Adjuvant Immunotherapy In Patients Research Articles

Disparities in Receipt of Adjuvant Immunotherapy among Stage III Melanoma Patients.

Melanoma survival has greatly improved with the advent of immunotherapy, but unequal access to these medications may exist due to nonmedical patient factors such as insurance status, educational background, and geographic proximity to treatment. We used the National Cancer Database to assess patients with nonmetastatic cutaneous melanoma who underwent surgical resection and sentinel lymph node biopsy (SLNB) with tumor involvement from 2015 to 2020. We evaluated rates of adjuvant immunotherapy among this patient population based on patient, tumor, and facility variables, including insurance status, socioeconomic status, pathologic stage (IIIA-IIID), and treatment facility type and volume. Adjuvant immunotherapy was associated with improved survival for stage III melanoma, with a slight increase in 5-year OS for stage IIIA (87.9% vs. 85.9%, P=0.044) and a higher increase in stages IIIB-D disease (70.3% vs. 59.6%, P<0.001). Receipt of adjuvant immunotherapy was less likely for patients who were older, low socioeconomic status, or uninsured. Low-volume and community cancer centers had higher rates of adjuvant immunotherapy overall for all stage III patients, whereas high-volume and academic centers used adjuvant immunotherapy much less often for stage IIIA patients compared with those in stages IIIB-D. Our results demonstrate inconsistent use of adjuvant immunotherapy among patients with stage III melanoma despite a significant association with improved survival. Notably, there was a lower use of adjuvant immunotherapy in patients of lower SES and those treated at high-volume centers. Equity in access to novel standards of care represents an opportunity to improve outcomes for patients with melanoma.

Adjuvant immunotherapy in patients with resected gastric and oesophagogastric junction cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): European Organisation of Research and Treatment of Cancer (EORTC) 1707 VESTIGE study.

Patients with gastroesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastroesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastroesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastroesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1:1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, loco-regional and distant failure rates and safety according to NCI-CTCAE v5.0. The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months (95% confidence interval [CI], 8.4-16.8 months) versus 20.8 months (95% CI, 15.0-29.9 months) for the chemotherapy group, HR 1.55 (95% CI, 1.07- 2.25, one-sided P=0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. Nivolumab/ipilimumab did not improve disease-free survival compared to chemotherapy in patients with ypN+ and/or R1 gastroesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.

Recent Noteworthy Studies in Thoracic Oncology.

In this paper, we review recent prospective surgical studies on resectable esophageal and lung cancer. A narrative literature review was performed using the terms 'resectable esophageal cancer' and 'multimodal therapy' and 'resectable non-small cell lung cancer'. Prospective surgical trials performed from 2010 to 2023 were identified and analyzed. gov was queried for ongoing studies. The studies on esophageal cancer demonstrate the benefits of neoadjuvant chemoradiation, compared with surgery alone, and the emerging role of immunotherapy as part of induction and adjuvant treatment protocols. The selected studies on lung cancer demonstrate the evolving role of sublobar resection for patients with peripheral node-negative clinical stage IA1 disease and the developing role of neoadjuvant and adjuvant immunotherapy for patients with stage II-IIIA disease. The methods of treating patients with resectable esophageal or lung cancer are changing. Efforts to limit patient morbidity and optimize tumor treatment before surgery are increasingly being pursued and these approaches will likely continue to evolve as tumor biology and long-term pharmacologic mechanisms of action become clearer. Personalized medicine strategies that are based on tumor characteristics and the host genetic profile remain on the horizon, not yet ready for adoption in routine clinical practice.

P2.07C.02 Prognostic Impact of Adjuvant Immunotherapy in Patients with Non-Small Cell Lung Cancer Following Neoadjuvant Immunotherapy

P2.07C.02 Prognostic Impact of Adjuvant Immunotherapy in Patients with Non-Small Cell Lung Cancer Following Neoadjuvant Immunotherapy

Outcome of adjuvant immunotherapy in a real-world nation-wide cohort of patients with melanoma

