.4%) of metachronous MN. 108 (13.2%) and 15 (1.8%) patients were MN-low and MN-high, respectively. The median follow-up was 15.6 months. No significant differences were found regarding ORR among subgroups. FHC-high patients had a significantly longer PFS (hazard ratio [HR] = 0.69 [95% CI: 0.48–0.97], p = .0379) and OS (HR = 0.61 [95% CI: 0.39–0.93], p = .0210), when compared to FHC-negative patients. FHC-high was confirmed as an independent predictor for PFS and OS at multivariate analysis. No significant differences were found according to MN categories. FHC-high patients had a significantly higher incidence of irAEs of any grade, compared to FHC-negative patients (p = .0012). Conclusions: FHC-high patients seem to benefit more than FHC-negative patients from anti-PD-1/PD-L1 checkpoint inhibitors.

Cancer immunotherapy and its potential cardiac complications.

Recent advances in immune therapy for cancer have significantly improved the clinical outcomes of patients with advanced cancers, where prognosis has historically been very poor. With these new treatments have come new toxicities and, as the use of immunotherapy increases, we will see an increasing incidence of immune-related adverse events, with patients presenting as an emergency. It is important that all cardiologists, and other physicians who see these patients, are aware of life-threatening immune-related toxicities, in addition to their recommended investigation and treatment. We describe a patient with acute cardiotoxicity secondary to immune therapy to illustrate the complexity of these adverse cardiovascular events, providing recommendations for screening, diagnosis and management.

ME-401-003 (TIDAL): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Two-Arm, Phase 2 Study of ME-401 Investigating Continuous and Intermittent Dosing Schedules in Patients with Relapsed/Refractory Follicular Lymphoma

ME-401-003 (TIDAL): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Two-Arm, Phase 2 Study of ME-401 Investigating Continuous and Intermittent Dosing Schedules in Patients with Relapsed/Refractory Follicular Lymphoma

Various immuno-related adverse events after IPI+NIVO therapy; a case report of metastatic choroidal melanoma

Abstract Background Choroidal melanoma with metastasis is known to have a poor prognosis with no established standard therapy. Recently there are some case reports that combination therapy of IPI and NIVO is effective, but with high incidence of immune-related adverse events (irAE). Case presentation A 53-year-old man presented with choroidal melanoma of the right eye and underwent stereotactic radio surgery but eighteen months later developed diffuse hepatic metastases. He was treated with combination therapy of IPI and NIVO, but he developed hyposalivation from the next day of first administration, and grade 3 hepatic disorder after 2 cycles. After 3 days administration of mPSL 125mg followed by PSL 0.5mg/kg, his hepatic enzymes normalized, then we started steroid tapering. At the dose of 30mg, he developed grade 4 Stevens-Johnson syndrome, for which 3 days pulse therapy of mPSL 1mg was effective. We re-escalated PSL to 1mg/kg and tapered carefully. At the dose of 15mg, MRI showed progression of liver metastasis. We decided to resume nivolumab monotherapy three months after termination of IPI+NIVO therapy, but it resulted in grade 3 diarrhea. Lower gastrointestinal endoscopy found seemingly normal mucosa, but histological examination showed inflammatory cell infiltration with hemorrhage, which means irAE. Now he is continuing steroid therapy at 15mg of PSL. Conclusion Our patient developed various irAEs after IPI+NIVO therapy for metastatic choroidal melanoma. Each irAEs responded to corticosteroid therapy, but unexpected severe irAEs occurred even with high dose steroid. As a result, prolonged steroid therapy is often needed to control various irAEs, and in those cases, we have to take extra attention to adverse events of steroids such as opportunistic infections.

