Setting Of Immune Checkpoint Inhibitors Research Articles

De novo autoimmune connective tissue disease and mortality in patients treated with anti-PD-1 and anti-PD-L1 therapy: a population-level cohort study.

Using a population-level cohort analysis, our study demonstrates that, although rare, de novo autoimmune cutaneous connective tissue diseases (AiCTDs) in the setting of immune checkpoint inhibitors (ICIs) are not associated with a greater risk of mortality and overall approach a statistically significant decrease in mortality when compared with patients treated with ICIs who do not experience cutaneous immune-related adverse events. These findings are significant and highly relevant to dermatologists and oncologists caring for ICI recipients as it adds to the limited information on development of cutaneous AiCTD following ICI administration, for which enhanced understanding is critical to improving the care for this challenging patient population.

Unilateral cortical autoimmune encephalitis: A case series and comparison to late-onset Rasmussen's encephalitis

ObjectiveTo report a novel anatomical pattern of autoimmune encephalitis characterized by strictly unilateral cortical inflammation and a clinical picture overlapping with late-onset Rasmussen's encephalitis. MethodsWe retrospectively gathered data of patients identified at two tertiary referral academic centers who met inclusion criteria. ResultsWe identified twelve cases (average age 65, +/− 19.8 years, 58% female). All patients had unilateral cortical inflammation manifesting with focal seizures, cognitive decline, hemicortical deficits, and unilateral MRI and/or EEG changes. Six cases were idiopathic, two paraneoplastic, two iatrogenic (in the setting of immune checkpoint inhibitors), and two post-COVID-19. Serologically, ten patients were seronegative, one had high titer anti-GAD65, and one had anti-NMDAR. Five patients met Rasmussen's encephalitis criteria, and six did not fully meet the criteria but had symptoms significantly overlapping with the condition. Most patients had significant improvement with immunotherapy. DiscussionUnilateral cortical AE seems to be more prevalent in the elderly and more frequently idiopathic and seronegative. Patients with this anatomical variant of autoimmune encephalitis have overlapping features with late-onset Rasmussen's encephalitis but are more responsive to immunotherapy. In cases refractory to immunotherapy, interventions used in refractory Rasmussen's encephalitis may be considered, such as functional hemispherectomy.

Abstract 16577: Unraveling T-cell and Macrophage Chemokine Crosstalk in Immunotherapy-Induced Myocarditis

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate immunity against tumor cells but can cause immune related adverse events such as myocarditis, a rare but serious side effect with up to 40% mortality. Hypothesis: Macrophages contribute to recruitment of cytotoxic T-cell subsets to the heart in the setting of ICI, causing myocarditis. Methods: To study the role of macrophage depletion on ICI myocarditis, we treated MRL/Pdcd1-/- mice with liposomal clodronate. To identify timing of immune infiltration, we performed serial single cell T-cell receptor and RNA sequencing of CD45+ cells from the hearts/blood of MRL/Pdcd1-/- myocarditis mice at 1, 2, and 4 weeks of age. We treated MRL mice with anti-PD1/CTLA4 to induce myocarditis and assessed if anti-CXCR3 could decrease effector CD8+ T-cell cardiac infiltration and mitigate myocarditis. We studied the effects of in vitro CXCR3 blockade on CXCR3+ T-cell migration in a transwell assay. Results: Serial single-cell TCR sequencing/scRNA-seq of immune cells from MRL/ Pdcd1-/- vs. MRL control hearts showed infiltration of CXCL9/10+ macrophages ( Fig. 1, A ) along with progressive clonal expansion of CXCR3+ effector CD8+ T-cells in the heart starting at 2 weeks of age, prior to clinical onset of myocarditis. Macrophage depletion with liposomal clodronate reduced myocarditis and improved survival in MRL/ Pdcd1-/- mice ( Fig. 1, B-C) . CXCR3 blockade with anti-CXCR3 antibody reduced myocarditis, decreased CXCR3+ CD8+ T-cell infiltration, and improved survival in mice treated with anti-CTLA4/anti-PD1 antibodies (Fig. 1, D-E) . CXCR3 blockade in transwell assay also reduced migration of CD8+CXCR3+ T-cells towards the macrophage compartment (Fig. 1, F) . Conclusions: CXCL9/10+ macrophages likely play a critical role in development of ICI myocarditis through the recruitment of CXCR3+ effector T-cells into the heart, making this pathway an attractive therapeutic target.