BackgroundClinical trials have demonstrated promising outcomes for adjuvant immunotherapy in patients with resected melanoma. Real-life data provide valuable insights to support patient guidance and treatment decisions. MethodsObservational population-based study examining a national cohort of patients with resected stage III-IV melanoma referred for adjuvant therapy. Data were extracted from the Danish Metastatic Melanoma Database (DAMMED). ResultsBetween November 2018 and January 2022, 785 patients received adjuvant anti-PD-1. The majority had stage III resected melanoma (87%), normal LDH levels (80%), and performance score 0 (87%). Patients were followed for a median of 25.6 months (95%CI 24−28). The median recurrence-free survival (RFS) and melanoma-specific survival (MSS) were not reached. The RFS was 78% (95%CI 75−81), 66% (63−70), and 59% (55−63); MSS was 97% (95−98), 93% (91−95), and 87% (84−90) at 1-, 2-, and 3-year; respectively. Less than half (42%) of the patients finalized planned therapy, 32% discontinued due to toxicity, and 19% due to melanoma recurrence. Patients discontinuing adjuvant treatment prematurely, without recurrence, had similar outcomes as patients finalizing therapy. In a multivariable analysis, ipilimumab plus nivolumab did not improve outcomes compared to ipilimumab monotherapy as a first-line metastatic treatment after adjuvant anti-PD-1. ConclusionSurvival outcomes in real-world patients with melanoma treated with adjuvant anti-PD-1 align with results from the randomized controlled trials. Patients discontinuing therapy prematurely, for other reasons than recurrence, had similar outcomes as patients finalizing planned treatment. First-line metastatic treatment with ipilimumab and nivolumab post-adjuvant anti-PD-1 did not show improved outcomes compared to ipilimumab/anti-PD-1 monotherapy.

Adjuvant immunotherapy in patients with renal cell carcinoma and urothelial carcinoma: A systematic review and network meta-analysis.

Adjuvant immune checkpoint inhibitor therapies have radically altered the treatment landscape for renal cell carcinoma and urothelial carcinoma. However, studies have reported negative data regarding adjuvant immune checkpoint inhibitor therapies. Thus, this study aimed to assess the role of adjuvant immune checkpoint inhibitor therapy for both renal cell carcinoma and urothelial carcinoma. A systematic review and network meta-analysis were conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Multiple databases were searched for articles published as of February 2023. Studies were deemed eligible if they evaluated disease-free survival in patients with renal cell carcinoma and urothelial carcinoma receiving adjuvant immune checkpoint inhibitor therapy. Five studies met the inclusion criteria. In a network meta-analysis, pembrolizumab was shown to be the most effective regimen for patients with renal cell carcinoma, whereas nivolumab was found to be the most effective regimen for patients with urothelial carcinoma. Additionally, these results were consistently observed in a sub-analysis of the T stage. The present analysis provides findings that support the usefulness of adjuvant nivolumab therapy in urothelial carcinoma and adjuvant pembrolizumab therapy in renal cell carcinoma, in agreement with the currently available guidelines. However, the caveat is that the randomized controlled trials included in this analysis differed in important respects despite being similar in study design. Therefore, with these differences in mind, care needs to be taken when selecting patients for these immune checkpoint inhibitor therapies to maximize their benefits.

Prospective Phase II Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed By Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy for Locally-Advanced Non-Small Cell Lung Cancer (LA NSCLC)

To report the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor SBRT followed by conventional chemoradiation to the lymph nodes and adjuvant immunotherapy in patients (pts) with unresectable LA NSCLC. Eligible pts included stage II-III LA NSCLC with peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions to the involved lymph nodes with concurrent platinum doublet chemotherapy. The trial was amended to allow pts without disease progression after chemoradiation to receive adjuvant durvalumab per the PACIFIC trial. The primary endpoint was 1 year progression free survival (PFS), evaluated as a binary variable. Frequencies and proportions were used for reporting this primary endpoint, in addition to adverse events and patterns of failure. Median PFS and OS were estimated using Kaplan Meier methods. Safety and efficacy is reported on the first 50 pts enrolled in the trial with a median follow-up of 24 months (mos) (range, 1-54 mos). Pts were primarily stage IIIA (60%) or stage IIIB (34%), with 6% of pts stage IIB. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 8% with two pts (4%) developing grade 3 pneumonitis and one pt having a grade 5 lung infection possibly related to radiation. Overall grade 2 pneumonitis related to SBRT or mediastinal radiation was 20%. Only one pt (2%) developed grade 3 esophagitis. No late cardiac events have been observed. The one-year PFS for all pts was 62% with a median PFS of 26.3 mos and median overall survival of 40.8 mos. Of the 50 pts enrolled, 37 received at least one dose of adjuvant durvalumab. The one-year PFS for pts who received at least one dose of durvalumab was 70.3% with a median PFS not yet reached in this group (median follow-up 24 mos). Patterns of failure were mostly distant with 26% of pts experiencing distant failure, 6% regional, and 2% distant and regional. There was only one local failure (2%) after SBRT in all 50 pts. SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and adjuvant immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for locally advanced NSCLC. The results of this trial will be further evaluated in a randomized phase III study, NRG LU-008. Pts will receive either conventional chemoradiation vs. SBRT to the primary tumor followed by chemoradiation to the involved lymph nodes followed by consolidative immunotherapy to evaluate the possibility of utilization of SBRT as a new standard of care for LA NSCLC.

