Adjuvant Immune Checkpoint Inhibitor Research Articles

Timing of Adjuvant Immunotherapy in Stage III Melanoma, Does it Matter?

The optimal time to initiate adjuvant immune checkpoint inhibitors (ICI) following resection remains undefined. Herein, we investigated the impact of time to adjuvant ICI on survival in patients with stage III melanoma. Patients with resected stage III melanoma receiving adjuvant immune therapy were identified within a multi-institutional retrospective cohort. Patients were stratified by time to adjuvant ICI: within 6weeks, 6-12weeks, and greater than 12 weeks from surgery. Recurrence-free survival (RFS) was compared among time strata with Kaplan-Meier and Cox proportional hazards methods in the multi-institutional cohort. Altogether, 626 patients were identified within the multi-institutional cohort: 39% of patients initiated adjuvant ICI within 6weeks, 42.2% within 6-12 weeks, and 18.8% greater than 12weeks from surgery. In a multivariate Cox model, adjusting for histology, nodal tumor burden, and pathologic stage, we found that increased time to adjuvant ICI was associated with improved RFS. Patients who initiated adjuvant ICI within 6 weeks of surgery had worse RFS. These findings were preserved in a conditional landmark analysis and separate subgroups of patients with (1) new melanoma diagnoses, (2) occult stage III disease, and (3) those receiving anti-PD-1 monotherapy. Outcomes for patients with stage III melanoma are not compromised when adjuvant ICI is initiated beyond 6 weeks from resection. Additional work is needed to better understand the underlying mechanisms and implications of timing of adjuvant ICI on long-term outcomes.

The role of immune checkpoint inhibitors (ICI) as adjuvant treatment in renal cell carcinoma (RCC): A systematic review and meta-analysis.

Pembrolizumab, a PD-1 ICI is approved for the adjuvant treatment of postnephrectomy patients with clear cell RCC in some countries worldwide. However, recent negative data from randomized clinical trials (RCT) with another ICIs makes the benefit of this treatment uncertain. A systematic review and study-level meta-analysis was performed to evaluate the benefit of disease-free survival (DFS) with adjuvant ICI treatment for patients with localized and/or metastatic resected RCC. Using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to September 15, 2022. The statistical analysis was performed by ProMeta 3 software in intention-to-treat (ITT) population and in predetermined subgroups. Four RCT totalizing 3407 patients were included in this analysis. Systemic immunotherapy was pembrolizumab, atezolizumab, nivolumab, and ipilimumab plus nivolumab in 496, 390, 404, and 405 patients, respectively. In the ITT population there was a nonstatistically significant DFS benefit with adjuvant ICI (HR: 0.85, 95% CI: 0.69-1.04). Regarding the subgroups, there was a DFS benefit for PD-L1 positive (HR: 0.72; 95% CI: 0.55-0.94), intermediate-high risk patients (HR: 0.77; 95% CI: 0.63-0.94), and patients with sarcomatoid component (HR: 0.66; 95% CI: 0.43-0.99). This meta-analysis did not demonstrate a statistically significant DFS benefit in overall population, however considering the heterogeneity between the RCTs the use of adjuvant ICI should be individualized.

EGFR expression and relapse in patients with melanoma receiving adjuvant PD-1-based immunotherapy.

