non-ICI Therapy Research Articles

NCOG-02. MANAGEMENT OF PATIENTS WITH MELANOMA BRAIN METASTASES AND PRIOR SYSTEMIC TREATMENT EXPOSURE: A SINGLE-CENTER EXPERIENCE

Abstract Although systemic therapy (ST) for melanoma patients with untreated brain metastases (BrM) has activity, ST options for patients with melanoma BrM that develop on or after ST are limited. In this single-center retrospective study, we describe the characteristics and survival outcomes of patients aged > 18 years with metastatic melanoma and who developed BrM > 90 days after their first dose of checkpoint inhibitor (CPI) or targeted therapy (TT). Relevant clinical data and data on ST prior to and after BrM diagnosis were collected. MRIs were reviewed to assess intracranial progression-free survival (IC-PFS) as per RANO-BM criteria. The primary outcome was overall survival (OS). Cox regression model was applied to identify factors associated with OS. Between 2010 and 2019, we identified 103 patients with median age 56 (29-92) years, 69 (67%) of whom were male; 57 (55%) had BRAF V600-mutant tumors. Ninety-four (91%) had no known BrM at the time of first-line therapy. Median number of BrM was 3 (1-58), median number of prior ST was 1 (1-5), 75 (73%) had prior CPI exposure and 70 (68%) were on concurrent CPI or TT at the time of BrM diagnosis. Local treatments included SRS in 43 (42%) and WBRT in 46 (44%) patients. From BrM diagnosis, median IC-PFS and OS were 3.5 (95% CI 2.6-4.3) and 6.9 (95% CI 5.2-8.6) months, respectively. Adverse prognostic factors were: BRAF wild-type (HR 2.04, 95% CI 1.15-3.64), ECOG 2-4 (HR 3.55, 95% CI 1.93-6.53), and increasing number of prior ST (HR 1.62, 95% CI 1.23-2.13). CPI therapy that was continued, started, or restarted after BrM was associated with improved median OS compared to non-ICI therapy (9.9 vs. 3.5 months, HR 0.45, 95% CI 0.27-0.74). In conclusion, our data support development of CPI-based trials for patients who experience progression with BrM on or after modern ST.

Development and validation of a novel defined mutation classifier based on Lasso logistic regression for predicting the overall survival of immune checkpoint inhibitor therapy in renal cell carcinoma.

Currently, immune checkpoint inhibitor (ICI)-based therapy has become the first-line treatment for advanced renal cell carcinoma (RCC). However, few biomarkers have been identified to predict the response to ICI therapy in RCC patients. Herein, our research aimed to build a gene mutation prognostic indicator for ICI therapy. This multi-cohort study explored the mutation patterns in 2 publicly available advanced RCC ICI therapy cohorts, the Memorial Sloan Kettering Cancer Center (MSKCC) advanced RCC ICI therapy cohort and the CheckMate ICI therapy cohort. A total of 261 patients in the CheckMate ICI therapy cohort were randomly assigned to either the training or validation set. Least absolute shrinkage and selection operator (Lasso) logistic regression analysis was subsequently used to develop a mutation classifier utilizing the training set. The classifier was then validated internally in the validation set and externally in 2 ICI therapy cohorts and 2 non-ICI therapy cohorts. Survival analysis, receiver operator characteristic curves and Harrell's concordance index were performed to assess the prognostic value of the classifier. Function and immune microenvironment analysis in each subgroup defined by the classifier were performed. A 10-gene mutation classifier was constructed based on the CheckMate ICI therapy cohort to separate patients into 2 risk groups, with patients in the high-risk group showing significantly lower overall survival probability than those in the low-risk group [the training set (HR: 1.791; 95% CI: 1.207-2.657; P=0.003), the validation set (HR: 1.842; 95% CI: 1.133-2.996; P=0.012) and combination set (HR: 1.819; 95% CI: 1.339-2.470; P<0.001)]. Further validation confirmed that the mutation classifier only showed predictive value for patients receiving ICI therapy instead of non-ICI therapy. Combined with the clinical characteristics, the risk score was proven to be an independent prognostic factor for overall survival in ICI therapy by multivariate Cox regression analysis. Functional and immune infiltration analysis demonstrated that lower risk scores tended to associate with immunologically "hot" status in RCC. Our 10-gene mutation classifier was found to be a biomarker for predicting the overall survival of patients with advanced RCC to ICI therapy.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring BRAF mutations.