O-6 EORTC 1707 VESTIGE: Adjuvant immunotherapy in patients (pts) with resected gastroesophageal adenocarcinoma (GEA) following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1)—an open-label randomized controlled phase II study

O-6 EORTC 1707 VESTIGE: Adjuvant immunotherapy in patients (pts) with resected gastroesophageal adenocarcinoma (GEA) following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1)—an open-label randomized controlled phase II study

Adjuvant immunotherapy for patients with renal cell carcinoma at increased risk of recurrence following resection: A National Cancer Database analysis.

649 Background: Radical nephrectomy is the standard management for locoregional renal cell carcinoma (RCC); however, patients with adverse pathological features are at increased risk of recurrence. IMmotion010 and KeyNote 564 trials investigated the adjuvant role of immune checkpoint inhibitors (ICI) for high-risk clear cell RCC (ccRCC) and have yielded conflicting results. We aimed to investigate real-world survival outcomes associated with the adjuvant use of ICI in high-risk ccRCC using the National Cancer Database Methods: In this nationwide contemporary cohort study, patients with newly diagnosed non-metastatic high-risk clear cell RCC undergoing radical nephrectomy between 2015-2019 were included. High-risk RCC was defined as cT2 with Fuhrman grade 4 or cT3a with Fuhrman grade 3/4 or cT3b/T3c/T4 with any grade, or TxN+ any grade. Patients receiving adjuvant ICI were classified as Group A and patients who did not receive adjuvant ICI were classified as Group B. Inverse probability weighting (IPW)-adjusted Kaplan Meier curves were utilized to compare overall survival (OS) between the groups and cox proportional hazard models were utilized to identify the predictors for OS. Results: Overall, 768 patients met the inclusion criteria; 270 patients in Group A and 498 patients in Group B. The mean age was 60.5(10.6) years, and 70.8% of patients were males (Table). The use of ICI in the adjuvant setting for high-risk RCC increased from 17.4% in 2015 to 61.8% in 2019. The unadjusted and IPW-adjusted Kaplan Meier 5-year overall survival was similar in the two groups [Unadjusted: 36.8% in Group A vs 50.1% in Group B, p=0.30 and adjusted: 39.5% in Group A vs 47.9% in Group B, p=0.17]. The use of adjuvant ICI did not appear to be an independent predictor for OS on multivariable cox regression analysis (HR=1.14, p=0.31) Conclusions: Adjuvant ICI therapy in non-metastatic high-risk ccRCC might not be associated with a benefit in overall survival. [Table: see text]

Adjuvant Immunotherapy in Patients with Early-Stage Non-small Cell Lung Cancer and Future Directions.

While cisplatin-based adjuvant chemotherapy has been the standard of care for the past two decades, the recent introduction of immunotherapy has heralded an important milestone in the adjuvant landscape of early-stage non-small cell lung cancer (NSCLC). The landmark approval of adjuvant atezolizumab based on disease-free survival (DFS) benefit in IMpower010 was swiftly followed by the recent data for use of adjuvant pembrolizumab in PEARLS/KEYNOTE-091, and similar trials involving other immune checkpoint inhibitors are eagerly anticipated. Although both atezolizumab and pembrolizumab demonstrated a significant DFS benefit in the intention-to-treat population, key subgroup analyses have raised questions about the role of predictive biomarkers such as PD-L1 expression and EGFR-mutation status. In this review, we examine the data from the two important trials (IMpower010 and PEARLS/KEYNOTE-091), discuss the controversies surrounding adjuvant immunotherapy including appropriate endpoints, biomarker selection and highlight key considerations in oncogene-driven NSCLC. Finally, we propose future directions including the impact of neoadjuvant therapy on developments in the adjuvant immunotherapy paradigm and role of minimal residual disease (MRD).

