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We report a case of multiple high-grade and rare immune-related adverse events (irAEs) in a patient with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A middle-aged MSI-H mCRC patient with metastases to the lungs and lymph nodes received several lines of chemotherapy and immunotherapy and developed five different high-grade irAEs during immunotherapy, including lymphadenitis, pneumonitis, hypophysitis, thyroiditis and transverse myelitis. Genomic profiling revealed high tumor mutational burden of 43 Muts/Mb. Cytokine profiling showed a threefold increase in MMP-9 shortly prior to the onset of lymphadenitis and a fourfold increase of Ang-1 1 week after the resolution of lymphadenitis. Further studies are warranted to investigate the association of MSI-H mCRC with irAEs and the role of cytokines in predicting irAEs.Immune-related adverse events (irAEs) are a potential side effect of taking immunotherapy treatment for cancer. We report a case of a patient with a highly mutated form of metastatic colon cancer who developed five unique and severe irAEs while receiving immunotherapy. The patient developed inflammation of the lymph nodes, lungs, pituitary gland, thyroid and spinal cord. Genetic testing showed that the tumor was highly mutated (43 Muts/Mb). Analysis of cell signaling proteins called cytokines revealed that MMP-9 sharply increased before the onset of lymphadenitis and Ang-1 sharply increased after its resolution. Further research is needed to understand the relationship between highly mutated colon cancer and irAEs as well as the role of cytokines in predicting the onset and resolution of irAEs.

Background Treatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies. Methods This multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided. Results Among 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P Conclusions Patients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.

Supplementary Figure 1

Flow chart of dose level patient enrollment

Supplementary Data from First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response

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Supplementary Figure 3

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum.Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months).Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.

Supplementary Figure 2

Purpose:The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors.Patients and Methods:In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed.Results:ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062).Conclusions:Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non–small cell lung cancer trial.See related commentary by Lee and Fong, p. 3633

Purpose:Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade.Patients and Methods:We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink.Results:Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1–7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3–4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3–5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood.Conclusions:We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.

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Supplementary table 1 and Supplementary figure legends.

Supplemental Data legends

Purpose:Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation.Experimental Design:We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3–5 adverse events (G3–5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models.Results:A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3–5 AEs was 34% with a significant 27% reduced risk in lower doses (P = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3–5 AEs was 20.1% which was lower in non–small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (P ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose–response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3–5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (P = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (P = 0.01), a relationship that was not observed in NSCLC.Conclusions:Our analysis shows a lack of consistent dose-toxicity or dose–response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.

Supplementary Data and Methods

Supplemental Table 3. Bacterial vector vaccine trials and their grade 3/4 vaccine-related toxicities.

PURPOSE With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone. METHODS We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration–approved label, and consideration of additional or orthogonal molecular testing. RESULTS We reviewed genomic data and provided clinical recommendations for 506 patients with GI cancer who underwent tumor molecular profiling between January and June 2019 and determined follow-up using the electronic health record. Summary reports were provided to 19 medical oncologists for patients with colorectal (n = 198, 39%), pancreatic (n = 124, 24%), esophagogastric (n = 67, 13%), biliary (n = 40, 8%), and other GI cancers. We recommended ≥ 1 precision medicine clinical trial for 80% (406 of 506) of patients, leading to 24 enrollments. We recommended on-label and off-label targeted therapies for 6% (28 of 506) and 25% (125 of 506) of patients, respectively. Recommendations for additional or orthogonal testing were made for 42% (211 of 506) of patients. CONCLUSION The integration of precision medicine in routine cancer care through a dedicated multidisciplinary molecular tumor board is scalable and sustainable, and implementation of precision oncology recommendations has clinical utility for patients with cancer.