Despite immune checkpoint inhibitors (ICI) being widely used to treat patients with advanced non-small cell lung cancer (NSCLC), few studies examine the role of ICI in patients with proto-oncogene B-Raf, serine/threonine kinase (BRAF) mutations. A retrospective study was conducted for patients with BRAF-mutant NSCLC who received treatment at Shanghai Pulmonary Hospital between 2014 and 2022. Primary end point was progression-free survival (PFS). Secondary end point was best response (RECIST, version 1.1). The study involved a total of 34 patients with 54 treatments recorded. The median PFS for the whole cohort was 5.8 months and the overall objective response rate (ORR) was 24%. Patients who were treated with ICI combined with chemotherapy reported a median PFS of 12.6 months and an ORR of 44%. Those who were treated with non-ICI therapy came with a median PFS of 5.3 months and an ORR of 14%. Specifically, patients had better clinical benefits with first-line ICI-combined therapy. The PFS was 18.5 months whereas that of non-ICI group was 4.1 months. The ORR was 56% in ICI-combined group and 10% in non-ICI cohort. The findings observed an evidential and significant susceptibility to ICIs combined therapy in patients with BRAF-mutant NSCLC, especially in first-line treatment.

Dynamic peripheral blood immune cell markers for predicting the response of patients with metastatic cancer to immune checkpoint inhibitors

PurposeImmune checkpoint inhibitors (ICIs) have shown durable responses in various malignancies. However, the response to ICI therapy is unpredictable, and investigation of predictive biomarkers needs to be improved.Experimental designIn total, 120 patients receiving ICI therapy and 40 patients receiving non-ICI therapy were enrolled. Peripheral blood immune cell markers (PBIMs), as liquid biopsy biomarkers, were analyzed by flow cytometry before ICI therapy, and before the first evaluation. In the ICI cohort, patients were randomly divided into training (n = 91) and validation (n = 29) cohorts. Machine learning algorithms were applied to construct the prognostic and predictive immune-related models.ResultsUsing the training cohort, a peripheral blood immune cell-based signature (BICS) based on four hub PBIMs was developed. In both the training and the validation cohorts, and the whole cohort, the BICS achieved a high accuracy for predicting overall survival (OS) benefit. The high-BICS group had significantly shorter progression-free survival and OS than the low-BICS group. The BICS demonstrated the predictive ability of patients to achieve durable clinical outcomes. By integrating these PBIMs, we further constructed and validated the support vector machine-recursive and feature elimination classifier model, which robustly predicts patients who will achieve optimal clinical benefit.ConclusionsDynamic PBIM-based monitoring as a noninvasive, cost-effective, highly specific and sensitive biomarker has broad potential for prognostic and predictive utility in patients receiving ICI therapy.

The pancreatic cancer immune tumor microenvironment is negatively remodeled by gemcitabine while TGF-β receptor plus dual checkpoint inhibition maintains antitumor immune cells.

Pancreatic ductal adenocarcinoma (PDA) tumors have a highly immunosuppressive desmoplastic tumor microenvironment (TME) where immune checkpoint inhibition (ICI) therapy has been exceptionally ineffective. Transforming growth factor-β (TGF-β) receptor activation leads to cancer and immune cell proliferation and phenotype, and cytokine production leading to tumor progression and worse overall survival in PDA patients. We hypothesized that TGF-β receptor inhibition may alter PDA progression and antitumor immunity in the TME. Here, we used a syngeneic preclinical murine model of PDA to explore the impact of TGF-β pathway inhibitor galunisertib (GAL), dual checkpoint immunotherapy (anti-PD-L1 and CTLA-4), the chemotherapy gemcitabine (GEM), and their combinations on antitumor immune responses. Blockade of TGF-β and ICI in immune-competent mice bearing orthotopically injected murine PDA cells significantly inhibited tumor growth and was accompanied by antitumor M1 macrophage infiltration. In contrast, GEM treatment resulted in increased PDA tumor growth, decreased antitumor M1 macrophages, and decreased cytotoxic CD8+T cell subpopulation compared to control mice. Together, these findings demonstrate the ability of TGF-β inhibition with GAL to prime antitumor immunity in the TME and the curative potential of combining GAL with dual ICI. These preclinical results indicate that targeted inhibition of TGF-β may enhance the efficacy of dual immunotherapy in PDA. Optimal manipulation of the immune TME with non-ICI therapy may enhance therapeutic efficacy.