Serial Circulating Tumor DNA in Monitoring the Effect of Neoadjuvant and Adjuvant Immunotherapy in Patients With Colon Cancer: Case Series and Review of the Literature.

Although programmed death 1 blockade has significantly improved the survival of advanced colorectal cancer patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H), clinical data in neoadjuvant and adjuvant setting are limited. The role of circulating tumor DNA (ctDNA) in precision oncology is promising, but its clinical significance in immunotherapy needs to be validated. We report a case series of 3 colon patients who received neoadjuvant and adjuvant immunotherapy and serial ctDNA analysis. This report summarizes clinical and molecular details for 3 patients with locally advanced or recurrent dMMR/MSI-H/polymerase epsilon ( POLE ) mutation-positive tumors treated with neoadjuvant/adjuvant immunotherapy. One stage IV recurrent colon cancer patient diagnosed with Lynch syndrome received adjuvant sintilimab monotherapy and had a progression-free survival (PFS) over 16 months, one stage Ⅲc colon cancer patient with MSI-H/high tumor mutation burden received neoadjuvant toripalimab monotherapy, was assessed as clinical complete response before surgery, continued with adjuvant sintilimab monotherapy and had a PFS over 17 months, one stage Ⅱ colon cancer patient with POLE P286R also received adjuvant sintilimab monotherapy and had a PFS over 17 months. All patients had detectable ctDNA after radical surgery and clearance of ctDNA during adjuvant immunotherapy. All 3 patients are free of tumor disease at the time of this report. Further studies are warranted to evaluate the long-term efficacy of neoadjuvant and adjuvant programmed death 1 blockade in locally advanced and metastasis in dMMR/MSI-H/ POLE mutated colorectal cancer and the role of ctDNA monitoring.

Adjuvant immunotherapy in patients with resected esophageal and gastroesophageal junction cancer: Real-world evidence from Nova Scotia.

e16047 Background: Post-operative immunotherapy (POI) with nivolumab has become the standard of care for eligible patients with esophageal and gastroesophageal junction cancers (EGEJC) who had pre-operative chemoradiation (POCRT) and definitive surgery. However, not all patients who receive POCRT are eligible for POI. Objective: The primary objective was to determine the proportion of patients who receive POCRT that are eligible for POI in a real-world population. Further, we aimed to identify the specific barriers to POI to determine factors which could be strategically addressed to maximize access to curative intent treatment. Methods: All patients residing in mainland Nova Scotia who received POCRT between July 2016 and April 2019 were analyzed. Disease, patient, and treatment characteristics were collected via chart review. The relative proportion of patients who (1) had definitive surgery, (2) were eligible to receive POI and (3) would have accepted POI were collected. The specific reasons for non-eligibility or refusal of POI were captured. Results: A total of 65 patients received POCRT during the study period. 44 of those went on to have definitive surgery. All 44 of these patients were then screened for eligibility to be enrolled in a trial of POI. 23 were eligible, but 12 declined trial enrolment. 21 were ineligible, with the most common reason being a pathological complete response (n=11). Of the 21 patients who did not undergo surgery, 12 were found to have new metastatic disease on pre-operative restaging and 9 were felt to be too frail. Conclusions: Only 35% of patient receiving POCRT were eligible for POI. This is important real-world data when planning allocation of resources and adapting health care budgets for novel treatments and indications.

Preferences for adjuvant immunotherapy in patients with resected stage III melanoma: A discrete choice experiment.

