Time Of Immune Checkpoint Inhibitors Initiation Research Articles

P09.13 Bone Metastases and Overall Survival in Patients with Metastatic Non-Small Cell Lung Cancer Treated with Pembrolizumab

Bone metastases (BM) and skeletal-related events (SRE) are a common cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data on the impact of BM on overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI) is limited. Here we report the incidence, impact on survival, and risk factors for SRE in patients with mNSCLC treated with first-line pembrolizumab monotherapy or pembrolizumab plus chemotherapy. We conducted a retrospective study of patients with mNSCLC treated with first-line pembrolizumab or pembrolizumab plus chemotherapy at our institution from 2017-2020. The associations between SRE and categorical variables were studied using Fisher’s exact test and with continuous variables using the Kruskal-Wallis test. Kaplan-Meier plots were used to visualize survival curves. The association between baseline BM and OS was examined using a Cox proportional hazard model. OS was calculated from date of ICI initiation to death from any cause or last follow-up. We identified a cohort of 202 patients: 93 (46%) treated with pembrolizumab and 109 (54%) treated with pembrolizumab plus chemotherapy; 39 (19%) had squamous histology and 163 (81%) had nonsquamous histology; median age 62.7; median OS 33.7 months (95% CI: 17.2 – NR). In our cohort, 87 (43%) patients had BM at time of ICI initiation and 47 (23%) developed SRE after ICI initiation. Patients who developed SRE were more likely to have baseline BM than those without SRE (91.5% vs 28.4%, p<0.001). Development of BM during treatment with ICI and performance status were also significantly associated with SRE (p<0.001 and p=0.006, respectively). Patients with BM at time of ICI, or development of new or progression of existing BM while on ICI, had shorter survival than those without (Figure 1a and Figure 1b, respectively). In multivariate survival analysis, the hazard of death for patients with baseline BM was 2.85 times those without (HR=2.85, 95% CI: 1.53, 5.29, p-value=0.0009) after controlling for age, BMI, performance status, histology, PD-L1 expression, smoking, and SRE. The use of bone-modifying agents (BMA) was not associated with OS, osseous progression, or risk of SRE. The presence of BM at time of ICI was associated with shorter survival after controlling for multiple clinical characteristics. These patients represent a high-risk cohort for worse outcomes when treated with ICI alone or in combination with chemotherapy. In our cohort BMA were not associated with increased OS or decreased risk of osseous progression or SRE.

Preexisting autoimmune disease and immune-related adverse events associated with anti-PD-1 cancer immunotherapy: a national case series from the Canadian Research Group of Rheumatology in Immuno-Oncology

Limited data are available on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with preexisting autoimmune diseases (PAD). Retrospective study of patients with PAD referred for rheumatologic evaluation prior to starting or during immunotherapy between January 2013 and July 2019 from 10 academic sites across Canada. Data were extracted by chart review using a standardized form. Twenty-seven patients with PAD on ICI therapy were identified. The most common PADs were rheumatoid arthritis (30%), psoriasis/psoriatic arthritis (30%), inflammatory bowel disease (IBD, 15%) and axial spondyloarthritis (11%), and the most frequently observed cancers were lung cancer and melanoma. All patients received anti-PD-1 therapies, and 2 received additional sequential anti-CTLA-4 therapy. PAD exacerbations occurred in 52% over a median (IQR) follow-up of 11.0 (6.0-17.5) months, with 14% being severe, 57% requiring corticosteroids, 50% requiring immunosuppression and 14% requiring ICI discontinuation. Flares were generally more frequent and severe in patients who previously required more intensive immunosuppression (i.e., biologics). Flares occurred despite background immunosuppression at the time of ICI initiation. In patients with preexisting psoriasis, IBD and axial spondyloarthritis, rheumatic immune-related adverse events (irAEs), mostly polyarthritis and tenosynovitis, were frequently observed. Tumor progression was not associated with exposure to immunosuppressive drugs before or after ICI initiation and was numerically less frequent in patients with irAEs. PAD exacerbations in the context of ICI treatment are common, although generally mild, and occur despite background immunosuppression. Exacerbations are more frequent and severe in patients on more intensive immunosuppressive therapies pre-immunotherapy.

