New ASH Summit Encourages Practical, Elevated Dialogue on Emerging Immunotherapies

BackgroundIn the INBUILD trial in patients with chronic fibrosing interstitial lung diseases (ILDs) and a progressive phenotype, nintedanib reduced the rate of ILD progression with adverse events that were manageable for most patients. We investigated the potential impact of immunomodulatory therapies on the efficacy and safety of nintedanib.MethodsSubjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had shown progression of ILD within the prior 24 months despite management in clinical practice, were randomized to receive nintedanib or placebo. Certain immunomodulatory therapies were restricted for the first 6 months. We analyzed post-hoc the rate of decline in forced vital capacity (FVC) over 52 weeks in subgroups by glucocorticoid use at baseline and in analyses excluding subjects or FVC measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies.ResultsOf 663 subjects, 361 (54.4%) were taking glucocorticoids at baseline (353 at a dose of ≤ 20 mg/day). In the placebo group, the adjusted rate of decline in FVC (mL/year) over 52 weeks was numerically greater in subjects taking than not taking glucocorticoids at baseline (− 206.4 [SE 20.2] vs − 165.8 [21.9]). The difference between the nintedanib and placebo groups was 133.3 (95% CI 76.6, 190.0) mL/year in subjects taking glucocorticoids at baseline and 76.1 (15.0, 137.2) mL/year in subjects who were not (interaction P = 0.18). The effect of nintedanib on reducing the rate of FVC decline in analyses excluding subjects or measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies was similar to the primary analysis. The adverse event profile of nintedanib was similar between subjects who did and did not use prohibited or restricted therapies at baseline or during treatment with trial drug.ConclusionsIn patients with progressive fibrosing ILDs, the effect of nintedanib on reducing FVC decline was not influenced by the use of immunomodulatory therapies. Nintedanib can be used in combination with immunomodulatory therapies in patients with progressive fibrosing ILDs.Trial registration ClinicalTrials.gov, NCT02999178. Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178

Introduction: Studies show that patients with IBD are at increased risk for pneumococcal disease relative to the general population. This may be linked to the underlying immune response in IBD and the risk is further increased in patients on immunomodulator therapy. The 2017 ACG guidelines for preventative care in IBD and other similar guidelines recommend pneumococcal vaccination in all adult IBD patients. However, data from the few studies that have analyzed pneumococcal vaccination trends in this population suggests that IBD patients are highly under-vaccinated including patients on immunosuppressant therapy. Methods: We conducted a chart review of patients age 18 and older seen by the gastroenterology group at our tertiary care academic center between 1/2010 and 9/2015 with an ICD-9 diagnosis of IBD. An abstraction form was used to document clinical history and health maintenance metrics which included any pneumococcal vaccination. Characteristics were compared between those with and without documented vaccine status using Chi-square or Wilcoxon Rank-Sum tests. Subgroup analysis was also conducted for patients on immunomodulator therapy. Results: A total of 184 patients had documented pneumococcus vaccination status with 29.3% (n=54) having received the vaccine. Crohn's disease was more common in the studied population (n=79) than ulcerative colitis (n=55). Notably, patients on immunomodulator therapy (n=81) were 2.7 times more likely to receive vaccination against pneumococcus than those not taking immunomodulators (40.7% versus 20.4%, odds ratio 2.7, 95% CI 1.4-5.2, p=0.003). Those with more than 1 month of steroid use were also more likely to be vaccinated (p=0.005). Age above 65 (recommended vaccination age for a healthy adult) did not have significant association with vaccination status and vaccination did not vary significantly by other demographic characteristics. Conclusion: Overall pneumococcal vaccination rates were higher than seen in other studies but still far below optimal targets. Our analysis showed patients on immunomodulator and biologic therapy are significantly more likely to have documented pneumococcal vaccination. However the rates are still suboptimal as this quality metric is met for less than half of patients. Overall a large number of patients were missing documentation of vaccination status in the medical record. The findings suggest addressing this preventable cause of mortality can be improved in the routine care and health maintenance of IBD patients.Table: Table. Characteristics of Patients in the Study (n=184) Compared by Pneumococcus Vaccination Status as Documented in Patient Chart

FRI0171 THE CHANGES OF IMMUNE FUNCTION AND CLINICAL INDEXES WITH SYSTEMIC LUPUS ERYTHEMATOSUS AFTER IMMUNOREGULATORY COMBINATION THERAPIES