9558 Background: Adjuvant immunotherapy has revolutionized the management of resectable melanoma, substantially reducing the risk of recurrence but at the risk of immune-related adverse events (AE). This study aimed to quantify patients' preferences for adjuvant immunotherapy, the influence of varying levels of key attributes, and baseline characteristics associated with preferences. Methods: We performed a discrete choice experiment (DCE), including patients with resected stage III melanoma considering or having received adjuvant immunotherapy. Patients chose between twelve randomly presented choice tasks of two alternative options (adjuvant immunotherapy versus observation without adjuvant immunotherapy). The two options varied across two-three levels of six attributes: chance of 3-year melanoma recurrence, mild, permanent, or fatal AE, drug regimen, and out-of-pocket costs. We calculated the marginal rate of substitution (MRS, how much an individual was willing to trade one attribute for preferred levels of another) and willingness-to-pay (WTP, maximum price to trade their preferred attributes) per year. Results: One hundred and sixteen patients completed the DCE. Patients chose adjuvant immunotherapy over observation without adjuvant immunotherapy in 70% of choice tasks. Patients preferred adjuvant immunotherapy with reduced probabilities of recurrence (OR 0.76, 95% CI 0.70-0.83, p&lt;0.001), fatal AE (OR 0.60, 95% CI 0.44-0.80, p=0.006), permanent AE (OR 0.94, 95% CI 0.89-0.99, p=0.046), and lowered out-of-pocket costs, for those with lower incomes (OR 0.63, 95% CI 0.47-0.85, p=0.003) and higher incomes (OR 0.84, 95% CI 0.15-4.86, p=0.064). Patients accepted an increase in their chance of mild AE from 1% to 37% (OR 2.06, 95% CI 1.13-3.78, p=0.019) in return for adjuvant immunotherapy. Willingness-to-pay was lower for patients with incomes that were lower rather than higher: US$595 (95% CI US-$555 to 1,305) and US$1,638 (95% CI US$ -1,235 to 3,419) per year for adjuvant immunotherapy with an absolute reduction of 1% in the 3-year risk of recurrence. Conclusions: Almost three-quarters of patients preferred adjuvant immunotherapy over observation without adjuvant immunotherapy. Patients were more likely to select immunotherapy if the risk of melanoma recurrence and the chance of fatal AE were reduced. Understanding patient preferences and acceptable trade-offs for adjuvant immunotherapy may allow better-informed decisions for individuals and assist policymakers in decisions about access and subsidization of effective and expensive treatments.

Adjuvant immunotherapy in patients with high-risk muscle-invasive urothelial carcinoma: The potential impact of informative censoring.

The results of 2 studies exploring adjuvant immune checkpoint inhibition (aCPI) in high-risk muscle-invasive urothelial cancer have yielded conflicting results. A trial employing placebo as the control arm demonstrated a significant prolongation in disease-free survival (DFS) whereas a trial employing observation as the control arm (IMvigor010) demonstrated no prolongation in DFS with CPI. Here, the authors aimed to estimate the aCPI benefit and to model the potential impact of informative censoring on trial results. Survival data from 1518 patients was reconstructed from Kaplan-Meier curves. A network meta-analysis approach was used to estimate aCPI benefit through the restricted mean disease-free survival time (RMDFST). To estimate the potential impact of informative censoring on IMvigor010, a simulation was performed. The minimum proportion of informative censoring on the observation arm that could account for the lack of observed improvement in DFS was estimated. Random variability from the time of censoring to progression was modeled using the exponential distribution. Patients receiving aCPI had better DFS: ΔRMDFST at 36 months of 2.2 (95% CI, 0.6-3.7, P = .006) months relative to observation/placebo. In IMvigor010, in the observation arm, 20.5% of patients were censored due to consent withdrawal, protocol violation and/or noncompliance, or lost to follow-up versus 8.2% in the treatment arm. On simulation, it was found that the lack of observed improvement in DFS could have resulted from as few as 14% of the censored patients on observation arm not being censored at random (simulated DFS with 14% informative censoring hazard ratio, 0.83; 95% CI, 0.69-0.99; P = .049). Phase 3 trials comparing adjuvant therapies to observation are at risk for informative censoring that could potentially impact interpretation of study results.

A0904 - Adjuvant immunotherapy in patients with high-risk muscle-invasive urothelial carcinoma and the potential impact of informative censoring

A0904 - Adjuvant immunotherapy in patients with high-risk muscle-invasive urothelial carcinoma and the potential impact of informative censoring

EORTC 1707 VESTIGE: Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1)—An open-label randomized controlled phase II study.