Abstract 5882: Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 demonstrated by transplantation of human feces into tumor-bearing mice

Abstract Background: Over the last decade, studies unraveled the cancer-immune dialogue in the setting of immune checkpoint inhibitors (ICI) and influenced by the gut microbiota. The first evidence of the key role of the microbiota in ICI modulation was observed during antibiotics (ATB) treatment, where altering the microbiota composition by ATB inhibited ICI responses. DAV132 (DAV) is an orally administered colon-targeted ATB adsorbent capsules designed to prevent ATB-induced dysbiosis. We investigated whether DAV co-administered with ATB could prevent ATB-related dysbiosis and ICI response. Methods: 72 human healthy volunteers (HV) were randomized to receive either IV ceftazidime-avibactam (CZA) or Piperacillin tazobactam (PTZ) alone or in combination with oral DAV. CZA and PTZ plasmatic and fecal pharmacodynamic levels were measured using HPLC-MS/MS. Microbiome was profiled with metagenomics at different timepoints. FMT experiments in germ-free mice were performed using fecal samples from HV from the trial, before (D1) or after 6 days (D6) of CZA or PTZ+/-DAV; subsequently mice were inoculated with MCA205 or B16 tumors and treated with anti-PD-1. Tumor infiltrating lymphocytes (TILs) were analyzed by flow cytometry. Results: DAV did not impact plasmatic CZA or PTZ concentrations, but significantly reduced ceftazidime and piperacillin concentrations in feces compared to ATB groups alone. DAV significantly prevented the reduction in microbiota alpha-diversity at D6 and was associated with a rapid return to baseline microbiota. 50 and 43 metagenomics species were preserved in the CZA+DAV vs CZA, or PTZ-DAV vs PTZ such as Faecalibacterium praunistzii, Alistipes Spp and Blautia obeum. FMT in germ-free mice using feces collected at D1 exhibited a significant anti-PD-1 activity. This anti-tumor response was inhibited in two tumors models in mice transplanted with D6 feces from patients in the CZA or PTZ alone groups. Conversely, the anti-tumor response was maintained in mice transplanted with D6 feces from HV treated with CZA+DAV or PTZ+DAV groups. Flow cytometry on TILs demonstrated that CZA decreased CD8+T cell and CD8+/Treg ratio compared to CZA+DAV. Conclusions: DAV prevented ATB-induced dysbiosis in HV treated with CZA or PTZ without influencing plasmatic concentrations. In avatar mice FMT from HV treated with CZA+DAV was able to preserve anti-PD-1 efficacy. These results provide rationale to launch clinical trials combining DAV in patients on ATB amenable to ICI. Citation Format: Meriem Messaoudene, Nathalie Saint-Lu, Frédérique Sablier-Gallis, Stéphanie Ferreira, Mayra Ponce, Clément Le Bescop, Thomas Loppinet, Tanguy Corbel, Céline Féger, Fabien Vitry, Antoine Andremont, Jean de Gunzburg, Bertrand Routy. Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 demonstrated by transplantation of human feces into tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5882.

Dosimetric Risk Factors for Radiation Pneumonitis in Patients with Prior Receipt of Immune Checkpoint Inhibitors: A Retrospective Study

<h3>Purpose/Objective(s)</h3> Dosimetric parameters (e.g., mean lung dose (MLD), V20, and V5) can predict radiation pneumonitis (RP). Constraints thereof were formulated before the era of combined immune checkpoint inhibitors (ICIs) and radiotherapy, which could amplify the RP risk. Dosimetric predictors of acute RP (aRP) in the context of ICIs are urgently needed because no data exist thus far. <h3>Materials/Methods</h3> All included patients underwent thoracic irradiation, previously received ICIs, and followed-up at least once. Logistic regression models examined predictors of aRP (including a priori evaluation of MLD, V20, and V5), and their discriminative capacity was assessed by receiver operating characteristic analysis. <h3>Results</h3> Median follow-up of the 40 patients was 5.3 months. Cancers were lung (80%) or esophageal (20%). ICIs were PD-1 (85%) or PD-L1 (15%) inhibitors (median 4 cycles). Patients underwent definitive (n=19), consolidative (n=14), or palliative (n=7) radiotherapy; the median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR, 51.8-64 Gy). Grades 1-5 aRP occurred in 25%, 17.5%, 15%, 2.5%, and 5%, respectively. The only variables associated with any-grade aRP were V20 (p=0.014) and MLD (p=0.026), and only V20 with grade ≥2 aRP (p=0.035). Graphs were constructed showing the incrementally increasing risk of aRP based on V20 and MLD, V20=5.2% and MDL=4.0Gy would predict for a 50% risk of ≥ grade 1 pneumonia, and V20=19.3% would predict for a 50% risk for grade 2 pneumonia. <h3>Conclusion</h3> This is the first study illustrating that V20 and MLD may impact aRP in the setting of prior ICIs. If these results are validated by larger studies with more homogeneous populations, the commonly accepted V20/MLD dose constraints could require revision if utilized in the setting of ICIs.

KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges.

KRAS is the most frequently mutated oncogene identified in human cancers. Despite the numerous efforts to develop effective specific inhibitors against KRAS, this molecule has remained “undruggable” for decades. The development of direct KRAS inhibitors, such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, was made possible with the discovery of a small pocket in the binding switch II region of KRAS G12C. However, a new challenge is represented by the necessity to overcome resistance mechanisms to KRAS inhibitors. Another area to be explored is the potential role of co-mutations in the selection of the treatment strategy, particularly in the setting of immune checkpoint inhibitors. The aim of this review was to analyze the state-of-the-art of KRAS mutations in non-small-cell lung cancer by describing the biological structure of KRAS and exploring the clinical relevance of KRAS as a prognostic and predictive biomarker. We reviewed the different treatment approaches, focusing on the novel therapeutic strategies for the treatment of KRAS-mutant lung cancers.

The Role of Radiomics in the Era of Immune Checkpoint Inhibitors: A New Protagonist in the Jungle of Response Criteria

Simple SummaryThe introduction of immune checkpoint inhibitors has represented a milestone in cancer treatment. Despite PD-L1 expression being the standard biomarker used before the start of therapy, there is still a strict need to identify complementary non-invasive biomarkers in order to better select patients. In this context, radiomics is an emerging approach for examining medical images and clinical data by capturing multiple features hidden from human eye and is potentially able to predict response assessment and survival in the course of immunotherapy. We reviewed the available studies investigating the role of radiomics in cancer patients, focusing on non-small cell lung cancer treated with immune checkpoint inhibitors. Although preliminary research shows encouraging results, different issues need to be solved before radiomics can enter into clinical practice.Immune checkpoint inhibitors (ICI) have demonstrated encouraging results in terms of durable clinical benefit and survival in several malignancies. Nevertheless, the search to identify an “ideal” biomarker for predicting response to ICI is still far from over. Radiomics is a new translational field of study aiming to extract, by dedicated software, several features from a given medical image, ranging from intensity distribution and spatial heterogeneity to higher-order statistical parameters. Based on these premises, our review aims to summarize the current status of radiomics as a potential predictor of clinical response following immunotherapy treatment. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2021 were selected, comprising those that explored computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) for radiomic analyses in the setting of ICI. Several studies have demonstrated the potential applicability of radiomic features in the monitoring of the therapeutic response beyond the traditional morphologic and metabolic criteria, as well as in the prediction of survival or non-invasive assessment of the tumor microenvironment. Nevertheless, important limitations emerge from our review in terms of standardization in feature selection, data sharing, and methods, as well as in external validation. Additionally, there is still need for prospective clinical trials to confirm the potential significant role of radiomics during immunotherapy.

Impact of angiotensin-converting enzyme inhibitors (ACEi) on pathologic complete response with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC).

485 Background: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. Angiotensin pathway inhibitors are postulated to favorably reprogram the stroma in part by inhibition of transforming growth factor-β, a major mechanism of resistance, and have been previously reported to be associated with improved outcomes in the setting of immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (Jain R, Clin Genitourin Cancer 2021). In this analysis, we examined the association of angiotensin inhibitors in the setting of NAC for MIBC preceding radical cystectomy (RC). Methods: Pts with MIBC who received NAC preceding radical cystectomy were assembled from 3 institutions: Dana-Farber Cancer Institute (DFCI), Moffitt Cancer Center (MCC) and McGill University Health Center (MUHC). Pts were retrospectively assessed for the association of concurrent ACEi/angiotensin receptor blockers (ARB) use at initiation of NAC on pathologic complete response (pCR), defined as pT0N0, and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. The Kaplan-Meier method was used to estimate OS. Logistic and Cox regression were used to explore factors potentially prognostic for pCR and OS respectively. Results: 302 MIBC pts who received NAC preceding RC were available from 3 institutions: DFCI (n = 187), MCC (n = 50) and MUHC (n = 65). Overall, 141 pts (46.7%) received Cisplatin/Gemcitabine, 130 (43.1%) received dose dense MVAC and the remaining received other regimens. The overall pCR rate was 26.2%. The 5-year OS was 62%. 63 (20.9%) pts were receiving an ACEi and 41 (13.6%) were receiving an ARB. ACEi prior to NAC approached significance for association with pCR (odds ratio = 1.71 (95% CI = 0.94-3.11) p = 0.077). Pts with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% (8/26) vs 17.7% (14/98), p = 0.056) than those not on ACEi; no difference was observed for pts with cT2N0 tumors (31.1% vs 31.3%, p = 0.99). pCR, ECOG-PS and clinical stage were significantly associated with improved OS. ARB intake was not associated with pCR or OS. Conclusions: ACEi intake appeared potentially associated with increased pCR in pts with MIBC receiving NAC, which was more pronounced in those with higher clinical stages cT3/4N0-1. Given the association of pCR with OS, our data suggest the potential relevance of angiotensin as a therapeutic target in aggressive MIBC. Future prospective validation is warranted to repurpose angiotensin inhibitors in this setting, given their excellent toxicity profile and low costs.