Clinical outcomes of solid organ transplant recipients with metastatic cancers who are treated with immune checkpoint inhibitors: A single-center analysis.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but to the authors' knowledge, limited data exist regarding the safety and efficacy of these agents in transplant recipients. Herein, the authors have reported their experience with 17 patients who were treated with ICIs for metastatic malignancies after undergoing solid organ transplantation. Data were abstracted for solid organ transplant recipients who received ICIs for the treatment of malignancy between January 1, 2016, and September 30, 2019. The authors identified 7 kidney, 8 liver, and 2 heart transplant recipients. Outcomes of interest were adverse drug reactions, cancer progression, and patient survival. The most common malignancies treated with ICIs were metastatic squamous cell carcinoma (5 patients; 29%) and hepatocellular carcinoma (5 patients; 29%), which were noted exclusively among liver transplant recipients. The median duration on ICIs was 1.7months (interquartile range, 0.4-7.6months). Five patients (29%) developed adverse reactions, including 4 patients (24%) with immune-related adverse events(irAEs), 3 patients (18%) with acute allograft rejections, 1 patient (6%) with autoimmune colitis, and 1 patient (6%) with ICI-induced cardiotoxicity (the patient was a heart transplant recipient). The cumulative incidence of cancer progression was 50% and 69%, respectively, at 6months and 12months. Eleven patients (65%) died over the median follow-up period of 4.6months (interquartile range, 1.5-13.2months) from the time of ICI initiation, with cancer progression being the most common cause of death. ICIs can be used as individualized therapy in selected patients who have undergone solid organ transplantation but more studies are needed to determine how best to use these agents to improve outcomes further.

Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer.

Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective. Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models. We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age ≥ 65years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age ≥ 65years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009). Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age ≥ 65years and lung cancers as independent risk factors for CIP.

SAT0536 IMMUNE CHECKPOINT INHIBITOR THERAPY IN PATIENTS WITH PREEXISTING SARCOIDOSIS

Background:Immune checkpoint inhibitors (ICI) have changed the treatment landscape of many cancer types, but are also associated with development of immune-related adverse events, includingde novosarcoid like reactions. However, little is known about the use of ICI therapy in patients with preexisting sarcoidosis as patients with preexisting autoimmune diseases have been systematically excluded from clinical trials of ICI therapy due to concerns of heightened toxicities. Emerging research suggests that ICI therapy can be considered in some patients with autoimmune diseases.1Objectives:To determine the risk of sarcoidosis exacerbation or flare in patients with preexisting sarcoidosis receiving ICI therapy.Methods:We conducted a retrospective cohort study of patients seen at The University of Texas MD Anderson Cancer Center between 2016-2019. Patients were included in the cohort if they received one of 7 ICI therapies (ipilimumab, nivolumab, pembrolizumab, durvalumab, avelumab, atezolizumab, or cemiplimab) and had an International Classification of Disease version 10 code of sarcoidosis (D86.*), prior to the ICI initiation, with diagnosis confirmed in medical record by treating physicians. A sarcoidosis diagnosis was considered “possible” if the medical record documented a history of sarcoidosis, “probable” if a history of biopsy proven sarcoidosis was mentioned, and “definitive” if histological evidence was available. Frequency of flares and outcomes of patients after receiving ICI were collected.Results:During the study timeframe a total of 32 patients with preexisting sarcoidosis received ICI therapy. Nine patients (28%) had a definitive diagnosis of sarcoidosis, 12 (37%) had a probable diagnosis and 11 (35%) had a possible diagnosis of sarcoidosis. The mean time between diagnosis of sarcoidosis and initiation of ICI therapy was 13 years (range: &lt;1 to 51 years). Twenty-seven patients (84%) received monotherapy and five patients (16%) received combination or sequential ICI therapy. Of the 32 patients, one patient with a 20-year remote history of sarcoidosis, never treated, developed a clinically symptomatic exacerbation of sarcoidosis one month after the initial dose of atezolizumab, with increased hilar nodules on imaging, skin nodules, arthritis and uveitis. Biopsy of a lymph node showed non-necrotizing granulomas, and biopsy of the skin panniculitis. The patient also developed colitis thought to be an immune-related adverse event. Atezolizumab was discontinued after 3 doses. Patient was treated with prednisone and azathioprine.Conclusion:Patients with a remote history of stable sarcoidosis at the time of ICI therapy infrequently develop a flare of their sarcoidosis. The risk of flares in patients with active sarcoidosis requiring immunosuppression at the time of ICI initiation is unknown.