e21566 Background: Since 2018, adjuvant immune checkpoint inhibitors (ICI) have been available for patients with resected stage III/IV melanoma. The Checkmate 238 and Keynote 054 studies showed a survival benefit in patients receiving adjuvant ICI. However, there is no validated biomarker to identify patients at high risk of relapse, despite receiving adjuvant therapy. Here we investigated resistance patterns to immune checkpoint inhibition in the adjuvant setting. Methods: In this cohort study, a discovery cohort of 30 patients from the Department of Dermatology, University Hospital Zürich, was used to evaluate resistance patterns to adjuvant ICI. A second cohort of 107 patients from the Department of Dermatology, University Hospital Tuebingen, was used to validate the findings. We measured epidermal growth factor receptor (EGFR) expression in primary tumor and metastatic tissue by immunohistochemistry and digital pathology using QuPath. The primary endpoint was relapse-free survival. Results: We included 137 patients with melanoma receiving adjuvant ICI: 63 (46%) were females, and 52 (38%) patients harbored a BRAFV600 mutation. The median follow-up was 45 and 39 months in the Zürich and Tuebingen cohorts, respectively (95% confidence interval (CI) 41.8-48.2 and 36.8-41.2, respectively). The two cohorts were homogenous in terms of patients' and tumor characteristics, except for the relapse rate, which was significantly higher in the Tuebingen cohort ( p< 0.002). 71 (52%) therapy naïve in transit or lymph node metastasis and 23 (17%) primary tumors were available to evaluate EGFR expression by immunohistochemistry and digital pathology using QuPath. Surprisingly, in both cohorts, patients with high EGFR expression in metastatic tissue had a significantly higher relapse rate than patients with low EGFR expression ( p= 0.0004 and p= 0.0168 for the Zürich and Tuebingen cohorts, respectively). EGFR expression in primary tumors did not correlate with relapse-free survival ( p= 0.7286). Next-generation sequencing revealed that EGFR expression assessed by immunohistochemistry was not associated with the presence of EGFR mutations and/or amplifications. Conclusions: Currently, there are no validated biomarkers to identify patients with melanoma at high risk of recurrence, despite receiving adjuvant ICI. We found in two independent cohorts that EGFR expression in therapy naive metastatic tissue is positively associated with relapse in patients receiving adjuvant ICI. Our data identified EGFR as a prognostic biomarker that can easily be assessed by immunohistochemistry, allowing us to stratify patients for adjuvant ICI therapy according to their risk of relapse. Stratification according to EGFR expression should be considered in future clinical trials in the adjuvant setting.

NEO-CESQ study: Neoadjuvant plus adjuvant treatment with cemiplimab in surgically resectable, high risk stage III/IV (M0) cutaneous squamous cell carcinoma.

9576 Background: In the last years, the treatment of locally advanced and/or metastatic cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of cemiplimab, an anti-PD-1 antibody, which showed a 50% overall response rate and long term benefit (1). Recently, a phase II trial of neoadjuvant cemiplimab in resectable CSCC patients (2), showed a major pathological response (MPR) rate of 63.3%. In the current multicenter, phase II trial we evaluated the efficacy of neoadjuvant plus adjuvant immune checkpoint inhibitor in patients with surgically resectable, high-risk stage III/IV (M0) CSCC. Methods: Patients with surgically resectable high-risk stage III/IV (M0) CSCC received cemiplimab at a dosage of 350 mg every 3 weeks for two cycles prior surgery and for one year after surgery. The study primary endpoint was MPR [pathological complete response (pCR) or near pCR ( < 10% remaining viable tumour cells in the surgical pathology sample)] per independent central pathology review. Key secondary endpoints included recurrence-free survival (RFS), overall survival (OS), safety and the analysis of predictive biomarkers. Results: From May 2021 to October 2022 twenty-three patients were enrolled in 6 centers. pCR was observed in 9 (39%) patients and near pCR in 2 (8%) patients, while pathological partial response (10-50% remaining viable tumour cells) and no pathologic response was observed in 1 patient and 11 patients, respectively. At data lock of 31st January 2023, only one patient was discontinued due to clinical progression. Furthermore, it was observed n = 60 (57%) any adverse events (AE) and n = 29 (30%) treatment-related AE. No any G3/G4 AE were observed. Conclusions: Neoadjuvant cemiplimab induced a pathological response in 52% of stage III/IV (M0) CSCC patients with a MPR in 48%. The study is still ongoing to evaluate the impact of combined neoadjvuant and adjuvant immunotherapy on RFS and biomarkers analysis. Clinical trial information: NCT04632433 .

Adjuvant immune checkpoint inhibitors and association with recurrence-free survival in postoperative hepatocellular carcinoma (PREVENT): A prospective cohort study.