Dosimetric Risk Factors for Acute Radiation Pneumonitis in Patients With Prior Receipt of Immune Checkpoint Inhibitors.

PurposeDosimetric parameters (e.g., mean lung dose (MLD), V20, and V5) can predict radiation pneumonitis (RP). Constraints thereof were formulated before the era of combined immune checkpoint inhibitors (ICIs) and radiotherapy, which could amplify the RP risk. Dosimetric predictors of acute RP (aRP) in the context of ICIs are urgently needed because no data exist thus far.Methods and MaterialsAll included patients underwent thoracic intensity-modulated radiotherapy, previously received ICIs, and followed-up at least once. Logistic regression models examined predictors of aRP (including a priori evaluation of MLD, V20, and V5), and their discriminative capacity was assessed by receiver operating characteristic analysis.ResultsMedian follow-up of the 40 patients was 5.3 months. Cancers were lung (80%) or esophageal (20%). ICIs were PD-1 (85%) or PD-L1 (15%) inhibitors (median 4 cycles). Patients underwent definitive (n=19), consolidative (n=14), or palliative (n=7) radiotherapy; the median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR, 51.8-64 Gy). Grades 1-5 aRP occurred in 25%, 17.5%, 15%, 2.5%, and 5%, respectively. The only variables associated with any-grade aRP were V20 (p=0.014) and MLD (p=0.026), and only V20 with grade ≥2 aRP (p=0.035). Neither the number of prior ICI cycles nor the delivery of concurrent systemic therapy significantly associated with aRP risk. Graphs were constructed showing the incrementally increasing risk of aRP based on V20 and MLD (continuous variables).ConclusionsThis is the first study illustrating that V20 and MLD may impact aRP in the setting of prior ICIs. However, these data should not be extrapolated to patients without pre-radiotherapy receipt of prior ICIs, or to evaluate the risk of chronic pulmonary effects. If these results are validated by larger studies with more homogeneous populations, the commonly accepted V20/MLD dose constraints could require revision if utilized in the setting of ICIs.

Abstract 355: Tumor mutational burden, microsatellite instability (MSI) status and mutational frequency of 30 DDR genes in Chinese patients with gastric or gastroesophageal junction (GEJ) cancers with different levels of PD-L1 expression

Abstract Background: Gastric or GEJ cancer with positive PD-L1 expression have been proved a subgroup who can benefit from first-line and second-line therapy of PD-1 inhibitors. Positive PD-L1 expression promises to be the most effective biomarker in gastric/GEJ cancer patients. The results of CheckMate-649 further revealed that patients with PD-L1 CPS≥5 were more favorable to PD-1 inhibitors. On the other hand, high level of tumor mutational burden, MSI-H and mutations in DDR genes had also been identified as biomarkers in setting of immune checkpoint inhibitors in cancers. The difference of genomic features in subgroups with PD-L1 expression level in gastric/GEJ cancers is a question of interest. Method: 613 cases of Chinese gastric/GEJ cancer patients were included in our analysis. Immunohistochemistry and 381-gene panel next-generation sequencing (NGS) testing had been performed in their tumor tissue specimen. PD-L1 expression level was evaluated by the combined positive score (CPS). Tumor mutational burden and MSI status were evaluated via NGS testing. Somatic and germline mutations in 30 DDR genes had also been analyzed. Result: 493 out of 613 patients were CPS&amp;lt;1, 54 cases were CPS&amp;lt;5, 64 cases were CPS &amp;lt;49, 16 cases were CPS≥50. The median TMB score of four subgroups were 5.59, 7.26, 7.26 and 8.06 respectively. The proportion of MSI-H patients in four subgroups were 3.25%, 9.26%, 12.5%, and 12.5% respectively. ARID1A and ARTX genes only were detected somatic mutated. There was a negative correlation trend in germline mutational proportion and PD-L1 expression level in some genes, such as MSH2, POLE, POLD1, PALB2 and PTEN. However, the somatic mutational proportion of MSH6, PMS2, POLE genes had a positive correlation trend with PD-L1 expression level. Conclusion: In Chinese gastric/GEJ cancer population, the TMB level of CPS≥1 subgroup was significantly higher than CPS&amp;lt;1 subgroup. MSI-H patients were enriched in CPS&amp;gt;5 subgroup. In addition, DDR genes had distinct mutational frequency in subgroups with different levels of PD-L1 expression, indicating they impact the immunogenicity of gastric/GEJ cancer through different mechanisms. Citation Format: Xiancheng Zeng, Xinyi Liu, Mengli Huang. Tumor mutational burden, microsatellite instability (MSI) status and mutational frequency of 30 DDR genes in Chinese patients with gastric or gastroesophageal junction (GEJ) cancers with different levels of PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 355.