Use of Immune Checkpoint Inhibitors in End Stage Kidney Disease Patients, Single Center Experience and Review of the Literature.

Immune checkpoint inhibitors (ICIs), immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis of patients with advanced malignancy. Although we are aware that there is no renal clearance of these agents (1), the data on the use of ICIs in patients with ESKD on hemodialysis (HD) as well as those on peritoneal dialysis (PD) is sparse. Published reports on the use of ICIs in patients with ESKD are limited to case reports and case series: one from Korea (2) and the second from Italy (3). We describe our single-center experience of ICI use in patients with ESKD and summarize the current literature of ICI use in this population. We used data from a large health system in the state of New York comprising 23 hospitals and >700 ambulatory facilities. Data for this study were obtained from the enterprise inpatient electronic health record (Sunrise Clinical Manager; Allscripts, Chicago, IL), which covers 13 of the hospitals, including the oncology infusion centers. Using an analytics database, we identified all patients with a minimum of one ESKD diagnosis code (Insertional Classification of Diseases 10th Edition, N18.6) who received at least one of the following agents between 2012 and 2019: ipilimumab, nivolumab, pembrolizumab, or atezolizumab. We included both prevalent patients on dialysis (those already receiving dialysis during the time of ICI initiation) and incident patients on dialysis (those who started dialysis after ICI initiation). Charts were reviewed manually to confirm that patients were on HD or PD during the ICI therapy. Clinical details such as demographics, comorbidities, cancer type, immune-related adverse …

Pulmonary Complications Secondary to Immune Checkpoint Inhibitors.

Background Immune checkpoint inhibitors (ICI) have changed the landscape in the treatment of a number of cancers. Immune-related adverse events (irAEs) have emerged as a serious clinical problem with the use of ICI. Methods All oncology patients diagnosed with pulmonary complications secondary to ICI at Mayo Clinic Rochester from January 1, 2012 to December 31, 2018 were reviewed. Demographics, comorbidities, smoking, and oncologic history were analyzed. Results A total of 10 patients developed pulmonary complications secondary to ICI. Seven patients were men (70%), and the median age at diagnosis was 61.5 (IQR 55.8-69.3) years. All patients had stage IV disease. Melanoma was the most common malignancy. Seven (70%) patients had a positive smoking history, and 6 (60%) were obese (BMI > 30). Most cases were grade 2 pneumonitis (70%). One patient with grade 4 pneumonitis required endotracheal intubation and a prolonged course of systemic corticosteroids (>30 days). Eight (80%) patients received prior radiation therapy. The median time from initiation of ICI to pneumonitis diagnosis was 3.5 months. Conclusion Melanoma was the most common malignancy, the majority of patients had grade 2 pneumonitis and required treatment with steroids, and all patients affected by ICI-related pneumonitis had stage IV malignancy. Potential risk factors included smoking history, prior radiotherapy, obesity, and advance stage at the time of ICI initiation. Extrapulmonary irAEs are common in patients with pneumonitis.

Kidney Biopsy Should Be Performed to Document the Cause of Immune Checkpoint Inhibitor-Associated Acute Kidney Injury: CON.