BACKGROUND AND AIMS Consensus guidelines recommend high-dose corticosteroids (1-2 mg/kg/day methylprednisolone equivalents) for treating grade ≥3 immune checkpoint inhibitor (ICI) hepatitis. We examined the effect of corticosteroid dosing on time to alanine aminotransferase (ALT) normalization, need for additional immunosuppression, and steroid-related complications. APPROACH AND RESULTS We conducted a retrospective cohort study of 215 ICI-treated patients from 2010-2020 who developed grade ≥3 (ALT>200 U/L) ICI hepatitis. Patients were grouped by initial corticosteroid dose (≥1.5 mg/kg or

Background In patients with genitourinary cancers, the effect of immune checkpoint inhibitors (ICIs) on kidney function is unknown. Patients and methods This is a retrospective cohort study of patients with renal cell carcinoma (RCC) and urothelial carcinoma who received ICIs at two major cancer centers between 2012 and 2018. Cumulative incidence and Fine and Gray subdistribution hazard models were performed to determine predictors of the co-primary outcomes, (1) acute kidney injury (AKI) and (2) sustained estimated glomerular filtration rate (eGFR) loss, defined as a >20% decline in eGFR sustained ≥90 days. We also determined the association between immune-related adverse events (irAE) and adverse kidney outcomes among patients surviving ≥1 year. Results 637 patients were included; 320 (50%) patients had RCC and 317 (50%) patients had urothelial carcinoma. Half of the cohort had eGFR Conclusion AKI and sustained eGFR loss are common in patients with genitourinary cancers receiving ICIs. irAEs may be a novel risk factor for kidney function decline among patients receiving ICIs.

Acinar cell carcinoma (ACC) is a very rare tumor of the exocrine pancreas, representing less than 1% of all pancreatic malignancies. The majority of data regarding ACC are limited to small case series.This is a retrospective study conducted at a large healthcare system from 1996 to 2019. Patients with pathologically confirmed ACC were included, and demographic data, tumor characteristics, and treatment outcomes were abstracted by chart review. Survival curves were obtained by using the Kaplan-Meier method and compared using the log-rank test.Sixty-six patients with ACC were identified. The median patient age at diagnosis was 64, and 42% presented with metastatic disease. The majority presented with abdominal pain or pancreatitis (69%), and laboratory parameters did not correlate with tumor size, metastatic disease, or survival. Several somatic abnormalities were noted in tumors (BRCA2, TP53, and mismatch-repair genes). In patients with localized disease that underwent resection, the median time to develop metastatic lesions was 13 months. The median overall survival (OS) was 24.7 months from diagnosis, with a survival difference based on metastatic disease at diagnosis (median 15 vs 38 mos). Surgery was associated with improved survival in non-metastatic cases (p = 0.006) but not metastatic cases (p = 0.22), and chemotherapy showed OS benefit in metastatic disease (p 0.01). Patients with metastatic ACC treated after 2010 utilized more platinum-based agents, and there was a OS benefit to FOLFOX or FOLFIRINOX chemotherapy compared to gemcitabine or capecitabine-based regimens (p = 0.006).Pancreatic ACC patients often present with advanced disease. Surgery was associated with survival benefit among patients presenting with localized disease. The use of FOLFOX or FOLFIRINOX chemotherapy regimens was associated with improved OS in metastatic patients. These data add to our knowledge in this rare malignancy, and improves understanding about the genomic underpinnings, prognosis and treatment for acinar cancers.

Cholangiocarcinoma (CC) is an uncommon malignancy with increasing incidence and dismal prognosis. We conducted a comprehensive analysis of the CC tumor immune microenvironment (TIME) based on tumor location to identify therapeutic targets. We hypothesized that the TIME of CC would vary by primary tumor location and that high tumor infiltration by CD8+ T cells and low infiltration by M2 macrophages would be associated with improved survival. A retrospective analysis was conducted of 99 CC tumor samples surgically resected between 2000 and 2014. Tissue microarrays were constructed from each tumor and stained by immunohistochemistry for 24 markers of immune cells, immune activation or inhibition, programmed cell death-ligand 1, and mesothelin. Most tumors were amply infiltrated with by CD4+, CD8+, and FoxP3+ T cells, as well as by myeloid cells. Mesothelin expression ≥1+ by immunohistochemistry was found in 68% of tumors. We identified higher densities of M1 macrophages in primary distal extrahepatic CC, as well as metastatic lesions. Mesothelin expression was also significantly higher in distal extrahepatic CC. There was no association with survival of infiltration by CD4+, CD8+, or FoxP3+ T cells, mesothelin expression, or programmed cell death-ligand 1 percentage expression, however, high CD14+ myeloid cells and high CD163+ M2 macrophages were associated with worse survival. In conclusion, the CC TIME is a heterogenous milieu highly infiltrated by innate and adaptive immune cells, which differs based on primary tumor location and between primary tumors and metastatic lesions. The correlation of intratumoral M2 macrophages and myeloid cells with a worse prognosis may suggest promising immunotherapeutic targets in CC.