Abstract 264: Development of companion tests based on continuous markers: Illustration with blood-based tumor mutational burden in NSCLC cancer patients treated with atezolizumab

Abstract As illustrated in the setting of immune checkpoint inhibitors (ICI), a crucial goal in the development of new therapeutics is to propose a companion diagnostic test. This challenge is particularly complex with a continuous marker for which a threshold is needed. We analyzed data that have demonstrated that blood-based tumor mutational burden (bTMB) may identify patients who may benefit from atezolizumab in second-line and higher NSCLC (Gandara, Nat Med 2018). Three approaches to determine a threshold for bTMB were used in the POPLAR dataset: 1) ROC curve to discriminate best overall response in the ICI arm (Youden index), 2) treatment effect on PFS among subgroups of high bTMB patients according to several thresholds, 3) marker-by-treatment predictiveness curves for PFS taking into consideration both arms. Effectiveness of predictive models was assessed on the OAK dataset using several utility measures (treatment effects, proportion of patients affected by the classification). Table 1 presents the threshold and the rate of patients in each bTMB subgroup for each approach. Treatment effects in bTMB groups were similar for the three methods, but the p-value for interaction between treatment and bTMB was the most significant for the predictive approach. Predictiveness analysis reclassified 72 patients (11.2%) as bTMB high compared to ROC analysis . In this reclassified subgroup, 6-month PFS rates were 6.65% [2.23; 19.8] (Control) and 23.40% [13.95; 39.3] (ICI). Marker-by-treatment predictiveness curves should be favoured over analyses on the experimental arm only. Prognostic approaches may not be useful for treatment selection. A prognostic value doesn't ensure that treatment effects will differ depending on marker value. Moreover, treatment interaction modelling at different timepoints is particulary relevant when proportional hazards assumption is violated. Pros and cons of each approach will be presented. Treatment effects within bTMB groups and interaction between treatment and bTMB in the OAK cohortDichotomization approachThresholdN (%)Treatment armHR for treatmentpinteractionROCbTMB&amp;lt;14451 (70.2%)Docetaxel1.00 [0.83; 1.22]0.035AtezolizumabbTMB≥14191 (29.8%)Docetaxel0.69 [0.50; 0.93]AtezolizumabSubpopbTMB&amp;lt;12426 (66.4%)Docetaxel1.00 [0.82; 1.23]0.029AtezolizumabbTMB≥12216 (33.6%)Docetaxel0.71 [0.53; 0.95]AtezolizumabMarker-treatment predictiveness curvesbTMB&amp;lt;10379 (59.0%)Docetaxel1.04 [0.84; 1.29]0.018AtezolizumabbTMB≥10263 (41.0%)Docetaxel0.72 [0.55; 0.93]Atezolizumab Citation Format: Julia Gilhodes, Frédérique Penault-Llorca, Julien Mazières, Maurice Pérol, Christos Chouaid, Eve Leconte, Jean-Pierre Delord, Thomas Filleron. Development of companion tests based on continuous markers: Illustration with blood-based tumor mutational burden in NSCLC cancer patients treated with atezolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 264.

Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy.

We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment. Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N = 77) or second-line (N = 51) settings. In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07-0.53; P < 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22-0.83; P = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti-PD-1 monotherapy, relative to those treated with combination anti-CTLA-4/anti-PD-1 inhibitors. Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.

Challenges in Combining Immunotherapy with Radiotherapy in Recurrent/Metastatic Head and Neck Cancer.