1395 Nivolumab-Induced Hemorrhagic Pancreatitis

INTRODUCTION: The checkpoint inhibitor nivolumab is an anti-PD-1 monoclonal antibody (mAb) that treats malignancy. Increased usage of checkpoint inhibitors has led to an increasing incidence of immune-related adverse events (irAEs) such as immune checkpoint inhibitor-induced pancreatic injury (ICIPI). We report a case of nivolumab-induced pancreatitis that progressed to fatal hemorrhagic pancreatitis. CASE DESCRIPTION/METHODS: A 61-year-old man diagnosed with small cell lung cancer with brain, adrenal, and osseous metastases presented with a one-day history of epigastric pain radiating to the back after starting a biweekly dose of nivolumab forty days prior. On admission, he had a lipase of 2700 U/L. His abdominal CT scan was consistent with acute interstitial pancreatitis. The patient was treated with hydromorphone as needed and Lactated Ringer's. He was continued on his home dexamethasone and discharged. Fourteen days after initial presentation, the patient reported increased abdominal cramping. MRCP findings were consistent with acute hemorrhagic pancreatitis with organizing complex peripancreatic fluid collections. He became febrile and hypoxic, and twenty-three days after initial presentation, chest CT scans showed acute respiratory distress syndrome or multifocal pneumonia. The patient decompensated and eventually died of cardiopulmonary failure secondary to hemorrhagic pancreatitis and worsening of his underlying malignancy. DISCUSSION: Nivolumab is a PD-1 mAb that works by enhancing the T-cell response to malignancies. Checkpoint inhibitors are known to cause irAEs including ICIPI due to their increased immune activation. However, reports of nivolumab-related pancreatitis are rare, with a reported rate of &lt;1%. While anti-PD-1 mAbs often cause asymptomatic pancreatic enzyme elevations, nivolumab-related pancreatitis may also progress to serious complications, such as pseudocyst or chronic pancreatitis. The mainstay of treatment for irAEs is a combination of immunosuppression with glucocorticoids and/or a removal of the checkpoint inhibitor, depending on the severity of the irAE. Expert opinion currently guides steroid and checkpoint inhibitor management based on the intensity of the reaction: at lower severity the drug can either be stopped temporarily or not at all. This case adds to the growing presentations of nivolumab-induced pancreatitis. Though the incidence of pancreatitis as a result of checkpoint inhibition remains low, the progression to severe disease is possible.

Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk?

A greater understanding of anti-tumor immunity has resulted in rapid development of immunotherapy for a wide variety of cancers. Antibodies targeting the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1), or its ligand (PD-L1) have demonstrated clinical activity and are approved for treatment of melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, bladder cancer, head and neck cancers, esophageal cancer, hepatocellular carcinoma, and Hodgkin lymphoma, among others. Treatment is generally well tolerated with relatively few adverse events compared with standard treatments such as chemotherapy. However, immune activation can potentially affect any organ system and a small fraction of patients are at risk for developing severe immune-related adverse events. Immune checkpoint inhibitors (ICIs) and other immunotherapeutic modalities such as cancer vaccines are in nascent stages of development for treatment of thymic epithelial tumors (TETs). Since the thymus plays a key role in the development of immune tolerance, thymic tumors have a unique biology which can influence the risk-benefit balance of immunotherapy. Indeed, early results from clinical trials have demonstrated clinical activity, albeit at a cost of a higher incidence of immune-related adverse events, which seem to particularly affect skeletal and cardiac muscle and the neuromuscular junction. In this paper we describe the effects of thymic physiology on the immune system and review the results of clinical trials that have evaluated immunotherapy for treatment of relapsed thymoma and thymic carcinoma. We review ongoing efforts to mitigate the risk of immune-related complications in patients with TETs receiving immunotherapy and offer our thoughts for making immunotherapy a feasible alternative for treatment of thymic tumors.

Abstract 3230: Safety and efficacy of immune checkpoint inhibitors (ICIs) in patients with HIV, hepatitis B, or hepatitis C viral infections