AGA Technical Review on the Management of Moderate to Severe Ulcerative Colitis

Background To evaluate the need for retreatment with anti-TNF due to relapse after discontinuation based on mucosal healing in inflammatory bowel disease (IBD), as well as the influencing factors and the response to reintroduction. Methods Descriptive retrospective study of IBD patients in whom anti-TNF treatment was discontinued after mucosal healing had been proved, between June 2009 and May 2016. Demographic and phenotypic characteristics, biologic and immunomodulator (IM) therapy history, laboratory markers and histopathologic evaluation were noted. We evaluated the relapse rate after discontinuation of anti-TNF, as well as the need for reintroduction and its success rate. Results We included 100 patients, 69 of them affected by Crohn’s disease (CD), 29 with ulcerative colitis (UC) and 2 unclassified colitis. From those with CD, inflammatory behaviour (62%) and ileocolonic localisation (53%) were the most frequent conditions. Seventy-four per cent of UC patients had pancolonic involvement. Biological therapy had been indicated because of corticodependence in 66% (vs. 32% corticorefractoriness). The anti-TNF drug was infiliximab in 60 patients, adalimumab in 38, 1 certolizumab and one had been treated with golimumab. Endoscopic biopsies showed quiescent disease in 63 of 83 patients. Eighty-three per cent of patients were treated with IM after removal of anti-TNF. After a mean follow-up of 57 months, 63 patients relapsed, 52 of them needing anti-TNF reintroduction. Reintroduction rates at 12, 36 and 60 months were 19.5%, 43.5% and 52% respectively with a response after the re-treatment of 76,6%. Univariant analysis showed a higher risk in CD (61 vs. 31%, p = 0.008). Within the CD patients, the risk of reintroduction was lower in A3 (30 vs. 66%, p = 0.03) and B2 (31 vs. 69%, p = 0.006) patterns, and higher if the indication had been corticodependence (68% vs. 37%, p = 0.02). Multivariant analysis confirms the protective effect of B2 behaviour and worse outcomes for corticodependence antecedent. Considering UC, the retreatment probability was superior for those patients without IM therapy after anti-TNF discontinuation (57 vs. 22%), although this association did not reach statistical significance (p = 0.08). Conclusion The risk of needing reintroduction of anti-TNF therapy after mucosal healing in IBD is around 50% in 5 years, being superior in CD patients. Reintroduction success rate is 76%. In CD, this risk is higher when the reason for starting anti-TNF was corticodependence, and much lower when stricturing/fibrotic pattern predominates. For UC patients, anti-TNF drugs should not be stopped if IM therapy cannot be held.

100 Background: Use of checkpoint inhibitors has expanded over recent years, and the gastrointestinal (GI) oncologic indications for immunotherapy (IO) continue to evolve. IO use in GI malignancies is still in its infancy, and we sought to describe our clinical experience thus far. Methods: We retrospectively identified all patients (pts) with GI malignancies treated with IO at the Wilmot Cancer Institute from December, 2015 through July, 2017. We examined patient and tumor-related clinicopathologic features. Our main outcomes of interest were best response on IO, and frequency/severity of IO toxicity. Fisher’s exact test was used to compare categorical factors between groups of interest. Results: 21 pts received IO for a GI malignancy, all of whom had metastases (mets). 76% of pts were male, and the median age was 62 years (range, 25 – 87). Common diagnoses were colorectal (CRC) (n = 10), gastroesophageal (GE) (n = 5), and hepatocellular cancers (HCC) (n = 4). 76% of pts received pembrolizumab, and 24% of pts received nivolumab. 67% received IO as ≥ 3rd-line therapy. The median time from diagnosis of metastatic disease to initiation of IO was 17.8 mos (range, 3 – 140). The median time on therapy was 2.62 months (95% CI 1.48, 6.52 mos) (range, 0.5 – 11 mos), with 3 pts still responding at the time of the analysis. Pts with HCC had the longest time on IO (8.95 mos), compared to 2.62 mos for GE, 2.39 mos for CRC, and 1.26 mos for all other (p = 0.10). Pts who received IO as 3rd or greater line of therapy had a significantly increased likelihood of non-response or progressive disease/death compared to pts who received IO as 2nd-line (p = 0.02). There was a trend towards non-response to IO in pts with liver mets vs. extrahepatic mets (p = 0.09). 57% experienced grade 3/4 toxicities: the most common were anemia (24%), hyponatremia (14%), and fatigue (14%). No IO-specific grade 3/4 immune-related toxicities were observed. Conclusions: The majority of our pts received IO as 3rd line therapy or beyond, and were significantly less likely to respond to treatment compared to those who received IO earlier on. The presence of liver mets is potentially associated with non-response to IO, and needs further exploration. No unexpected or severe IO-related toxicities were observed.