Simple SummaryImmunotherapy offers new hope for patients with recurrent or metastatic head and neck cancer. However, only 20% of patients respond to this treatment. Combining radiotherapy in novel ways with immunotherapy can lead to synergistic effect by enabling cancer recognition by immune system and rendering tumor microenvironment less immunosuppressive. Based on a literature review, the main factors that need to be considered in future trials of immunoradiotherapy in head and neck cancer are discussed. The significance of proper timing of the treatment, the radiotherapy fractionation, patient selection, the number and the site of irradiated lesions, and the irradiated volume have been established in preclinical and clinical trials across different solid tumors. However, the trials using immunoradiotherapy in patients with recurrent or metastatic head and neck cancer have shown poor results so far and the reasons for this are elaborated on.Immunotherapy with immune checkpoint inhibitors (ICI) has recently become a standard part of the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), although the response rates are low. Numerous preclinical and clinical studies have now illuminated several mechanisms by which radiotherapy (RT) enhances the effect of ICI. From RT-induced immunogenic cancer cell death to its effect on the tumor microenvironment and vasculature, the involved mechanisms are diverse and intertwined. Moreover, the research of these interactions is challenging because of the thin line between immunostimulatory and the immunosuppressive effect of RT. In the era of active research of immunoradiotherapy combinations, the significance of treatment and host-related factors that were previously seen as being less important is being revealed. The impact of dose and fractionation of RT is now well established, whereas selection of the number and location of the lesions to be irradiated in a multi-metastatic setting is something that is only now beginning to be understood. In addition to spatial factors, the timing of irradiation is as equally important and is heavily dependent on the type of ICI used. Interestingly, using smaller-than-conventional RT fields or even partial tumor volume RT could be beneficial in this setting. Among host-related factors, the role of the microbiome on immunotherapy efficacy must not be overlooked nor can we neglect the role of gut irradiation in a combined RT and ICI setting. In this review we elaborate on synergistic mechanisms of immunoradiotherapy combinations, in addition to important factors to consider in future immunoradiotherapy trial designs in R/M HNSCC.

31. RADIATION NECROSIS IN STEREOTACTIC RADIOSURGERY AND CHECKPOINTS INHIBITORS FOR BRAIN METASTASES FROM LUNG ADENOCARCINOMA

PURPOSETreatment with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) is increasingly common for brain metastases (BM) from lung adenocarcinoma. Rates of radiation necrosis (RN) with SRS in the setting of ICIs is an ongoing area of research. We investigated rates of RN in patients with BM from lung adenocarcinoma treated with SRS with or without concurrent ICIs.METHODSWe identified 39 patients at a single institution who underwent SRS treatment for BM from lung adenocarcinoma. Of these, 19 (49%) received SRS without ICIs and 20 (51%) patients received ICIs within a month of SRS. The rate of RN, defined by MRI features and histology when available, was compared between each group using multivariate analysis. Kaplan Meier survival estimates were calculated based on overall survival and compared to median survival predicted by the graded prognostic assessment.RESULTSOverall survival for all patients from diagnosis of brain metastases was 16.6 months (range 3.6–45.9) and median survival predicted by the graded prognostic assessment was 13.7 months (range 6.9–26.5). In total 11 (28%) patients developed MRI and/or histologic evidence for RN during the follow-up period; 5 of 20 (25%) from the SRS with ICI group and 6 of 19 (31%) from the SRS without ICI group. In multivariate analysis, ICI treatment had no significant impact on rates of RN between groups (OR 0.72 [95% CI: 0.17–2.93]; p=0.65) while bevacizumab treatment was associated with a decreased RN risk (OR 0.88 [95% CI: 0.43–0.99]; p=0.02).CONCLUSIONRetrospective analysis of patients with BM from lung adenocarcinoma treated with SRS suggested that administration of ICIs does not increase risk for development of RN. Further, concomitant treatment with bevacizumab may decrease risk of RN. These findings suggest that patients with BM from lung adenocarcinoma can be treated with combination therapy without increased risk of neurologic toxicity.

Any regression of tumor (ART) within 12 weeks versus RECIST 1.1 response category as an intermediate endpoint to assess the activity of immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (mUC).