Background: National guidelines including NCCN and ASCO clearly state the indication of genomic profiling for all patients diagnosed with advanced or metastatic breast cancer. Despite this, there remains a large gap between those guidelines and real-world practice. Increasing numbers of therapies have been approved or are under investigation for specific genomic mutations including PIK3CA, NTRK, BRCA, and most recently immunotherapy based on PD-L1 and microsatellite status. Accordingly, it is critical that advanced and metastatic breast cancer patients are offered and receive genomic testing. We explored patients’ knowledge and perception of genomic testing as well as their testing status using the Outcomes4MeTM app, a digital application that helps breast cancer patients engage in their care. Methodology: The study was conducted virtually on the Outcomes4MeTM mobile app. Eligible patients (n=203) had stage III/IV breast cancer and resided in the United States. Participants were surveyed on their awareness of Comprehensive Genomic Profiling (CGP), if they have been tested, incentives and barriers to testing, and their willingness to talk to their doctors to learn more/initiate genomic testing. Participants were also able to access educational content on CGP through the app. Analyzed data included: tested vs not tested, cancer subtype and stage, geographic location, and time since diagnosis. Results: Participants represented all 4 breast cancer subtypes, were well-distributed in time since diagnosis, and were located across 43 states. 105 (52%) of patients were HR+HER2-, 152 (75%) were metastatic, and 51 (25%) were stage III/advanced. Most patients (59%) were at least somewhat aware of the availability of CGP and 60% of participants were at least somewhat familiar with CGP. However, only 56 out of 203 eligible surveyed patients (28%) had been tested. Of those patients that were not tested (n=147), only 73 patients (50%) were at least somewhat aware or familiar with CGP. Further, 88% of patients that were not tested said they were interested in genomic testing and 85% said they were likely to ask their doctor about getting genomic testing, after learning about CGP. Conclusion: Despite under-testing, many advanced and metastatic patients are interested in learning more and getting genomic testing. These results are important because they demonstrate the discrepancy between patients’ willingness to get genomic testing and the extent of genomic testing being offered to patients. They also highlight the importance of educational digital apps such as the Outcomes4MeTM app in raising awareness and providing access to CGP, which can ultimately improve outcomes. In fact, many studies have shown that ~40% of patients with HR+HER2- advanced breast cancer have a PIK3CA mutation, where now a new therapy (alpelisib) targeting this mutation is FDA approved. Additional data needs to be collected to identify barriers to genomic testing and how to overcome such barriers to decrease the gap with current guidelines. Chart 1: Results from patient-reported surveysDimension ValueN (%)StageStage IV (Metastatic)152 (75)Stage III (Advanced)51 (25)SubtypeHR+HER2-105 (52)HR+HER2+36 (18)HR-HER2-30 (15)HR-HER2+12 (6)Unknown20 (10)Time from Diagnosis5 years37 (18)Testing StatusHad genomic testing56 (28)Did not have genomic testing147 (72)AwarenessVery aware or somewhat aware of CGP120 (59)Not very aware or not at all aware of CGP83 (41)FamiliarityVery familiar or somewhat familiar with CGP123 (60)Not very familiar or not at all familiar with CGP80 (40)Interest in GCP (non-tested)Very interested or somewhat interested129 (88)Not very interested or not at all interested18 (12)Likeliness of talking to their Doctor (non-tested)Very likely or somewhat likely125 (85)Not very likely or not at all likely22 (15)HR+HER2- (stage III/IV)Tested34 (32)Not Tested71 (68)Interest in learning more about GCP (non-tested HR+HER2-)Very interested or somewhat interested64 (90)Not very interested or not at all interested7 (10)Likeliness to talk to their doctor about CGP (non-tested HR+HER2-)Very likely or somewhat likely60 (85)Not very likely or not at all likely11 (15) Citation Format: Amanda G Stroiney, Osama E Rahma, Maya R Said. Understanding genomic testing in real-world populations at outcomes4Me (GENOME) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-42.

Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels. We analyzed expression of 34 cytokines in 52 melanoma patients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels and longitudinal log2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment. There were no differences in baseline cytokine levels between patients who developed grade 1–2 irAEs (N = 28) vs. grade 3–4 irAEs (N = 24). Dermatitis patients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitis patients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman’s correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%). Baseline levels of certain cytokines correlate with specific irAEs in melanoma patients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment.

7 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EAs) in LARC. EAs are not intended for direct comparison, but rather to concurrently randomized control arm (CA) patients. Primary endpoint (EP) and available secondary EPs (from EA1 using veliparib [V], PARPi; and EA2 using pembrolizumab [P], anti-PD-1) have been previously reported. We present long-term outcomes of all pts enrolled (NCT02921256). Methods: Stage II/III pts with MSS LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to CA (neoadjuvant FOLFOX [x 4mo] → chemoRT [capecitabine with 50.4Gy] → surgery 8-12 wks later). EA1 added V (400mg PO BID) and EA2 added P (200mg IV Q3 wks x 6 doses) each concurrent with chemoRT. Primary EP: 4-point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α=0.10, 80% power. NAR compared by linear model controlling for clinical T4 at entry (Y/N). Secondary EPs: OS, DFS. p-values are two-sided. Results: From 10/2016-2/2018, 178 pts were randomized (88 CA, 90 EA1). From 8/2018-5/2019, 185 pts were randomized (95 CA, 90 EA2). Baseline characteristics were previously reported. Median follow-up is 3.50 yrs for the 1st comparison. Median follow-up is 3.15 yrs for the 2nd comparison. Updated primary and long-term secondary outcomes are in the table. Conclusions: With longer follow-up, addition of V to TNT provided no significant differences in the NAR score or 3yr outcomes. The addition of P to TNT was associated with a statistically significant improvement in 3yr OS, but not DFS. Correlative molecular analyses are ongoing. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie; Merck. Clinical trial information: NCT02921256 . [Table: see text]

326 Background: HER2-low tumors, defined as a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+ and negative results on in situ hybridization (ISH), are not well characterized among gastric or gastroesophageal junction adenocarcinomas. More importantly, this patient population is currently treated as HER2-negative (HER2-low and HER2-zero [IHC score of 0]) without anti-HER-2 directed therapy. Herein, we describe a real world outcome analysis of this distinct genomically defined underrepresented population. Methods: De-identified, multimodal real-world data (RWD) of 429 advanced gastric, esophageal, and GEJ adenocarcinomas from the Tempus Lens database was analyzed. Inclusion criteria was a diagnosis of gastric, esophageal, or GEJ adenocarcinoma between January 2017 to May 2021 and treatment with first-line therapy. Median overall survival (mOS) was estimated using Kaplan-Meier methods. Results: HER2-low was identified in 24.9% (107/429) of the total cohort. Histologies within HER2 low group were 83.2% (89/107) adenocarcinoma (NOS), 7.5% (8/107) signet ring cell carcinoma, 5.6% (6/107) diffuse-type, and 3.7% (4/107) mucinous-type. PDL-1 TPS status was available in only 50.5% (54/107) of the HER2-low group. TPS distribution was: 74.1% (40/54) for TPS =1-= 10: 3.7% (2/54). ERBB2 amplification or focal gain was detected in 1.1% (1/88) of patients in the HER-2 low group that had undergone tumor genomic sequencing, and 0% (0/28) of patients that had circulating tumor DNA (ctDNA) sequenced. Median followup time was 20.7 (8.5, 35.6) months. Median OS (mOS, months) was 9.8 (9.0, 12.7) for HER2-low, 13.2 (8.9, 27.0) for HER2(-), and 14.1 (11.0, 19.2) for HER2(+). Survival differences were also compared with variations across ERBB2 RNA expression and copy number variation (CNV). HER2 groups were defined on RNA expression and copy number estimates based on thresholds determined from the proportion of samples in each of the HER2 groups from IHC/ISH data. For RNA expression analysis, the mOS was 10.8 (8.8, 13.5) months for HER2-low, 10.9 (7.2, 17.4) months for HER2(-), and 13.0 (11.4, 20.5) months for HER2(+). For CNV data, the mOS(months) was: HER2-low: 10.9 (8.5, 14.1), HER2(-): 10.2 (7.0, 15.7), HER2(+): 14.2 (11.5, 21.4). Conclusions: Our real world, biomarker outcome analysis suggests that advanced gastric and GEJ patients with HER2-low expression identified by IHC and RNA expression have a poor prognosis with shortest survival. Furthermore, our data suggest that there is a heterogeneity of PDL-1 enrichment within this group. Hence, targeting expression of low levels of HER2 similar to HER2+ group alone or in combination with immunotherapy should be evaluated in future clinical trials to improve efficacy outcomes.