Immune checkpoint inhibitors (ICPis) have revolutionized the treatment of cancers by engaging the patient’s own immune system against the tumor (1⇓–3). Checkpoint pathways are innate mechanisms to put the brakes on immune activation. Approved agents target checkpoint pathways mediated by cytotoxic T lymphocyte–associated antigen 4 (CTLA4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PDL-1) (1,4⇓⇓–7). Releasing the breaks on the immune system enhances destruction of tumor cells, but can lead to immune-related adverse effects (8,9), including renal toxicity (1,2,10⇓⇓–13). The incidence of renal toxicity with ICPis ranges from 1% to 5% (12). This risk is higher in patients that are on combination therapy with both anti-CTLA4 and anti–PD-1/PD-L1 with an odds ratio of 3.88 (95% CI, 2.21 to 6.81) (14). Further, a lower baseline GFR before therapy increases risk of kidney injury with an odds ratio of 1.99 (95% CI, 1.43 to 2.76) for every 30 ml/min per 1.73 m2 decline (14). The time to prevent kidney injury starts at the time of ICPi initiation. Based on a recent multicenter review of 138 patients, risk of ICPi-associated AKI (ICPi-AKI) was higher with concomitant use of proton pump inhibitors (PPIs) with an odds ratio of 2.85 (95% CI, 1.81 to 4.48) (14). Cortazar et al. describe that 70% of patients with ICPi-AKI were on potential acute interstitial nephritis (AIN)–causing medications including PPIs (15,16), nonsteroidal anti-inflammatory drugs (NSAIDs) (17), and antibiotics (18) where PPI was present on >50% of patients’ medication lists. Baseline use of PPIs was also associated with ICPi-AKI in a large study by Seethapathy et al. (1), particularly 2.5 months after being on ICPi. Appropriate counseling to stop or substitute these medications …

Efficacy of immune checkpoint inhibitors (ICI) treatment in special populations of metastatic renal cell carcinoma (mRCC).

673 Background: Immunotherapies involving a PD-1/PD-L1 immune-checkpoint inhibitor (ICI) are highly effective treatments for mRCC and are now standard of care. Nevertheless, special populations such as patients (pts) with renal impairment (RI) and elderly age were either excluded or underrepresented in registration trials. Here we investigate the efficacy of ICI in mRCC with RI and age above 70 years (yrs). Methods: We utilized the mRCC Princess Margaret database to select pts treated with an ICI agent from May 2005 to May 2018. Renal impairment (RI) was defined as a baseline creatinine &gt; 1.5 ULN or clearance of creatinine &lt; 40 mL/min. Pts were classified as elderly if their age was over 70yrs at the time of ICI initiation. Descriptive statistics and survival analysis were performed. Results: Of 387 pts, 74 received an ICI agent or combination. Mean age was 61yrs and median creatinine was 105 umol/L. Fifty-four pts (73%) were treated with single agent PD-1/PD-L1 ICI and 46 (62%) received treatment as 2nd line. Respectively, 19 (26%), 43 (58%) and 12 (16%) pts were classified as International Metastatic RCC Database Criteria (IMDC) prognostic groups good, intermediate and poor. Of 73 pts with available creatinine levels, 7 (9.5%) were classified as having RI. Ten pts (13.5%) were &gt; 70yrs. Despite not statistically different, pts with RI had worse median overall survival (OS) compared to pts without RI: 7.8 months (m) vs. 28.3m (p=.10). There was no OS difference between pts &gt; 70yrs compared to ≤ 70yrs: not reached (NR) vs. 28m (p=.65). Both RI and elderly patients had no differences in distribution of IMDC prognostic groups compared controls. Conclusions: RI was associated with a non-statistical detriment in OS of mRCC treated with ICI. RI may be a surrogate for comorbid factors that impact OS and needs further analysis in a larger patient sample. Age does not affect ICI efficacy in our cohort. Larger studies to confirm our findings in these special populations are necessary.

Safety and efficacy of immune checkpoint inhibitors (ICI) in metastatic non-clear cell renal cell carcinoma (nccRCC): An institutional experience.