Uptake and Survival Outcomes Following Immune Checkpoint Inhibitor Therapy Among Trial-Ineligible Patients With Advanced Solid Cancers

Immune checkpoint inhibitors (ICIs) are part of standard of care for patients with many advanced solid tumors. Patients with poor performance status or organ dysfunction are traditionally ineligible to partake in pivotal randomized clinical trials of ICIs. To assess ICI use and survival outcomes among patients with advanced cancers who are traditionally trial ineligible based on poor performance status or organ dysfunction. This retrospective cohort study was conducted in 280 predominantly community oncology practices in the US and included 34 131 patients (9318 [27.3%] trial ineligible) who initiated first-line systemic therapy from January 2014 through December 2019 for newly diagnosed metastatic or recurrent nontargetable non-small cell lung, urothelial cell, renal cell, or hepatocellular carcinoma. Data analysis was performed from December 1, 2019, to June 1, 2021. Trial ineligibility (Eastern Cooperative Oncology Group performance status ≥2 or the presence of kidney or liver dysfunction); first-line systemic therapy. The association between trial ineligibility and ICI monotherapy uptake was assessed using inverse probability-weighted (IPW) logistic regressions. The comparative survival outcomes following ICI and non-ICI therapy among trial-ineligible patients were assessed using treatment IPW survival analyses. Because we observed nonproportional hazards, we reported 12-month and 36-month restricted mean survival times (RMSTs) and time-varying hazard ratios (HRs) of less than 6 months and 6 months or greater. Among the overall cohort (n = 34 131), the median (IQR) age was 70 (62-77) years; 23 586 (69%) were White individuals, and 14 478 (42%) were women. Over the study period, the proportion of patients receiving ICI monotherapy increased from 0% to 30.2% among trial-ineligible patients and 0.1% to 19.4% among trial-eligible patients. Trial ineligibility was associated with increased ICI monotherapy use (IPW-adjusted odds ratio compared with non-ICI therapy, 1.8; 95% CI, 1.7-1.9). Among trial-ineligible patients, there were no overall survival differences between ICI monotherapy, ICI combination therapy, and non-ICI therapy at 12 months (RMST, 7.8 vs 7.7 vs 8.1 months) or 36 months (RMST, 15.0 vs 13.9 vs 14.4 months). Compared with non-ICI therapy, ICI monotherapy showed evidence of early harm (IPW-adjusted HR within 6 months, 1.2; 95% CI, 1.1-1.2) but late benefit (adjusted HR among patients who survived 6 months, 0.8; 95% CI, 0.7-0.8). In this cohort study, compared with trial-eligible patients, trial-ineligible patients with advanced cancers preferentially received first-line ICI therapy. A survival difference was not detected between ICI and non-ICI therapies among trial-ineligible patients. Positive results for ICI in phase 3 trials may not translate to this vulnerable population.

Adoption of immune checkpoint inhibitors (ICI) for unresectable locally advanced or metastatic urothelial carcinoma (u/mUC): A retrospective assessment of community oncology practices.

293 Background: ICI approval provided new treatment options for patients (pts) with u/mUC. We aimed to assess the adoption of ICI and describe 1L treatment patterns in the US community oncology setting. We hypothesized that most pts would receive ICI either as first- (1L) or second- line (2L) treatment given their FDA approval indications within the study period. Methods: This was a retrospective study of all study-eligible adult pts with u/mUC who initiated 1L treatment between 5/1/16 – 11/30/18 within The US Oncology Network. Data were sourced from structured and unstructured electronic health record data through 5/31/19 and assessed descriptively. Results: Among 750 eligible pts, 327 received 1L ICI (median age 74, 72.5% men, 77.1% white, 27.2% never smokers, 63.6% Eastern Cooperative Oncology Group performance status (ECOG PS] score of 0/1) and 423 1L non-ICI agents (median age 72, 74.0% men, 84.2% white, 26.0% never smokers, 60.5% ECOG PS score of 0/1). The most common treatment sequences were 1L ICI or 1L non-ICI without 2L treatment (n = 301 [40.1%] and n = 197 [26.3%], respectively), followed by 1L non-ICI and 2L ICI (n = 176, 23.5%). Platinum-based chemotherapy was the most common non-ICI therapy. Among a subset of patients randomly selected for chart review who received 1L ICI (n = 70), the most common reasons for 1L discontinuation were death (22.9%), transition to hospice (21.4%) and disease progression (11.4%). In contrast, the most common reason for 1L discontinuation among patients who received 1L non-ICI therapy selected for chart review (n = 133) were toxicity (27.8%), disease progression (22.6%) and completion of planned treatment (19.5%). Conclusions: As a retrospective observational study, limitations include lack of randomization, missing data, selection bias and unmeasured confounders. The high proportion of pts who received ICI during this period suggests enthusiasm for new therapies with less toxicity than chemotherapy. Nonetheless, the high attrition across treatment lines indicates an unmet need for tolerable and effective 1L u/mUC therapies, including switch maintenance ICI, which recently emerged as the new standard of care with level I evidence. Further investigation is needed to understand factors considered by pts and providers when determining treatment, as well as prognostic and predictive biomarkers.