Outcomes Of Stereotactic Radiosurgery And Immunotherapy In Renal Cell Carcinoma With Brain Metastases

The Impact of the Timing of PD-1 Inhibition on Disease Control for Brain Metastases Treated with Stereotactic Radiosurgery

e19222 Background: Use of EOL CTx is an established quality metric in patients with advanced malignancies but less is known about which types of CTx are most commonly used and association with ED and ICU utilization. We sought to describe the different types of EOL CTx and to quantify the frequency of EOL ED and ICU care associated with them. Methods: Patients in the cancer registry of an urban cancer center who died between January 1, 2018 and October 10, 2019, and ever received CTx were included. EOL CTx was defined as any CTx given within 30 days of death, while any ED visits or ICU admissions in the last 30 days of life were defined as EOL ED and ICU care, respectively. CTx was categorized by administration route (intravenous (IV), oral (PO), other), and by type (immunotherapy (IMT), non-immunotherapy biologics (NIB), other). We used Pearson’s chi-squared to measure associations between EOL CTx and EOL ED and ICU care, logistic regression to assess how CTx type modulates those associations, and Mood’s median test to compare median IMT doses between groups. Results: Among 390 eligible patients, 32% received EOL CTx, 30% EOL ED care, and 11% EOL ICU care. Most received IV CTx (78%), and 10% received IMT. Median age at diagnosis was 69 years (interquartile range (IQR) 62 - 77), and median days from diagnosis to death was 390 (IQR 185 - 665). Most common malignancies were pancreatobiliary (40%), other gastrointestinal (15%), lung (13%) and hematologic (6%). Patients treated with EOL CTx were significantly more likely to receive IMT (p = 0.03). Receipt of any EOL CTx was significantly associated with EOL ED care (p < 0.0001) and EOL ICU care (p < 0.0001). Subgroup analyses showed significant modulatory effect of IMT on association of EOL CTx with EOL ED care (b = -0.89, p = 0.046), but was not significant for ICU care (b = -0.67, p = 0.29). Median doses of IMT was 2.5 (IQR 2 - 3.8) among patients who were given EOL IMT and 4 doses (IQR 2 - 6) in those that discontinued IMT before EOL (p = 0.06). Conclusions: EOL CTx is associated with significantly increased rates of EOL ED and ICU care, which may indicate poorer quality of life. While rates of use of other CTx modalities did not significantly differ at EOL, patients were more likely to receive IMT within 30 days of death, which could be due to the belief that IMT is more tolerable or more effective than other CTx modalities at EOL. IMT at EOL is associated with a reduced risk of EOL ED care, but not ICU care. Further research on strategies to reduce EOL CTx and appropriateness of IMT at EOL is warranted.

Background: Data from prospective clinical trials support the use of immunomodulatory therapies (IT) for treatment of SSc-ILD. However, outcomes for SSc-ILD in respect to IT use in large real-life cohorts has only sparsely been reported. Methods: The German Network for Systemic Scleroderma (DNSS), which includes SSc pts. prospectively, was analyzed for SSc-ILD. Patients were categorized in IT vs. no-IT users and outcome was assessed. Results: SSc-ILD was reported in 1886 out of 4306 pts. 1109 used IT while 777 did not. Baseline characteristics at ILD diagnosis were similar with regards to gender, FVC (no IT 82% vs. IT 78%, p=0.117) and use of PH drugs. Significant differences in no-IT vs. IT were found for age, time since SSc diagnosis (10 vs. 7 years p Conclusions: In this large real-life cohort of SSc-patients, the use of immunomodulatory therapies had no significant impact on outcomes in SSc-ILD. Yet, differences in baseline characteristics have to be taken into account.

Current status and future perspectives of immunotherapy in Latin America and Cuba

Immunotherapy (IMT) has revolutionized the treatment of stage IV non-small cell lung cancer (NSCLC). However, optimal timing of IMT in relation to stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) is unknown. Utilizing the National Cancer Database, we examined trends in IMT use in metastatic NSCLC patients and the potential survival implications of IMT timing in relation to SBRT/SRS. We queried the NCDB for patients with Stage IV NSCLC diagnosed between 2004-2015. Patients receiving IMT and SBRT/SRS to any site were included. Multivariate logistic regression identified predictors of IMT use. Receiver operator characteristic curve analysis determined an a priori timeframe between SBRT and IMT predictive of optimal overall survival (OS). Univariate and multivariate analyses identified factors predictive of OS. Propensity-adjusted Cox proportional hazard ratios were used to mitigate indication bias. Of 13,862 eligible patients, 371 received IMT. The majority (75%) received chemotherapy. IMT use was associated with improved median OS on univariate analysis (17 vs. 13 months, p<0.0001). Adenocarcinoma histology, chemotherapy use, and recent treatment year were associated with IMT. On multivariate propensity-adjusted Cox regression, predictors for improved OS included: younger age, lower comorbidity score, lower grade, private insurance, IMT use, and female sex. Patients treated ≥ 21 days (a priori threshold) after SBRT/SRS initiation had improved median OS (19 vs. 15 months, p=0.0335). In patients with Stage IV NSCLC, IMT use following SBRT/SRS has increased. OS improved when IMT was given ≥3 weeks after initiating SBRT/SRS; suggesting a potential optimal time-frame between RT and IMT.