640 Background: ICIs have improved outcomes in clear cell RCC patients (pts), and emerging data suggest that they may be effective against nccRCC. nccRCC comprises ~25% of renal tumors and consist of a diverse group of diseases. Despite recent evidence, data regarding the efficacy of ICIs in nccRCC remain limited, especially among rarer nccRCC subtypes. Methods: We identified all cases of metastatic nccRCC that received at least one dose of ICI therapy at UT Southwestern Medical Center from 2014 – 2018. Baseline characteristics and IMDC criteria were evaluated at the time of ICI initiation. Outcomes included objective response rate (ORR) per RECIST v1.1 criteria, time to next treatment (TNT), and overall survival (OS). Immune-related adverse events (irAE) were graded per CTCAE 4.0 criteria. Survival estimates were evaluated using Kaplan Meier methods. Results: We identified 28 pts with metastatic nccRCC; 12 (42.9%) unclassified RCC (uRCC), 8 (28.6%) papillary RCC (pRCC), 3 (10.7%) chromophobe RCC (chRCC), 3 (10.7%) hereditary leiomyomatosis and renal cell cancer (HLRCC), 1 (3.6%) translocation RCC (tRCC) and 1 (3.6%) acquired cystic disease-associated RCC (ACD-RCC). 23 (82.1%) pts were intermediate or poor risk by IMDC criteria. In total, 13 (46.4%) pts received nivolumab monotherapy, and 15 (53.6%) in combination with ipilimumab. 12 (42.9%) pts received ICI in the first line. The median TNT and OS amongst all nccRCC subtypes was 4.9 (95% CI: 1.7-8.1) and 15.9 (95% CI: 5.9 – 25.9) months respectively. The ORR was 3/28 (10.7%), with 2 complete responses. All responses were restricted to the pRCC and uRCC subtypes. 11 (39.3%) pts experienced any irAE and 5 (17.9%) had a grade 3/4 irAE, including one case of grade 4 myocarditis. The median time to onset of an irAE was 1.9 months (Range: 0.1 to 12.0). At a median follow up of 10.8 months (95% CI: 10.2 – 17.9), 4 pts remain on therapy and 13 pts have died. Conclusions: ICI therapy demonstrated modest efficacy in this cohort with comparable irAE profiles to ccRCC. Objective responses were not seen in pts with HLRCC, ACD-RCC, tRCC, or chRCC in this study.

Immune checkpoint inhibitors (ICI) in clear cell renal cell carcinoma (ccRCC) following high-dose interleukin-2 (IL-2).

635 Background: IL-2 can be curative in a small subset of ccRCC patients (pts). Recent data suggest that ICIs may lead to long lasting responses, and ICI therapy following progression on IL-2 seems reasonable. However, data regarding the safety and efficacy of ICI following IL-2 is limited. Methods: ccRCC pts treated with ICI after first line were identified at UT Southwestern Medical Center from 2014 – 2018 and assessed by comparison to IL-2 naïve pts at the time of ICI initiation. Outcomes included objective response rates (ORR) determined by RECIST v1.1, time to next treatment (TNT) and overall survival (OS). Immune-related adverse events (irAEs) were graded per CTCAE v4.0. Comparisons were performed using Pearson Chi-square, independent t-tests, and Fischer’s exact tests as appropriate. The log-rank test was utilized for Kaplan-Meier survival analyses. Results: We identified 127 ccRCC pts treated with ICI after first line, 17.3% (22) who had received prior IL-2 and 83.7% (105) who were IL-2 naïve. Pts in the IL-2 group were younger (mean age, 56 vs. 63 years; p=0.003), and more heavily pretreated (median 2 prior lines vs. 1; p &lt;0.0001). The distribution by IMDC criteria was similar with 86.4% (19) and 76.4% (81) in intermediate/ poor group in IL-2 vs. IL-2 naïve groups, respectively (p = 0.431). The ORR was 9.1% (2/22) vs. 21.2% (22/104) in the IL-2 vs. IL-2 naïve groups, respectively (p=0.244). The median TNT was 7.5 (95% CI: 1.8 to 13.2) vs. 9.2 (95% CI: 6.0 – 12.4; p= 0.667) months in the IL-2 vs. IL-2 naïve groups, respectively. The median OS was 26.4 (95% CI: 17.3 – 35.5) vs. 29.8 (23.1 to 36.4) months in the IL-2 vs. IL-2 naïve group, respectively. 18.2% (4) vs. 21.9% (23) pts developed a grade 3/4 irAE in the IL-2 vs. IL-2 naïve group, respectively (p=0.698). Conclusions: Our study suggests that ICI therapy following treatment with high-dose IL-2 remains efficacious and is not associated with an increased risk of irAEs.

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.