Uptake and effectiveness of checkpoint inhibitor therapy among trial-ineligible patients with advanced solid malignancies.

e18595 Background: Immune checkpoint inhibitors (ICIs) are part of standard of care in many advanced solid malignancies. Patients (pts) with poor performance status or organ dysfunction have been usually ineligible in pivotal clinical trials of ICIs. Methods: In this retrospective cohort study, we assessed ICI uptake and effectiveness among 34,131 pts diagnosed with advanced non-targetable non-small cell lung (NSCLC), urothelial cell (UCC), renal cell (RCC), or hepatocellular (HCC) carcinoma between January 1, 2014 and December 31, 2019. Pts were identified from the Flatiron Health electronic health record-derived database, consisting of pts receiving care in 280 mostly community oncology practices in the US. 9,318 (27.3%) pts were trial-ineligible based on ECOG performance status ≥ 2 or liver (total bilirubin ≥ 3 mg/dL) or kidney (eGFR &lt; 30 ml/min/1.73m2) dysfunction. The association between trial-ineligibility and ICI monotherapy uptake was assessed using inverse probability weighted logistic regression. We hypothesized that there would be no differences in overall survival between ICI and non-ICI therapies in the trial-ineligible cohort. To test this hypothesis, we used inverse probability of treatment weighted survival analyses. Because we observed non-proportional hazards, we report 12- and 36-month restricted mean survival times (RMSTs) and time-varying hazard ratios &lt; and ≥ 6 months. Results: Between 2014-2019, the proportion of pts who received ICI monotherapy rose from 0% to 30.2% among trial-ineligible pts and from 0.1% to 19.4% among trial-eligible pts. Trial-ineligible pts received ICI monotherapy more frequently than trial-eligible pts (22.5% vs 12.7%, adjusted odds ratio [aOR] relative to non-ICI therapy 1.8, 95% CI 1.7-1.9). Among trial-ineligible pts, there were no OS differences between ICI monotherapy, ICI combination therapy, and non-ICI therapy at 12 months (RMST 7.8 vs. 7.7 vs. 8.1 mos) or 36 months (15.0 vs. 13.9 vs. 14.4 mos). Relative to non-ICI therapy, ICI monotherapy was associated with early mortality (adjusted hazard ratio [aHR] within 6 months 1.19) but late benefit (aHR after 6 months 0.80) in trial-ineligible pts (Table). Conclusions: Trial-ineligible pts with advanced malignancies preferentially receive first-line ICI, despite the lack of a survival benefit and possible early mortality associated with ICI use. Positive results for ICI in phase III trials may not translate to this vulnerable population. [Table: see text]

Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

BackgroundThis study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.MethodsThree cohorts including...

Rechallenge of nivolumab in metastatic renal cell carcinoma, an ambispective multicenter study (RENIVO).