TPS4156 Background: Gastroesophageal adenocarcinoma (GEA) patients with metastatic lymph nodes (ypN+) or a microscopically incomplete surgical resection (R1) following neoadjuvant chemotherapy are at high risk of disease recurrence. Current practice is to continue with the same perioperative chemotherapy used prior to surgery, despite these suboptimal outcomes. Adjuvant immunotherapy with nivolumab has shown efficacy in poor risk GEA patients following chemoradiotherapy and surgery in the CheckMate 577 trial, and nivolumab and ipilimumab have demonstrated activity in advanced GEA. We hypothesise that high risk (ypN+ and/or R1) post resection GEA patients who are treated with nivolumab and ipilimumab will have better disease free survival than patients who continue with standard post-operative chemotherapy. Methods: VESTIGE is an ongoing, international, open label randomized phase II study designed to evaluate the efficacy of adjuvant nivolumab plus ipilimumab versus standard post-operative chemotherapy in high risk (ypN+ and/or R1) post resection GEA patients. Eligible patients (n=240) will be randomised 1:1 to receive post-operative adjuvant chemotherapy (identical regimen as pre-operatively) or nivolumab 3mg/kg IV q2w plus ipilimumab 1mg/kg IV q6w x 1 year. Key inclusion criteria include ypN+ and/or R1 status following neoadjuvant chemotherapy plus surgery and an adequate pre-specified surgical resection. The primary endpoint of the study is disease free survival, with secondary endpoints of overall survival, safety, toxicity and quality of life. Since start of recruitment in August 2019, the trial has recruited 85 of 240 patients at 18 sites in the Czech Republic, France, Germany, Israel, Italy, Norway, Poland, Spain, and United Kingdom. The VESTIGE translational research programme includes collection of pre-treatment biopsies, post-chemotherapy resection specimens and serial liquid biopsy on treatment to explore biomarkers predictive of immune checkpoint blockade efficacy. Clinical trial information: NCT03443856.

Symptomatologic pathomechanism of N-methyl D-aspartate receptor encephalitis.

N-methyl D-aspartate receptor (NMDAR) encephalitis is a well-characterized clinical syndrome. The main molecular mechanism of NMDAR encephalitis is autoantibody-mediated NMDAR hypofunction in the neuronal synapse. Several pathomechanistic hypotheses might explain how NMDAR hypofunction causes the typical symptoms and prognosis of NMDAR encephalitis. Suppression of NMDAR-dependent gamma-aminobutyric acid interneurons provokes an accelerated activation of the positive feedback loops of the dorsolateral prefrontal cortex/subiculum-nucleus accumbens circuit in the striatum, the ventral tegmental area (VTA), and the nucleus reuniens in the thalamus-hippocampus-VTA loop. Dysregulated activation of the VTA and cortex via those positive feedback loops may explain the rapid clinical deterioration at acute stages of the disease and the well-characterized syndrome that includes limbic system dysfunction, intractable seizures, dyskinesia, coma, and the characteristic extreme delta brush. Progressive cerebellar atrophy is correlated with cumulative disease burden and is associated with worse long-term outcomes, which might be explained by the NMDAR-dependent pathways required to maintain neuronal survival. Those pathomechanistic hypotheses for NMDAR encephalitis support the rationale for the early introduction of combination immunotherapy and the use of adjuvant immunotherapy in patients with persisting symptoms in chronic disease phases.

Phase II prospective trial of primary lung tumor stereotactic body radiation therapy (SBRT) followed by concurrent mediastinal chemoradiation and adjuvant immunotherapy for locally-advanced non-small cell lung cancer (NSCLC): Planned toxicity analysis.

e21047 Background: The care of pts with locally-advanced NSCLC has continued to evolve. Dose escalation with conventional radiation and concurrent chemotherapy has failed to improve outcomes and is associated with low primary tumor control rates and high toxicity rates. We initiated a phase II study to evaluate full dose SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes followed by adjuvant immunotherapy in patients (pts) with unresectable locally-advanced NSCLC. Methods: Eligible pts included peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions with concurrent chemotherapy (physician choice of carboplatin/paclitaxel or cisplatin/etoposide). Pts without disease progression after chemoradiation then received adjuvant durvalumab (PACIFIC trial). Planned analysis of early toxicity was performed given this is the first prospective trial to replace conventional fractionation and deliver full dose SBRT to the primary tumor in the locally advanced setting. Results: From May 2017 to January 2020, 35pts were enrolled. Median follow up is 7.9 months (range 0-27 months). Toxicity related to either SBRT or mediastinal radiation was lower than previous published prospective trials with a grade 2 radiation pneumonitis incidence of only 17%. There was no ≥grade 3 pneumonitis. Grade 3 esophagitis was observed in 1 pt (3%) with grade 2 esophagitis in 37%. No grade ≥3 toxicity has been attributed to SBRT with 26% of pts experiencing a grade 2 toxicity from SBRT. Overall incidence of grade ≥3 pulmonary toxicity attributed to any therapy was 9%. One pt died of neutropenic sepsis due to legionella while on therapy attributed to chemotherapy. No major cardiac events were reported to date. Conclusions: Full dose SBRT to the primary tumor followed by standard chemoradiation to the involved lymph nodes appears to have a favorable toxicity profile when compared with conventional dose escalation and to previously published experiences with SBRT boost following chemoradiation in the treatment of locally advanced NSCLC. Our trial continues to enroll with a target of 56 pts. Clinical trial information: NCT03141359 .