473 Background: Many ICIs are approved to treat mUC following platinum-based chemo and as 1st-line therapy for selected patients (pts). While RECIST 1.1 responses are generally durable and associated with prolonged survival, the benefit of ICIs extends beyond this group of pts. Stable disease (SD) consists of a heterogeneous population of pts with both increase and decrease in tumor size and is confounded by the impact of pre-ICI disease pace. We hypothesized that in the setting of ICIs, any regression of tumor (ART) within 12 weeks may capture early benefit and correlate with survival more comprehensively than RECIST 1.1. Methods: mUC pts who received an ICI following platinum-based chemo at DFCI were eligible for analysis. Pts were required to have tumor size changes, RECIST 1.1 response by week 12 and survival data available. Demographics and prognostic factors were collected. Descriptive stats were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of ART and RECIST 1.1 with overall survival (OS). Results: 104 pts were evaluable. The median age was 66 (range 34-89). 71% were male. The numbers of pts with ART and RECIST1.1 partial response (PR) were 45 (43.3%) and 32 (30.1%), respectively. Univariable analyses identified an association between ART and RECIST 1.1 response with OS (p&lt;0.001). The 1-year OS (95% CI) for ART vs. no ART was 83.6 % (68.7, 91.8) and 35.9 % (23.1, 48.8), while the 1-year OS (95% CI) for RECIST 1.1 response vs. no response was 81.3% (62.9, 91.1) and 45.6% (32.9, 57.4), respectively. RECIST 1.1 category was not significantly associated with OS (p-value=0.68) after adjusting for ART; however, statistically, ART associated with OS (p=0.002) after adjusting for RECIST 1.1 category. The modest size of this cohort is a limitation. Conclusions: ART within 12 weeks is identified early and is robustly associated with OS in pts with mUC receiving post-platinum ICIs. ART may serve as a more optimal intermediate endpoint for survival compared to RECIST 1.1 in the setting of ICIs. Evaluating this endpoint in other malignancies is warranted.

Association of the Lung Immune Prognostic Index with outcome in patients with metastatic urothelial cancer treated with immune checkpoint inhibitor.

545 Background: Prognostic factors for survival in metastatic urothelial carcinoma (mUC) have been reported in patients (pts) treated with chemotherapy (Bellmunt and al, JCO 2010). However, no biomarkers have been clearly identified in the setting of immune-checkpoint inhibitors (ICI). The Lung immune prognostic index (LIPI) was associated with clinical outcomes for ICI in lung cancer (Mezquita et al, Jama Oncol 2018) and other tumor types (Varga et al, TAT 2019). In this multicenter retrospective study, we correlated LIPI with outcomes in pts with mUC treated with ICI. Methods: Pts with mUC enrolled from May 2013 to July 2018 in 7 high volume centers were analysed. LIPI score includes: LDH &gt; upper limit of normal and neutrophil/[leukocytes minus neutrophils] ratio (dNLR) &gt; 3. The following LIPI subgroups were defined: good prognosis (0), intermediate prognosis (1) and poor prognosis (2 factors). Median (m) progression-free survival (PFS) and median overall survival (OS) were calculated using Kaplan-Meier method, log rank test was used for statistical comparison. Cox model was used for multivariate analysis. Results: To date, 152 mUC pts have been enrolled and preliminary analysis have been performed in 135 pts. Median age was 67 years, 111 (82%) pts were male, 106 pts (79%) had ECOG PS 0-1, 31 pts (23%) had liver metastasis. Median follow-up was 21.1 months (mo) (95% CI; 16.3-24.5), mPFS was 3.6 mo (95% CI; 2.6-6.0) and mOS was 13.8 mo (95% CI; 11.5-23.2). LIPI classified the population in good (56%), intermediate (35%) and poor (9%) prognosis group. In multivariate analysis, estimated mPFS in good, intermediate and poor prognosis were 5.8 mo (95% CI; 2.6-6.0), 3.6 mo (95% CI; 3.3-16.2) and 1.2 mo (95% CI;0.1-NR), respectively (p = 0.001). Estimated mOS in good, intermediate and poor prognosis were 17.3 mo (95% CI; 13.0-36.8), 16.9 mo (95% CI; 6.9-NR) and 5.4 mo (95% CI;2.5-NR), respectively (p = 0.19). OS data will be validated on larger cohort. Conclusions: The LIPI score is associated with clinical outcome to ICI and may be a useful tool for identifying patients who may not benefit from ICI. Validation in independent prospective cohort is ongoing.

Analysis of systemic inflammatory biomarkers in neuroendocrine carcinomas of the lung: prognostic and predictive significance of NLR, LDH, ALI, and LIPI score.

Background:Lung neuroendocrine carcinoma (NEC) is characterized by aggressive clinical behavior and lack of treatment advances. We evaluate the prognostic and the predictive roles of systemic inflammatory biomarkers in patient circulating blood: neutrophil–lymphocyte ratio (NLR), lactate dehydrogenase (LDH), advanced lung cancer inflammation index (ALI), and the Lung Immune Prognostic Index (LIPI) score.Methods:A total of 120 patients with small-cell lung cancer (SCLC) (n = 110) and large cell neuroendocrine carcinoma (LCNEC) (n = 10) were enrolled. Overall survival (OS) was evaluated by Kaplan–Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS while χ2 test was used for categorical data.Results:NLR cutoff value was 1.93. NLR was measured before and after first-line chemotherapy; 25 (21%) patients had higher NLR (delta NLR >1), whereas NLR was lower in 37 (31%). At the univariate analysis, median OS was 12 months: OS for SCLC and LCNEC were 11 months and 14 months, respectively. OS had a prognostic positive value in patients with pre-treatment NLR <1.93 (p = 0.0002), LDH <600 U/L (p = 0,03) and ALI ⩾34 (p = 0,0065). At the multivariate analysis, Eastern Cooperative Oncology Group performance status, LDH levels and response after first-line chemotherapy were independently associated with OS. Median OS for good, intermediate, and poor LIPI was 15 months, 11 months, and 9 months, respectively(p = 0.091). Patients with higher NLR (>1.93) had an increased probability of tumor progression (p = 0.045, χ2 test).Conclusion:This study demonstrated that systemic inflammatory biomarkers could facilitate the understanding of survival differences in the clinical management of lung NEC patients, underlying the need for prospective biomarker-driven studies in the immune checkpoint inhibitors setting.