Abstract Background: Immune checkpoint inhibitors (ICIs) have become standard of care for many malignancies. However, patients (pts) with human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C (HCV) were excluded from many clinical trials. Therefore, the safety and efficacy of ICI therapy in these patient populations is not well characterized. Methods: We performed a retrospective analysis of pts with HIV, HBV, or HCV treated with ICI therapy at five MedStar Health hospitals from January 2011 to April 2018. The incidence of immune-related adverse events (irAEs) per CTCAE4.03, objective response rate (ORR) per RECIST v1.1, changes in viral status and CD4 T-cell counts during treatment were analyzed. Results: A total of 50 pts were identified; (21 HIV, 4 HIV/HCV, 1 HIV/HBV, 15 HBV, 22 HCV, and 3 HBV/HCV) treated with anti-PD-(L)1 monotherapy (43) or in combination with ipilimumab (1) or chemotherapy (6). In the HIV group (21), the median age was 62 (29-85), 52% were male, 33% white, and 67% African American (AA). Tumor types included non-small-cell lung carcinoma (NSCLC; n=12), Hodgkin’s lymphoma and anal carcinoma (2 each), head and neck cancer, colorectal cancer, renal cell carcinoma (RCC), Burkitt’s lymphoma, and hepatocellular carcinoma (HCC) (one each). Any grade irAEs was 24% (5), and grade ≥ 3 irAEs was 10% (hepatitis and pneumonitis). Four pts had elevated HIV viral loads at baseline; 2 of 2 assessed had decreased levels after starting ICI therapy without changes in their antiretroviral therapy. Nine pts maintained an undetectable HIV viral load during ICI therapy. CD4 T-cell counts improved in 5 pts and decreased in 6 pts during ICI therapy. The ORR in response-evaluable pts for the entire group (16) was 25% (1 CR, 3 PR, 4 SD, and 8 PD). In the HBV/HCV cohort (34), median age was 62 (37-77), 71% were male, 24% white, and 50% AA. Tumor types included HCC (16), NSCLC (10), RCC (3), and head &amp; neck, gastric and small cell lung cancer, one each. Any grade irAEs were noted in 50% (17) and grade ≥3 in 26% [colitis (2), hepatitis (3), pneumonitis, diabetic ketoacidosis, neurological weakness and rash, one each]. Of 15 HBV pts, 4 pts had detectable, and 8 pts had undetectable viral load before initiation of ICI. Among 4 pts with detectable viral load, no transaminitis was observed. Of 22 HCV pts, 9 were previously treated, 11 were untreated and no data available in 2. Among 4 pts with pre- and post-viral loads, 2 untreated pts’ viral loads showed small improvement and other 2 previously treated pts’ viral loads remained undetectable. The ORR in response-evaluable pts for the entire group (27) was 22% (6 PR, 7 SD, and 14 PD) and HCC pts (13) treated with anti-PD-(L)1 monotherapy was 23% (3 PR, 3 SD, and 7 PD). Conclusion: ICI therapy was not associated with any new safety signal in pts with HIV, HBV, or HCV infection with no evidence of viral reactivation. Prospective trials are needed to validate the above findings. Citation Format: Neil J. Shah, Ghassan AL-Shbool, Matthew Blackburn, Michael Cook, William J. Kelly, Anas Belouali, Sebastian Ochoa, Bradley S. Colton, Jeevan Puthiamadathil, Michael T. Serzan, Alice R. Knoedler, Stephen V. Liu, Michael J. Pishvaian, Mahsa Mohebtash, Subha Madhavan, Aiwu R. He, Michael B. Atkins, Geoffrey T. Gibney, Chul Kim. Safety and efficacy of immune checkpoint inhibitors (ICIs) in patients with HIV, hepatitis B, or hepatitis C viral infections [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3230.

Early incidence of immune-related adverse events (irAEs) predicts efficacy in patients (pts) with solid tumors treated with immune-checkpoint inhibitors (ICIs).