330 Background: Immune checkpoint inhibitors (ICIs) in combination with another ICI or an antiangiogenic targeted therapy have been approved for frontline therapy in metastatic renal cell carcinoma (mRCC). However, progression disease (PD) often occurs and subsequent therapies are needed. Rechallenge of ICI may then be an option, but there is a lack of data regarding this strategy. Methods: This ambispective multicenter study included patients who received a rechallenge of Nivolumab (ICI-2) between January 2014 and September 2020, after a first-ICI therapy (ICI-1), regardless of the reason of the discontinuation. Patients could have either a non-ICI therapy or have a prolonged free-interval (≥ 12 weeks) between ICI regimens. Those with ongoing rechallenge at inclusion were followed prospectively. Primary endpoint was investigator-assessed best ORR. Results: 45 rechallenges were included from 16 centers. Median age was 60 years (range, 42-90), 64% were male. Most of them had clear cell histology (91%) and a Fuhrman or ISUP grade ≥ 3 (80%). Single-agent Nivolumab and Nivolumab-Ipilimumab association were used in 78% and 11% during ICI-1 and in 93% and 7% during ICI-2, respectively. Discontinuation for PD, toxicity or clinical decision occurred in 49%, 27% and 24% for ICI-1 and in 94%, 3% and 3% for ICI-2, respectively. The ORR were 51% (n = 23) at ICI-1 and 16% (n = 7) at ICI-2. One patient had a complete response during both ICI-1 and ICI-2 and two had a partial response at ICI-2 although they had PD as best ICI-1 response. After a median follow-up of 14.9 months (mo), median duration of response for ICI-2 was 5.1 mo (95% CI, 2.7-not reached [NR]). For ICI-1 and ICI-2: median progression-free survival (PFS) was 11.4 mo (95% CI, 9.8-23.5) and 3.5 mo (95% CI, 2.8-9.7); median overall survival was NR (95% CI, 37.8-NR) and 24 mo (95% CI, 9.9-NR). Poor prognostic factors for PFS at ICI-2 were Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2, presence of liver metastases, inflammatory syndrome and PFS under ICI-1 &gt; 6 months. Grade ≥ 3 immune-related adverse events occurred in 24% (n = 11) during ICI-1 but only in 4% (n = 2) during ICI-2. There was no treatment-related death. Conclusions: Our study suggests that resumption of ICI with Nivolumab has a moderate efficacy in mRCC and acceptable tolerance. Predictive factors of response are needed to propose this strategy to selected mRCC patients. Larger prospective cohorts are needed to confirm these results. [Table: see text]

Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies

PurposeThe receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+).MethodsA retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation.ResultsOf 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16–0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04–0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25–1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation.ConclusionOur study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

Immune Checkpoint Inhibitor-Related Adverse Cardiovascular Events in Patients With Lung Cancer

ObjectivesThe purpose of this study was to evaluate whether immune checkpoint inhibitors (ICIs) are associated with an increased risk of major adverse cardiovascular events (MACE) compared with non-ICI therapies in patients with lung cancer. BackgroundICIs activate the host immune system to target cancer cells. Though uncommon, cardiovascular immune-related adverse events can be life-threatening. MethodsA retrospective single-institution cohort study of 252 patients with pathologically confirmed lung cancer who received ICI or non-ICI therapy was analyzed. The primary endpoint was MACE, defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure. ResultsDuring a median follow-up of 6 months, MACE occurred in 13.3% of ICI-treated patients, with a median time to event of 51 days, compared with 10.3% and 64 days in non-ICI patients. ICIs were not associated with MACE (hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.57 to 2.43; p = 0.66) in a univariable Fine-Gray regression analysis incorporating noncardiovascular death as a competing risk. Multivariable regression analyses determined that patients treated with ICIs with elevated serum troponin I >0.01 ng/ml (HR: 7.27; 95% CI: 2.72 to 19.43; p < 0.001) and B-type natriuretic peptide (BNP) >100 pg/ml (HR: 2.65; 95% CI: 1.01 to 6.92; p = 0.047) had an increased risk of MACE. Patients pre-treated or receiving combined immunotherapy with ICIs and vascular endothelial growth factor inhibitors (VEGFIs) or tyrosine kinase inhibitors (TKIs) had an increased risk of MACE (HR: 2.15; 95% CI: 1.05 to 4.37; p = 0.04). ConclusionsICIs were not independently associated with an increased risk of MACE in patients with lung cancer, although power is an important limitation in these analyses. ICI-associated cardiotoxicity was associated with elevations in serum troponin and BNP, and combined immunotherapy with VEGFIs or TKIs. Future studies are needed to further define the role of cardiac biomarkers as a monitoring strategy with ICI therapy.

1277P - Immune checkpoint inhibitors (ICIs) as “chemotherapy (Ctx) sensitization” strategy in advanced solid tumours

1277P - Immune checkpoint inhibitors (ICIs) as “chemotherapy (Ctx) sensitization” strategy in advanced solid tumours

Abstract 4997: Responsiveness to immune checkpoint inhibitors in RET dependent cancers