EORTC 1707 VESTIGE: Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): An open-label randomized controlled phase II study.

TPS467 Background: Gastroesophageal adenocarcinoma patients with metastatic lymph nodes (ypN+) or a microscopically incomplete surgical resection (R1) following neoadjuvant chemotherapy are at high risk of disease recurrence. Current practice is to continue with the same perioperative chemotherapy used prior to surgery, despite these suboptimal outcomes. Immune checkpoint blockade with nivolumab and ipilimumab has demonstrated activity in advanced gastroesophageal adenocarcinoma. We hypothesise that high risk (ypN+ and/or R1) post resection gastroesophageal adenocarcinoma patients who are treated with nivolumab and ipilimumab will have better disease free survival than patients who continue with standard post-operative chemotherapy. Methods: VESTIGE is an ongoing, international, open label randomized phase II study designed to evaluate the efficacy of adjuvant nivolumab plus ipilimumab versus standard post-operative chemotherapy in high risk (ypN+ and/or R1) post resection gastroesophageal adenocarcinoma patients. Eligible patients (n=240) will be randomised 1:1 to receive post-operative adjuvant chemotherapy (identical regimen as pre-operatively) or nivolumab 3mg/kg IV q2w plus ipilimumab 1mg/kg IV q6w x 1 year. Key inclusion criteria include ypN+ and/or R1 status following neoadjuvant chemotherapy plus surgery and an adequate pre-specified surgical resection. The primary endpoint of the study is disease free survival, with secondary endpoints of overall survival, safety, toxicity and quality of life. The trial will recruit 240 patients at 24 number of sites in the Czech Republic, France, Germany, Israel, Italy, Norway, Poland, Portugal, Spain, and United Kingdom. Recruitment commenced July 2019 and is anticipated to take 30 months. The VESTIGE translational research programme includes collection of pre-treatment biopsies, post-chemotherapy resection specimens and serial liquid biopsy on treatment to explore biomarkers predictive of immune checkpoint blockade efficacy. Clinical trial information: NCT03443856.

VESTIGE: Adjuvant Immunotherapy in Patients With Resected Esophageal, Gastroesophageal Junction and Gastric Cancer Following Preoperative Chemotherapy With High Risk for Recurrence (N+ and/or R1): An Open Label Randomized Controlled Phase-2-Study.

Background: Perioperative chemotherapy plus surgery is one recommended standard treatment for patients with resectable gastric and esophageal cancer. Even with a multimodality treatment more than half of patients will relapse following surgical resection. Patients who have a poor response to neoadjuvant chemotherapy and have an incomplete (R1) resection or have metastatic lymph nodes in the resection specimen (N+) are especially at risk of recurrence. Current clinical practice is to continue with the same chemotherapy in the adjuvant setting as before surgery. In the phase II randomized EORTC VESTIGE trial (NCT03443856), patients with high risk resected gastric or esophageal adenocarcinoma will be randomized to either adjuvant chemotherapy (as before surgery) or to immunotherapy with nivolumab and low dose ipilimumab (nivolumab 3 mg/kg IV Q2W plus Ipilimumab 1 mg/kg IV Q6W for 1 year). The primary endpoint of the study is disease free survival, with secondary endpoints of overall survival, safety and toxicity, and quality of life. This is an open label randomized controlled multi-center phase-2 superiority trial. Patients will be randomized in a 1:1 ratio to study arms. The trial will recruit 240 patients; recruitment commenced July 2019 and is anticipated to take 30 months. Detailed inclusion/exclusion criteria, toxicity management guidelines, and statistical plans for EORTC VESTIGE are described in the manuscript.Clinical Trial Registration: The trial is registered with www.ClinicalTrials.gov, identifier: NCT03443856.