2563 Background: Treatment with ICIs can manifest immune-related adverse events (irAEs), which have correlated with clinical outcomes in certain tumors. However, timing of these events and how early irAEs correlate with outcomes is unclear. We assessed whether early occurring irAEs could predict survival in pts treated with durvalumab (D), an anti-PDL1 and combined with tremelimumab (D+T), an anti-CTLA4 in two clinical studies. Methods: Two phase 2 non-randomized clinical trials evaluating D (D4190C00001 (1108), N=756; available data per internal data re-use policy) or D+T (D4190C00010 (C10), N=327; expansion and ICI naïve cohorts) in multiple solid tumor types were analyzed. Prevalence of pts experiencing irAEs, regardless of grade was 30% and 59% in studies 1108 and C10, respectively, with most frequent including dermatitis/rash (25%), thyroid (15%), diarrhea/colitis (14%), and pancreatic enzyme elevation (5%). Overall survival (OS) was correlated with irAE timing prior to 6, 8, 12, 16, 20 and 24 weeks following D or D+T treatment. Kaplan Meier and log-rank analyses were used. Results: In both studies, pts who experienced at least one irAE by study completion had improved median OS (mOS, 1108: 23.1 mos [18.2, 26.9]; C10: 16.3 mos [12.5, 31.4]) relative to those who experienced none (1108: 6.3 mos [5.4, 7.3]; C10 4.6 mos [3.3, 6.1]). Median time (weeks) to first and second irAE occurred earlier in C10 compared to 1108, 3.9 vs. 5.6 and 6.9 vs. 10.1, respectively. When associating timing of irAEs with survival, there was a significant differential in mOS at each time interval evaluated between pts with at least one irAE and those with none, with differentiation at 6 weeks and maximal survival benefit at 24 weeks following treatment with D or D+T (Table). Conclusions: Early occurrence of irAEs may be predictive of survival benefit in pts treated with D or D+T. OS by 1+ or no irAE(s) occurring up to 6 or 24 weeks post treatment. [Table: see text]

Immune related adverse events in NSCLC patients treated with immune checkpoint therapy who received the influenza vaccination versus no vaccination.

e20657 Background: Influenza vaccination is recommended by the CDC for cancer patients to reduce the risk of influenza-related complications. There is concern that the incidence of immune-related adverse events (irAEs) may be greater in vaccinated patients receiving immune checkpoint inhibitors (ICPI). We sought to interrogate if influenza vaccination in patients with NSCLC receiving ICPI therapy had an increased incidence of irAEs compared to non-vaccinated patients. Methods: We conducted a single-center retrospective analysis of patients with advanced NSCLC who received PD-1 or PD-L1 inhibitor monotherapy between 3/2015 – 12/2018. Influenza immunization records from both institutional and state-wide registries were obtained from 2014 -2019. Comparisons of adverse event incidence between flu vaccinated and control patients were tested using chi-square statistics. Results: 117 patients were included in our analysis, 33 (28%) were vaccinated during ICPI therapy, 19 (58%) received quadrivalent influenza vaccine, 13 (39%) received trivalent influenza vaccine and 1 (3%) was undetermined. 22 (67%) vaccinated patients had an irAE vs 53 (63%) patients who were not vaccinated during ICPI therapy (p = 0.720). 8 (24%) vaccinated patients had an irAE leading to discontinuation of therapy vs 12 (14%) patients who were not vaccinated during ICPI therapy (p = 0.198). The most frequent irAE in both groups was fatigue 16 (48%) vs 28 (33%) (p = 0.128). Notable irAEs included colitis (0 vs 1), pneumonitis (3 vs 3), hepatitis (1 vs 4) in vaccinated patients vs without vaccine, respectively. There were no statistically significant differences in baseline demographics between both groups including age, race, gender, tumor histology or ECOG performance status. Conclusions: Our study suggests that irAEs are not significantly increased with vaccination for influenza during ICPI therapy. However, there is a slight trend toward increased incidence of irAE warranting ICPI discontinuation for which further investigation is needed. Limitations of this study include a small sample size and inability to grade irAE retrospectively.

Response rate and safety of standard-dose nivolumab with reduced-dose ipilimumab in metastatic melanoma.

140 Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab was shown to improve overall response rate (58%), progression free survival (11.5 months), and overall survival compared to ipilimumab alone in Checkmate 067. Improved outcomes were accompanied by an increased risk of toxicities with a 59% rate of grade 3-4 toxicities for the combination. Keynote 029 evaluated standard-dose pembrolizumab with reduced-dose ipilimumab with a slightly lower risk of grade 3-4 toxicities at 45%. Here we report outcomes for standard-dose nivolumab combined with reduced-dose ipilimumab in metastatic melanoma. Methods: We conducted a retrospective review of metastatic melanoma patients that received standard-dose nivolumab with reduced-dose ipilimumab at West Virginia University Cancer Institute. Response to therapy and incidence of immune-related adverse events were assessed. Results: From February 2017 to October 2018, 11 patients received the alternative dosing regimen. Only 1 (9%) patient experienced a grade 3-4 toxicity, and 3 (27%) additional patients experienced a grade 1-2 toxicity. The overall response rate was 54%. Conclusions: Standard-dose nivolumab in combination with reduced-dose ipilimumab is better tolerated than reduced-dose nivolumab with standard-dose ipilimumab without a loss in overall response rate.

Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer

ObjectivesGut microbiome plays a dominant role in modulating therapeutic efficacy of immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor/ligand-1 (PD-1/PD-L1) pathway, suggesting that co-administration of antibiotics (Abx), which might result in dysbacteriosis, can attenuate the clinical outcomes of ICIs. The current study aimed to investigate the predictive role of Abx on ICIs treatment in patients with advanced non-small cell lung cancer (NSCLC). The impact of proton pump inhibitors (PPIs), another medication that can induce dysbacteriosis, was also investigated. Materials and methodsWe retrospectively reviewed the medical records of eligible patients who received anti-PD-1-based therapies in our hospital. Tumor responses, patients’ survival, the incidence of immune-related adverse events (irAEs) and other baseline variables were examined. The application of Abx or PPIs treatment were also collected. Clinical outcomes and clinicopathologic features were compared according to the status of Abx or PPIs co-administration. ResultsA total of 109 patients were included. Of them, 20 (18.3%) patients were categorized in Abx-treated group. No major difference in baseline characteristics was observed between Abx-treated and -untreated groups. Concomitant Abx treatment was significantly associated with shorter progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p = 0.0021). And primary disease progression tended to increase in Abx-treated group (p = 0.092). Yet, the occurrence and grades of irAEs were comparable between two groups. In multivariable analysis, Abx treatment was markedly associated with worse PFS (HR=0.32, 95%CI 0.18-0.59, p < 0.0001) and OS (HR=0.35, 95%CI 0.16-0.77, p = 0.009). Regarding the use of PPIs, no significant difference was observed in clinical outcomes between the patients with or without concomitant PPIs treatment. ConclusionsAbx treatment was significantly associated with attenuated clinical outcomes derived from anti-PD-1-based ICIs in a Chinese cohort of patients with advanced NSCLC.

Safety and efficacy of PD-1 inhibitors in non–small cell lung cancer patients positive for antinuclear antibodies

ObjectivesTo examine the possible effects of antinuclear antibodies (ANA) on the safety and efficacy of programmed cell death–1 (PD-1) inhibitors in patients with advanced non–small cell lung cancer (NSCLC). Patients and methodsClinical data including ANA status were reviewed retrospectively for patients with advanced NSCLC who received monotherapy with a PD-1 inhibitor. ResultsOf the 83 patients analyzed, 18 (21.7%) were positive for ANA. The incidence of immune-related adverse events (irAEs) did not differ significantly between patients with ANA (6/18, 33.3%) and those negative for ANA (21/65, 32.3%), although it tended to increase as the ANA titer increased. Progression-free survival (2.9 versus 3.8 months, p = 0.03) and overall survival (11.6 versus 15.8 months, p = 0.03) were significantly shorter in patients positive for ANA than in those without ANA. ConclusionPD-1 inhibitors can be administered safely in advanced NSCLC patients positive for ANA without obvious exacerbation of autoimmune disease, although patients with a high titer of such antibodies may warrant close monitoring. However, the presence of ANA might be associated with a poor outcome of such treatment.

Immunotherapy-related toxicities: More common than originally reported?

184 Background: Population level data regarding incidence of immune-related adverse events (irAE) is lacking. This study evaluated the frequency of irAEs among a large population of patients with non-small cell lung cancer (NSCLC) who received immune checkpoint inhibitors. Methods: Administrative claims data from a large U.S. commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify patients with NSCLC who received PD-1 or PD-L1 inhibitors between January 1, 2015 to December 31, 2017. The frequencies of irAEs were reported, identified by having a new medical claim with a corresponding ICD-9 or ICD-10 code during the time period in which the patient was on immunotherapy. Results: Of 2,798 patients with NSCLC (median age at PD-(L)1 initiation: 69 years, interquartile range: 60-75, 1558 male [55.7%], 1240 [44.3%] female), 1,998 (71.4%) received nivolumab, 699 (25.0%) received pembrolizumab, and 101 (3.6%) received atezolizumab. Most patients (1463, 52.3%) received a PD-(L)1 inhibitor as second line therapy; the majority of patients (744) received alkylating agents and antimetabolites prior to receiving PD-(L)1 therapy. See Table 1 for frequencies of irAEs. Conclusions: The current study suggests that the frequencies of some irAEs related to immune checkpoint inhibitor therapies may be higher than those which were reported in the initial trials that led to the FDA approvals for immunotherapies. For example, hypophysitis was noted to occur in 0.6% of patients in the KEYNOTE-024 trial, but was identified in 2.4% of patients in this large cohort. Real world data may refine provider and patient expectations for outcomes beyond what is observed in clinical trials. [Table: see text]