Angiotensin-converting enzyme (ACE) inhibitor prescription affects non-small-cell lung cancer (NSCLC) patients response to PD-1/PD-L1 immune checkpoint blockers

ABSTRACT Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension and congestive heart failure. Preclinical data show that ACE plays a role on both innate and adaptive immune responses. Since interactions between ACE inhibitors and immune checkpoint inhibitors (ICIs) have not been reported, the aim of this study is to investigate the influence of ACE inhibitors on non-small cell lung cancer (NSCLC) patients treated with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. We conducted a retrospective cohort analysis of NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinical and co-medication data as well as tumor biopsies were collected. Groups were defined according to patients’ co-medications at the time of ICI initiation. Among the 178 patients included, 22 (13.1%) received ACE inhibitors. While baseline characteristics were similar in both groups, ACE inhibitors group had a shorter median PFS (Progression-Free Survival) compared to the control group: 1.97 vs. 2.56 months, p = .01 (HR = 1.8 CI95% 1.1–2.8). Using CIBERSORT, RNA sequencing suggested that tumors from the ACE inhibitors group had less M1 macrophages, activated mast cells, NK cells and memory activated T cells, thus suggesting an immunosuppressed state. In vitro, the ACE inhibitor, captopril, induced M2 marker at the cell surface of monocytes engaged into M1 differentiation. Thus, ACE inhibitors prescription concomitant to PD-1/PD-L1 inhibitors treatment seems to be associated with impaired outcome and with a tumor immunosuppressed state in patients with advanced NSCLC. These results should be validated in larger prospective cohorts.

Immune checkpoint inhibitors may be safe for patients with preexisting autoimmune disease.

Immune checkpoint inhibitors may be safe for patients with preexisting autoimmune disease.

Outcomes of patients (pts) with metastatic urothelial cancer (mUC) and poor performance status (PS) receiving anti-PD(L)1 agents.

4525 Background: Anti-PD(L)1 immune checkpoint inhibitors (ICI) prolong overall survival (OS) after platinum chemotherapy in mUC. However, clinical outcomes in pts with poor PS at time of ICI initiation are unknown. We hypothesized that ICI initiation in pts with ECOG PS 2-3 would be associated with worse outcomes vs. pts with ECOG PS &lt; 2, and impact death location. Methods: A retrospective cohort study in 8 institutions identified pts with mUC who received ICI. Demographic, clinicopathologic, treatment (tx) patterns, tx response, and outcomes were collected. Primary endpoint: overall response rate (ORR). Secondary endpoints: median (m) OS in pts receiving ICI as 1st and 2nd line (1L, 2L); odds of dying in hospital (vs elsewhere) for pts receiving ICI (vs no tx) within 30 days of death; and estimated drug cost for pts with ICI within 30 days of death based on average wholesale price. Unadjusted logistic regression was used to assess association between ORR and ECOG PS (2-3 vs &lt; 2) and wald test was used to compare mOS between ECOG PS (2-3 vs &lt; 2). Results: 194 consecutive pts (30% women, 41% never smokers, median age at diagnosis 69) treated with ICI for mUC were identified. Median number of total tx lines was 2; all pts received ≥1 ICI line (6 pts received 2 ICI lines); 97, 79, 17 and 7 pts received ICI in 1L, 2L, 3L and 4L, respectively; 26% pts with ICI in 1L and 2L had ECOG PS 2-3. ORR and mOS are shown in table. Among 106 pts who died, 96 had available death location; of those, 8% received ICI within 30 days of death. Starting ICI within 30 days of death (vs no tx) was associated with higher odds of hospital death (OR 6.05, 95%CI 1.3-27.6). Estimated average ICI cost/pt within 30 days of death was $1400.58. Conclusions: Pts with ECOG PS 2-3 at time of ICI initiation had similar ORR vs ECOG PS &lt; 2 but worse mOS. ICI initiation within 30 days from death was associated with higher likelihood of hospital death. ICI may not circumvent the negative prognostic role of poor PS, so biomarker-based pt selection is critical. Limitations include lack of adjustment for selection bias and other confounders at time of ICI initiation; data validation is ongoing. [Table: see text]

What impact do the proton pump inhibitors have on the efficacy of immune check point inhibitors in metastatic malignant melanoma?