Background Programmed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte−associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors. Methods This was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records. Results The final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (, Graphical abstract

BackgroundThe combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors.MethodsThis is a multicenter phase IB dose-escalation study of the combination of ziv-aflibercept (at 2–4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in programmed cell death protein 1 (PD-1)/programmed death-ligand 1(PD-L1)-naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (CRC), and ovarian cancer. The primary objective was to determine maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy with tumor and peripheral immune population densities.ResultsOverall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose-expansion cohort was 16.7% (5/30, 90% CI 7% to 32%). Complete responses occurred in melanoma (n=2); partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Median OS was as follows: melanoma, not reached (NR); RCC, 15.7 months (90% CI 2.5 to 15.7); CRC, 3.3 months (90% CI 0.6 to 3.4); ovarian, 12.5 months (90% CI 3.8 to 13.6); other solid tumors, NR. Activated tumor-infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression, and increased peripheral memory CD8 T cells correlated with clinical response.ConclusionThe combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1-resistant melanoma.Trial registration numberNCT02298959.

PURPOSE: Enterocolitis is among the leading adverse events associated with immune checkpoint inhibitors (ICIs). There are limited retrospective data regarding the safety of ICIs in patients with inflammatory bowel disease (IBD; ulcerative colitis, Crohn’s disease) because they have been generally excluded from clinical trials testing ICIs. Furthermore, there are no outcome data available in patients with microscopic colitis, a leading cause of chronic diarrhea. We aimed to study the safety of ICIs in patients with cancer with pre-existing IBD or microscopic colitis. METHODS: We retrospectively reviewed the records of patients with cancer treated at our institution who received at least 1 dose of either a programmed cell death-1 (PD-1)/ PD-1 ligand inhibitor, cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or both between 2011 and 2018. We identified patients with pre-existing IBD or microscopic colitis. RESULTS: Of 548 patients with solid tumor treated with an ICI, we identified 25 with pre-existing colitis (21 IBD; 4 microscopic colitis). An enterocolitis flare occurred in 7 patients (28%): 3 of 4 patients (75%) with microscopic colitis and 4 of 21 (19%) with IBD. All were treated with systemic corticosteroids, 2 required an anti–tumor necrosis factor agent, and one required an anti-integrin agent and colectomy for treatment of refractory colitis. ICI therapy was discontinued in all patients who experienced an enterocolitis flare. CONCLUSION: In our cohort, exacerbation of enterocolitis occurred in a notable percentage of patients with IBD and a majority of patients with microscopic colitis, leading to discontinuation of ICIs. Although these data suggest that patients with cancer with pre-existing IBD/microscopic colitis may be treated with ICIs, additional studies are needed to validate our results.

Immune checkpoint inhibitors (ICI) have improved outcomes in patients with various malignancies; however, they can cause immune-related hepatitis and enterocolitis. Patients on ICI may also develop upper gastrointestinal symptoms and undergo measurement of gastric emptying. Our aim was to review records of patients with gastroparesis following ICI therapy at two medical centers. We performed a retrospective review of all patients at Mayo Clinic and Brigham and Women’s/Dana-Farber Cancer Center (BWH/DFCC) who underwent gastric scintigraphy for the assessment of symptoms of gastroparesis following ICI treatment up to January 2020. Clinical presentation, medical history, laboratory evaluation, imaging, treatment, and outcomes were retrieved from the records. Gastroparesis was diagnosed as delayed gastric emptying (GE) measured by gastric scintigraphy. At Mayo Clinic, 2 patients (median age 59 years, 1 male [M], 1 female [F]) had delayed GE, while 4 patients (median age 53 years, 3M, 1F) had normal GE following ICI use. Of those with delayed GE (diagnosed after 38 and 2 months of ICI initiation), 1 patient was treated for non-Hodgkin’s lymphoma and melanoma with ipilimumab; a second patient with breast cancer was treated with pembrolizumab. At BWH/DFCC, 2 patients (median age 56 years, 1M, 1F) had normal GE after ICI treatment, while a 62-year-old female with non-small cell lung cancer developed gastroparesis 3 months following initiation of nivolumab. This report documents gastroparesis as a potential adverse effect of ICI. Further studies should explore the potential for ICI therapy to damage anti-inflammatory macrophages that preserve the enteric neurons.