Survival in Metastatic Renal Cell Carcinoma Treated with Immunotherapy and Stereotactic Radiation Therapy or Immunotherapy Alone: A National Cancer Database Analysis

Immunotherapy (IT) is widely used across multiple cancer types, yet its impact on second primary cancers (SPC) remains poorly understood. It is unclear whether IT enhances immune surveillance that prevents progression of preclinical malignancies into clinically apparent cancers. We conducted a retrospective cohort study of adult patients with cancer treated between 2010 and 2022 across Cleveland Clinic Ohio centers. Patients (≥18 years) with cancers eligible for first-line IT were included. After excluding ineligible patients, 5,576 patients were included. Patients who received IT (with or without additional systemic therapy or radiation) were compared with those who did not. Multivariable Cox models treated IT as a time-dependent covariate and adjusted for confounders. Follow-up continued until death or loss to follow-up. Among 5,576 patients, 1,296 (23%) received first-line and 948 (17%) received subsequent-line IT, predominantly anti-PD-1/PD-L1 and/or anti-CTLA-4 agents (99.9%). Over a median follow-up of 47.5 months (IQR, 27.4-75.4), 264 SPCs were diagnosed. In the first-line IT group, 2- and 4-year SPC-free probabilities were 97% [95% confidence interval (CI), 96-98] and 94% (95% CI, 92-97) versus 95% (95% CI, 94-96) and 92% (95% CI, 91-93) in the non-IT group (log-rank P < 0.01). In multivariable analysis, IT was associated with a lower hazard of SPC (HR, 0.57; 95% CI, 0.41-0.79; P < 0.001). The treatment of primary cancer with IT was associated with a reduced clinical incidence of SPCs. These findings support further investigation into the potential of IT as a cancer prevention strategy in both cancer survivors and high-risk, cancer-free individuals.

1086 Background: Hyperprogression of disease (HPD), a rapid acceleration of tumor growth rate (TGR) has been reported with IO in other tumor types. Here, we explore HPD in aTNBC. Methods: A retrospective chart review identified aTNBC patients who consented for IO clinical trials at Princess Margaret Cancer Centre between June 2013 and June 2018. Demographic data, medical history, details of trial enrolment and RECIST 1.1 response to study treatment were recorded. Patients with RECIST 1.1 measurable disease on CT scans or physical examination before trial entry, at trial baseline and at protocol-defined interval following IO start were evaluable for TGR as defined by Champiat et al. Clin Cancer Res 2017. HPD defined as a ≥2-fold increase in TGR between baseline and on-trial restaging assessment. Univariable logistic regression used to identify variables [age, co-morbidity index, prognostic index, performance status, distant disease free interval (dDFI), lactate dehydrogenase, no. of metastatic sites, visceral disease and no. of prior treatment lines] associated with HPD. Overall survival (OS) curves were estimated with the Kaplan-Meier method and compared by the log-rank test. Results: 99 patients with aTNBC consented for 15 IO clinical trials, 60% IO monotherapy, 22% chemotherapy+/-IO and 18% IO combinations. Median age 52 (range 25-78), median no. of lines of prior systemic therapy for advanced disease 1 (range 0-8). 15% had de-novo metastatic disease, 58% recurred after a dDFI of &lt; 3 years and 25% after a dDFI of &gt; 3 years. 61% had &lt; 3 metastatic disease sites, and 71% had metastases involving the viscera. 66 received IO treatment, 40 patients (20 monotherapy, 7 IO combination, 13 chemotherapy+/-IO) were evaluable for TGR. Median TGR pre-IO was 74.3 (range -17 – 1680) and post-IO was 2.5 (-71.4 – 223). 4 patients (10%) met criteria for HPD. All 4 treated with monotherapy PD1 inhibitor and received at least 2 further lines of therapy post-trial; 1 patient treated with IO as first-line therapy, 3 in the second or later lines. There was no significant difference in the overall OS of patients with HPD and patients who did not meet definition for HPD HR 0.89, (95% CI: 0.26-3.01; p = 0.41). Univariable analysis did not identify factors associated with HPD. Conclusions: HPD was observed in 10% of aTNBC treated on IO clinical trials. HPD was not associated with worse survival outcomes or known prognostic factors in our analysis.