Abstract CT001: Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Efficacy and safety results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial

Abstract Background: The checkpoint inhibitors ipilimumab and nivolumab are approved by FDA as adjuvant therapy for patients with resected high-risk stage III melanoma. We conducted the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients with resected high-risk stage III melanoma. Methods: Eligible patients included those ≥18 years of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (excluding those with in-transit metastasis). A total of 1019 patients were randomized (stratification by stage and region) to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year) or until disease recurrence or unacceptable toxicity. In the absence of brain metastases, patients with recurrence were eligible for cross-over or re-challenge (those who received pembrolizumab and recurred more than 6 months after completing 1 year of therapy). The 2 co-primary endpoints were recurrence-free survival (RFS) in the intention-to-treat overall population and in patients with PD-L1-positive tumors. A total of 409 RFS events were needed to provide 92% power to detect a hazard ratio (HR) for recurrence or death of 0.70 (1-sided alpha=1.4%). The interim analysis was performed at 1-sided alpha=0.8% (O'Brien-Fleming alpha error spending function) in the overall patient population, and at 2.5% in the PD-L1 positive population. Results: Overall, 15%/46.5%/37.5% of patients had stage IIIA/IIIB/IIIC. At 1.25 yr median follow-up, pembrolizumab (135 events) compared with placebo (216 events) significantly prolonged RFS in the overall population (12-month RFS rate: 75.4% vs 61.0%; HR 0.57, 98.4% CI 0.43-0.74; P&amp;lt;0.0001). Same was true in those with a PD-L1-positive tumor (N=852; HR 0.54, 95% CI 0.42-0.69; P&amp;lt;0.0001) or a PD-L1-negative tumor (N=116; HR 0.47, 95% CI 0.47 (0.26, 0.85); P=0.01). RFS was consistently prolonged across subgroups. Drug-related grade 3 to 5 adverse events were reported in 14.7% (N=75) in the pembrolizumab group and 3.4% (N=17) in the placebo group. There was only one pembrolizumab-related death due to myositis. The highest incidence of immune-related adverse events (irAEs), mostly grade 1 to 2, observed in the pembrolizumab vs placebo group were endocrine disorders (23.4% versus 5.0%) [hypothyroidism (14.3% vs 2.8%), hyperthyroidism (10.4% vs 1.2%), thyroiditis (3.1%) vs 0.2%)]. The incidence of grade 3-4 irAEs was 7.1% vs 0.6%: colitis (2.0% vs 0.2%), pneumonitis (0.8% vs 0%), hepatitis (1.4% vs 0.2%), all others had incidences &amp;lt; 1%. Conclusions: As adjuvant therapy for resected high-risk stage III melanoma pembrolizumab 200 mg every 3 weeks, for up to 1 year, resulted in significantly prolonged RFS with a favorable benefit-risk profile. Citation Format: Alexander M. Eggermont, Christian U. Blank, Mario Mandala, Georgina V. Long, Victoria Atkinson, Stéphane Dalle, Andrew Haydon, Mikhail Lichinitser, Adnan Khattak, Matteo S. Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Rutger Koornstra, Leonel Hernandez-Aya, Michele Maio, Alfonsus J. van den Eertwegh, Jean-Jacques Grob, Ralf Gutzmer, Rahima Jamal, Veronica Rivas, Nageatte Ibrahim, Sandrine Marreaud, Sven Janssen, Alexander van Akkooi, Stefan Suciu, Caroline Robert. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Efficacy and safety results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT001.