Background There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. Methods We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. Results The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. Conclusions This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.

Locoregional therapies (LRTs) including radiofrequency ablation, surgical resection, and TACE, play a pivotal role in the treatment of early stage/locally advanced hepatocellular carcinoma (HCC). Besides their direct effect on tumor cells, LRTs also play an essential role in the immunomodulation of the tumor microenvironment which is of interest in the current era of cancer immunotherapy. In this review, we describe the HCC immune microenvironment and how it is affected by LRTs as described in multiple pre-clinical and clinical studies and provide the rationale for combining LRTs with immunotherapy.

Purpose: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. Patients and Methods: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. Results: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). Conclusions: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non–small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633

BackgroundPancreatic cancer (PC) is a challenging target for immunotherapy due to its immune-suppressive microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of tumor-infiltrating lymphocytes (TILs). We hypothesized that the combination of CRT and pembrolizumab can further expand and activate TILs.MethodsPatients with resectable or borderline resectable PC were randomized 2:1 to the investigational treatment (Arm A) of pembrolizumab 200mg IV every 3 weeks concurrently with CRT (capecitabine 825 mg/m2 orally twice daily and radiation 50.4 Gy in 28 fractions over 28 days) or CRT only (Arm B) prior to surgical resection. The primary endpoints were safety and difference in TILs density between Arm A and B assessed using multiplexed immunofluorescence on resected tumor specimens. As a correlate analysis, single cell RNA-sequencing (scRNA-seq) was performed to quantify gene expression in T cells from tumors and peripheral blood, and to track expanded T cell clonotypes in these compartments (n=4 patients Arm A; n=3 patients Arm B). The study was amended after enrollment of 37 patients to allow FOLFIRINOX prior to CRT, given changes in standard of care.Results37 patients were enrolled (24 Arm A, 13 Arm B). After neoadjuvant therapy, 13 patients had unresectable disease (9 on A, 4 on B), and 24 patients underwent surgery and were evaluable for the TILs primary endpoint (17 arm A, 7 arm B). The mean difference (A-B) in CD8+ T cell density was 36 cells/mm2 (95% CI -85 to 157, stdev 130) (p 0.48). Additional analysis did not show significant differences in activated cytotoxic T cells, regulatory T cells, M1- or M2-like polarized macrophages, or granulocytes. The median recurrence free survival (RFS) was 18.2 months on Arm A and 14.1 on Arm B (p 0.41). Overall survival was 27.8 months on Arm A and 24.3 on Arm B (p 0.68) with a median follow up of 2.2 years. The most common grade 3 treatment-related toxicities were lymphopenia reported in 29% on Arm A and 31% on Arm B, respectively followed by diarrhea in 8% on Arm A attributed to CRT. scRNA-seq revealed clonal expansion and expression of co-inhibitory markers among TIL subsets.ConclusionsThe combination of CRT and pembrolizumab is safe. Preliminary analysis shows that the addition of pembrolizumab to CRT has minimal effects on intratumoral densities of TILs and other immune cell populations. Single cell transcriptome analyses enable in-depth characterization of the functional responses of T cells to pembrolizumab in the setting of CRT.AcknowledgementsThis study was funded by MerckTrial RegistrationNCT02305186Ethics ApprovalThe study was conducted at 6 sites: University of Virginia, Dana Farber Cancer Institute, MD Anderson Cancer Center (MDACC), Mayo Clinic, Hartford Healthcare Cancer Center, and University of Miami. Written informed consent was provided by the study participants and the protocol was approved by the relevant local IRBs in each site.