Enfortumab Vedotin in urothelial cancer.

The treatment landscape for metastatic urothelial cancer (mUC) beyond first-line platinum-based chemotherapy has changed significantly over the last 5 years with the recent approvals of the immune checkpoint inhibitors (ICIs), fibroblast growth factor receptor (FGFR) inhibitors and most recently Enfortumab Vedotin (EV). EV is a novel antibody–drug conjugate (ADC), that delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, inside cells harboring the cell surface nectin-4 receptor. In mUC, EV has shown encouraging response rates and received accelerated approval from the Food and Drug Administration (FDA) in December 2019 in the post-platinum and ICI setting. EV is generally well tolerated, with the main toxicities being neuropathy, skin rash, alopecia and fatigue. Notably EV can also be administered to patients with renal dysfunction, which is commonly a concern in this patient population. EV is now being tested in combination strategies and in earlier disease settings in urothelial cancers. In this review, we will discuss its mechanism of action, clinical trials leading to FDA approval as well as ongoing trials and future directions.

Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature

BackgroundMyasthenia gravis (MG) is a rare but life-threatening adverse event of immune checkpoint inhibitors (ICI). Given the limited evidence, data from a large cohort of patients is needed to aid in recognition and management of this fatal complication.MethodsWe reviewed our institutional databases to identify patients who had cancer and MG in the setting of ICI. We systematically reviewed the literature through August 2018 to identify all similar reported patients. We collected data on clinical and diagnostic features, management, and outcomes of these cases.ResultsSixty-five patients were identified. Median age was 73 years; 42 (65%) were males, 31 (48%) had metastatic melanoma, and 13 (20%) had a preexisting MG before ICI initiation. Most patients received anti-PD-1 (82%). Sixty-three patients (97%) developed ICI-related MG (new onset or disease flare) after a median of 4 weeks (1 to 16 weeks) of ICI initiation. Twenty-four patients (37%) experienced concurrent myositis, and respiratory failure occurred in 29 (45%). ICI was discontinued in 61 patients (97%). Death was reported in 24 patients (38%); 15 (23%) due to MG complication. A better outcome was observed in patients who received intravenous immunoglobulin (IVIG) or plasmapheresis (PLEX) as first-line therapy than in those who received steroids alone (95% vs 63% improvement of MG symptoms, p = 0.011).ConclusionsMG is a life-threatening adverse event of acute onset and rapid progression after ICI initiation. Early use of IVIG or PLEX, regardless of initial symptoms severity, may lead to better outcomes than steroids alone. Our data suggest the need to reassess the current recommendations for management of ICI-related MG until prospective longitudinal studies are conducted to establish the ideal management approach for these patients.

Is cytoreductive nephrectomy relevant in the immunotherapy era?

The recent approval of immune checkpoint inhibitors (ICI) revolutionized the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, the role of cytoreductive nephrectomy is not well defined in this setting. Here, we review the contemporary role and timing of cytoreductive nephrectomy for advanced RCC in the era of immunotherapy. Evidence concerning combination systemic therapy and cytoreductive nephrectomy in the multimodal management of mRCC is primarily limited to studies conducted in the targeted therapy era. The oncologic role of cytoreductive nephrectomy in the setting of ICI remains largely undefined and is supported primarily by case reports. Nonetheless, patient selection for cytoreductive nephrectomy is paramount, and appropriate candidacy in the ICI era will likely be refined as increasing evidence emerges. Until then, a cautious balance between perceived oncologic benefit and risks of intervention must be exercised. Several trials are ongoing to help shed light on patient selection, technical feasibility, and optimal timing of cytoreductive nephrectomy in the immunotherapy era. Although the role and timing for cytoreductive nephrectomy remain to be further elucidated in the immunotherapy era, patient selection remains critical for treatment planning. Further studies are urgently needed to better define the role of cytoreductive nephrectomy in this setting.