Abstract Background: The RET receptor tyrosine kinase can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib, and vandetanib have demonstrated activity in RET dependent (RET+) malignancies. Recent development of selective RET inhibitors is poised to alter their treatment paradigm. However, the responsiveness of RET+ malignancies to immune checkpoint inhibition (ICI) is unknown. We compared the time to progression (TTP) on ICI with non-ICI therapy in patients with malignancies harboring activating RET mutations/fusions. Methods: A retrospective chart review of all RET+ patients who were referred to the phase 1 clinical trials program at MD Anderson Cancer Center between September 2014 and October 2018 was conducted. Patients who had not discontinued treatment or had discontinued treatment for reasons besides disease progression were censored. Time to progression was estimated using Kaplan-Meier analysis. Results: Out of 72 patients who had received systemic therapy for RET+ malignancies, 39 (54.2%) harbored RET mutations (RETm) and 33 (45.8%) harbored RET fusions (RETf). Nineteen patients (26.4%) received ICI and 53 (73.6%) received non-ICI therapy. Thirty four patients (47.2%) had medullary thyroid cancer, 29 (40.3%) had NSCLC and 9 (12.5%) had other types of cancer. PD-L1 expression was only available for 7 patients of which 5 (71.4%) were positive (≥ 1%). Patients had received a median of 1 (1-7) prior lines of therapy. Overall median TTP (mTTP) was 10.5 months (95% CI 6.7-30.1). Hazard ratio for ICI vs. non-ICI therapy was 1.73 (0.70, 4.26) p=0.25 in patients with RETf and 8.0 (2.27, 28.2) p=0.0025 in patients with RETm. Conclusions: In patients with RET+ malignancies, mTTP was shorter with ICI compared to non-ICI therapy. The effect of type of therapy was dependent on the type of RET pathway aberration, with a statistically significant higher risk of progression in RETm malignancies treated with ICI compared to non-ICI therapy. Time to ProgressionRETTherapyNmTTP (months)Freedom from Progression at 6 months (%)Freedom from Progression at 12 months (%)FusionNon-ICI218.36335FusionICI123.03624MutationNon-ICI3231.98273MutationICI75.6430 Citation Format: Aparna Hegde, Le Huang, Shuang Liu, Kenneth Hess, Maria Cabanillas, Mimi Hu, Naifa Busaidy, Steven Sherman, George Simon, George Blumenschein, Vassiliki A. Papadimitrakopoulou, David S. Hong, Funda Meric-Bernstam, John Heymach, Vivek Subbiah. Responsiveness to immune checkpoint inhibitors in RET dependent cancers [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 4997.

Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment

BackgroundImmune checkpoint inhibitors (ICIs) represent a promising novel class of cancer therapy, but immune-mediated adverse events can complicate ICI treatment. Acute cholecystitis in patients receiving ICI therapy has not been characterized. We aimed to describe the clinical features of patients who developed ICI-related cholecystitis.MethodsWe evaluated a case series of patients at a tertiary cancer center who received ICI therapy and developed cholecystitis, diagnosed by clinical presentation and diagnostic imaging, during 2010–2018. Patients with a history of chronic cholecystitis or other etiologies of acute cholecystitis, such as cholelithiasis, were excluded. A chi-square test was used to compare the frequency of cholecystitis between ICI regimens. Kaplan-Meier and log rank analyses were used to compare survival between subgroups.ResultsOf the 4253 patients who received ICIs in the study period, 25 (0.6%) patients developed suspected ICI-related cholecystitis. Alternatively, of the 31,426 cancer-matched patients who received non-ICI therapy, 72 (0.2%) developed acalculous cholecystitis (P < 0.001). Among the 25 included patients, the median time from ICI initiation to cholecystitis was 6 months (range, 0.1–31 months). Fifteen (60%) patients received an inhibitor of programmed death protein 1 (anti–PD-1) or of its ligand (anti–PD-L1) as a single agent, and 10 (40%) patients received an inhibitor of cytotoxic T-lymphocyte associated protein 4 (anti–CTLA-4) therapy alone or combined with anti–PD-1/L1. Anti–CTLA-4 monotherapy was associated with a higher risk of cholecystitis (P = 0.006). ICI therapy was discontinued in 20 patients, in three (12%) as a result of acute cholecystitis. Two (8%) patients developed sepsis, and four (16%) had perforation of the gallbladder wall. Five (20%) patients underwent surgical cholecystectomy, and eight (32%) underwent percutaneous drainage. Five (20%) patients were treated with steroids; two of them required surgery. Ten (40%) patients were able to restart ICI therapy. Patients who received a combination of anti–CTLA-4 and anti–PD-1/L1 had more complications of cholecystitis than did patients who received either agent alone (P = 0.03).ConclusionsICI treatment can result in a clinical condition similar to typical acute cholecystitis in a minority of patients. ICI-related cholecystitis should be managed in a similar fashion to typical cholecystitis. The efficacy of steroids for the treatment of ICI-related cholecystitis is unclear.