BackgroundAngiogenic factors play a role in regulating immune suppression in the tumor microenvironment and driving resistance to immune checkpoint inhibitor therapy.1 Ziv-aflibercept is a soluble decoy receptor that ”traps” endogenous vascular endothelial growth factor (VEGF) with 100-fold increased binding affinity compared to Bevacizumab.2 The combination of ziv-aflibercept with either cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1) blockade has shown promising antitumor efficacy in mouse models.3 4 We hypothesized that a novel combination of ziv-aflibercept and anti-PD-1 would be tolerable and lead to clinical benefits in tumors that traditionally do not respond to checkpoint blockade.MethodsThis is a multicenter phase 1B dose escalation study (NCT02298959) of the combination of ziv-aflibercept (at 2–4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in PD-1/PD-L1 naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (MSS CRC), and ovarian cancer (figure 1). The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy and immune population densities in the tissue and periphery.ResultsOverall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities (DLTs) were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 treatment-related adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose expansion cohort was 16.7% (5/30; 95% CI, 7–32%). Complete responses occurred in melanoma (n=2), partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Efficacy outcomes by tumor type are shown in table 1 and figure 2. Median OS was as follows: melanoma, not reached; RCC, 15.7 months (90% CI, 2.5–15.7); CRC, 3.3 months (90% CI, 0.6–3.4), ovarian, 12.5 months (90% CI, 3.8–13.6), other solid tumors, not reached (figure 3). Activated tumor infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression (figure 4), and increased memory CD8 T cells in the periphery (figure 5) correlated with clinical response to the combination therapy.Abstract 374 Figure 1Study Schema of dose escalation and dose expansion. (A) Cohort 1 included the following tumors: clear cell sarcoma, triple negative breast cancer (TNBC), and mesothelioma. (B) Other solid tumors in Cohort 2 were: epithelioid mesothelioma (2) and TNBC (1).Abstract 374 Table 1Efficacy outcomes by dose level and tumor typea. Solid tumors included clear cell sarcoma (1), breast cancer (2), mesothelioma (3).b. Both patients with CR had melanoma and were in Cohort 2 (DL2).Abstract 374 Figure 2Waterfall plot of best RECIST response. Waterfall plot of maximum change from baseline in sum of target lesions for 28 patients with tumor measurements over time. Plot is color-coded by tumor type. Triangles indicate patients who developed new lesions, yellow circles indicate the 3 patients who received DL1.Abstract 374 Figure 3Progression and overall survival by tumor type. Kaplan-Meier curves for (A) progression-free survival and (B) overall survival based on tumor type.Abstract 374 Figure 4Luminex assay analysis of clinical response. Luminex analysis of baseline biomarkers. Patients were analyzed by clinical response (complete response [CR] and partial response [PR]) and durable clinical benefit (DCB) which includes patients with CR, PR, and stable disease (SD). (A) Baseline levels of IL-6 were lower in responders vs. non-responders (median 2.605 vs. 9.847 pg/mL, p = 0.009). Baseline CD40L was increased in responders (median 2,840 vs. 2,267 pg/mL, p = 0.06). (B) Baseline levels of GroB (median 1,272 vs. 592 pg/mL, p = 0.006), CXCL5 (median 547.5 vs. 296.2 pg/mL, p = 0.02), and CD40L (median 2,807 vs. 1,595 pg/mL, p = 0.001) were higher in patients with DCB vs. no DCB. P-values for baseline comparisons were obtained through Wilcoxon rank-sum test. The solid black line indicates median. Violins show range and kernel density estimate distributions of each group. (*) p < 0.05, (**) p < 0.01.Abstract 374 Figure 5Flow cytometry analysis. Flow cytometry analysis comparing T cell populations and monocytes between patients with clinical response (CR or PR, n = 5) and non-responders (n = 18) and patients with disease control (CR, PR, or SD, n = 12) and no disease control (n = 11). (A) CD4+ populations were increased in responders vs. non-responders at all time points. (B) CD8+ populations were decreased in responders vs. non-responders at all time points. (C) Treg CD4+/CD25+/FoxP3+ was decreased at baseline in responders. (D) Treg CD4+/CD25+/FoxP3+ were decreased at baseline and 1-month in patients with disease control vs. no disease control. (E) TCM CD8+/CD45RO+/CCR7+ was increased at all time points in responders vs. non-responders. (F) TEMRA CD8+/CD45RO-/CCR7- was decreased in responders at baseline. (G) Non-classical TIE2 was increased at baseline in non-responders. (H) Classical monocytes were increased at all time points in non-responders.ConclusionsThe combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1 resistant melanoma.AcknowledgementsThis trial was supported by the National Cancer Institute (NCI) and by Merck, Sharpe, and Dohme and Sanofi via Cooperative Research and Development Agreements with the NCI. PLB was supported by NCI UM1 Grant CA186644.Trial RegistrationNCT02298959ReferencesRahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res September 15 2019;25(18):5449–5457. doi:10.1158/1078-0432.CCR-18-1543Holash J, Davis S, Papadopoulos N, et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proceedings of the National Academy of Sciences 2002;99(17):11393–11398. doi:10.1073/pnas.172398299Burova E, Ioffe E, Taduriyasas C, et al. Abstract 5035: blockade of VEGF with ziv-aflibercept (VEGF Trap) enhances anti-tumor efficacy of CTLA-4 blocking antibody in an Fc dependent manner. Cancer Research 2014;74(19 Supplement):5035–5035. doi:10.1158/1538-7445.am2014-5035Di Tacchio M, Macas J, Weissenberger J, et al. Tumor vessel normalization, immunostimulatory reprogramming, and improved survival in glioblastoma with combined inhibition of PD-1, angiopoietin-2, and VEGF. Cancer Immunology Research 2019;7(12):1910–1927. doi:10.1158/2326-6066.cir-18-0865Ethics ApprovalThis trial (NCT02298959) was approved by all participating IRBs.