e21040 Background: Acidic microenvironment facilitates the proliferation, progression, and metastasis of the tumors. Mouse models have shown that the proton pump inhibitors (PPI) cause neutralization of the acidic tumor microenvironment (TME) and inhibit the tumor growth. PPI also sensitize the resistant tumors to chemotherapeutic and immunotherapeutic effects. Moreover, PPI’s modify the gut microbiota, that impact the efficacy of immune checkpoint inhibitors (ICI). Clinical studies have shown variable impact of PPI on efficacy of ICI, ranging from no benefit at all to a negative impact. Since, PPI are one of the most commonly used medications, it is important to evaluate its impact on the efficacy of ICI. Methods: We conducted a retrospective analysis on 120 metastatic malignant melanoma patients treated with anti- CTLA-4 (ipilimumab), anti PD-1(pembrolizumab) alone or in combination. Cohort A included patients who were taking PPI at the time of ICI initiation. Cohort B included non-PPI users. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression free survival (PFS) were calculated. ORR and PFS were the primary outcomes. Cox regression univariate and multivariate analyses were performed. The proportions of grade 3 or 4 immune related adverse events (IrAE) were compared between PPI users and nonusers using the Fisher’s exact test. Results: Cohort A included 29 (24.2%) patients, of which 68.7% patients were male. Median age was 65 years. Majority of the patients were taking omeprazole (58.6%). Proportion of the patients taking ipilimumab and pembrolizumab or nivolumab were almost similar (48.3% vs. 44.8%, respectively). Significantly higher proportion of patients achieved ORR and DCR in cohort A [76%, OR = 3.8(1.39 – 10.5), P = 0.009) and 84%, OR = 4.3(1.37 – 13.7), P = 0.013, respectively). The median PFS was significantly higher in cohort A [A = 27.6 vs. B = 4.4 months, HR = 0.3, P = 0.005(0.1 – 0.7)]. Although, median OS was considerably higher in cohort A, the difference was not statistically significant [A = 39.3 vs. B = 28.0 months, HR = 1.01, P = 0.9(0.4-2.0). PPI did not significantly increase the Odds of having grade 3 or 4 IrAE. Conclusions: In this retrospective review, we have observed favorable outcomes in patients receiving PPI when starting on ICI contrary to some of the studies suggesting negative impact of PPI on ICI efficacy. As PPI is one of the commonly used chronic medications, prospective studies are needed to evaluate the real impact of PPI on ICI when taking concomitantly.

Clinical and molecular characteristics of responders versus non-responders to immune checkpoint inhibitors (ICI) in NSCLC.

114 Background: Evidence from randomized clinical trials and retrospective studies has shown that tumors with specific driver mutations may be less likely to respond to ICI; the optimal timing of ICI is unknown in this population. In this analysis, we evaluated the characteristics of responders to ICI compared to non-responders, with emphasis on the role of driver mutations. Methods: We retrospectively collected clinical characteristics and outcomes for patients who received ICI for NSCLC at Stanford University between April 2015 and August 2016. Patients were classified as responders if time on ICI was 180 days or more, and as non-responders if less than 180 days. Outcomes included radiographic improvement while on ICI, survival from diagnosis, and survival from ICI initiation. Results: Data were available for 84 patients, with median follow-up of 31 months. 18 patients were deemed responders (21%); 66 were deemed non-responders (79%). Of the patients who underwent genomic testing, 13% (2/15) of responders had mutations in EGFR/ALK/ROS1, compared to 32% (17/49) of non-responders (p = 0.195). Within the responders, 89% (16/18) had an associated radiographic improvement, compared to 11% (7/66) of non-responders (p &lt; 0.0001). Patients with mutations in EGFR/ALK/ROS1 had a median overall survival of 46 months from diagnosis, compared to 26 months in those without these mutations (p = 0.08). Patients with mutations in EGFR/ALK/ROS1 had a median survival of 4.9 months from ICI initiation, compared to 7.0 months in those without (p = 0.45). Conclusions: Patients receiving ICI for 180 days or more had a significantly higher rate of radiographic improvement, suggesting that time on therapy appears to be a surrogate endpoint of clinical benefit. While there was not a statistically significant smaller number of responders with EGFR/ALK/ROS1, there appeared to be clinically meaningful lower response rate in these patients. This was likely limited by sample size; expansion of the sample size is planned. There was a trend to overall survival benefit in patients with driver mutations, likely driven by targeted therapy as there were no statistical differences in survival from time of ICI initiation.