BackgroundImmune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.MethodsWe collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.ResultsICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.ConclusionsPatients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

This cohort study examines the association of liver biopsy with management and outcomes of high-grade immune checkpoint inhibitor hepatitis.

BackgroundGWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed.MethodsPatients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10–1500 mg) or GWN323+spartalizumab (GWN323 10–750 mg+spartalizumab 100–300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1.ResultsOverall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures.ConclusionsGWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination.Trial registration numberNCT02740270.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, improving outcomes in patients with advanced malignancies. The use of ICIs in clinical practice, and the number of ICI clinical trials, are rapidly increasing. The use of ICIs in combination with other forms of cancer therapy, such as chemotherapy, radiotherapy, or targeted therapy, is also expanding. However, immune-related adverse events (irAEs) can be serious in up to a third of patients. Critical questions remain surrounding the characteristics and outcomes of irAEs, and how they may affect the overall risk–benefit relationship for combination therapies. This article proposes a framework for irAE classification and reporting, and identifies limitations in the capture and sharing of data on irAEs from current clinical trial and real-world data. We outline key gaps and suggestions for clinicians, clinical investigators, drug sponsors, patients, and other stakeholders to make these critical data more available to researchers for pooled analysis, to advance contemporary understanding of irAEs, and ultimately improve the efficacy of ICIs.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes. ispartof: KIDNEY INTERNATIONAL vol:100 issue:1 pages:196-205 ispartof: location:United States status: published

Purpose: Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti–PD-1 monotherapy remains unclear. Experimental Design: In this multicenter retrospective analysis, patients treated with anti–PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti–PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed. Results: Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) n = 90], early-onset irAE (within 8 weeks of anti–PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10–13.70; P < 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20–16.09; P < 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) n = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04–2.76; P = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15–3.39; P = 0.01]. Similar findings were also observed in the 26-week landmark analysis for post–irAE-PFS but not for post–irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results. Conclusions: Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti–PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.

Both immune checkpoint inhibitors (ICI) and antiangiogenesis agents have changed the landscape of cancer treatment in the modern era. While antiangiogenesis agents have demonstrated activities in tumors with high vascularization, including renal cell carcinoma and colorectal cancer, the effect of ICIs has been seen mainly in immunologically recognized tumors, with highly immune-infiltrative lymphocytes. The main challenge in the drug development of ICIs is moving their activities to noninflamed tumors and overcoming resistance that is driven, in part, by the immune-suppressive microenvironment. Angiogenesis factors drive immune suppression by directly suppressing the antigen-presenting cells as well as immune effector cells or through augmenting the effect of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM). Those suppressive immune cells can also drive angiogenesis, creating a vicious cycle of impaired immune activation. The combination of bevacizumab and ipilimumab was the first to show the promising effect of antiangiogenesis and ICIs. A plethora of similar combinations has entered the clinic since then, confirming the promising effects of such approach.