4119 Background: Adjuvant therapy may improve survival of patients with hepatocellular carcinoma (HCC) after curative resection, yet no such therapy is universally recommended. This study compared safety and efficacy outcomes between patients at high risk of recurrence who received different types of adjuvant therapy or no such therapy after hepatic resection for HCC. Methods: Recurrence-free survival (RFS), overall survival, and adverse events were compared among patients who received adjuvant immune checkpoint inhibitors (ICIs) alone, ICIs with tyrosine kinase inhibitors (TKIs), or no adjuvant therapy at our medical center between 13 March 2019 and 19 March 2022. In some analyses, patients who received adjuvant therapy were matched based on propensity scores to patients who did not, in order to reduce confounding due to baseline differences. This study was registered on ClinicalTrials.gov (NCT05221398). Results: Of the 492 patients in our final analysis, 410 (83.3%) received no adjuvant therapy, 50 (10.2%) received ICIs alone, and 32 (6.5%) received adjuvant ICIs and TKIs. During median follow-up of 23.3 months (IQR 15.6 to 31.1 months), HCC recurred in 221 (53.9%) of patients who received no adjuvant therapy, compared to 22 (44.0%) of patients who received ICIs and 18 (56.3%) of patients who received ICIs and TKIs. RFS was significantly longer among patients who received either type of adjuvant therapy (23.9 months, 95%CI 14.0-33.7) than among those who received none (16.8 months, 95%CI 13.2-20.3), and this difference remained significant after propensity score matching (HR 0.61, 95%CI 0.39-0.94, P = 0.033). However, overall survival was unaffected by either type of adjuvant therapy, even after propensity score matching. The rate of grade 3 or 4 adverse events was similar between the two types of adjuvant therapy. Conclusions: ICIs alone or with TKIs may improve RFS of patients at high risk of recurrence after curative resection. Clinical trial information: NCT05221398 .

Electronic health record (EHR)-based machine learning (ML) to predict disease recurrence after surgical resection of early-stage non-small cell lung cancer (eNSCLC).

6626 Background: Surgical resection (SR) is a guideline-recommended definitive therapy for patients (pts) with eNSCLC. However, 30–50% pts develop disease recurrence (DR) within the first 5 years (yrs) after surgery. ML applied to routinely collected EHR data could facilitate timely identification of pts at risk of DR who would benefit from enhanced surveillance or initial treatment (Tx) intensification. Methods: eNSCLC pts with stage IB-IIIA at the time of SR between Jan 2010 – February 2022 were identified from ConcertAI Patient360 oncology database comprising structured and curated records from US-based EHR. DR was defined as the human-curated earliest advanced/metastatic diagnosis date from SR. Gradient boosting (GB), random forest (RF), and logistic regression (LR) algorithms with 6-fold nested cross-validation were trained and compared to predict the risk of DR or death at 2 yrs from SR. Pts who did not experience DR and were lost to follow-up within 2 yrs from SR were removed. Feature importance was defined using Shapley Additive Explanation (SHAP)-derived odds ratios (OR). Due to low prevalence of DR at 2 yrs, AUPRC was used as performance metric. Pts in the 1st and 4th quartiles of predicted probabilities from XGB model were defined as low-risk vs. high-risk groups. Results: Among 3597 pts, median age was 68.3 yrs (IQR 12.5), 51.8% were female, and 8.6% were Black. 24.4% developed DR within 2 yrs. GB, RF, and LR models had similar ability to predict DR at 2 yrs with mean hold-out set AUPRC of 0.33. In GB model, DR prevalence at 2 yrs was 34% in the high-risk vs. 18% in the low-risk group in hold-out set. N0 stage, T stage < 3, receipt of adjuvant immune checkpoint inhibitor (ICI), and presence of EGFR mutations were protective against DR at 2 yrs, while history of anemia and congestive heart failure (CHF) were risk factors (Table). SHAP revealed a N stage-by-adjuvant therapy and a N stage-by-CHF interaction: benefit from adjuvant chemotherapy (CT) was limited to higher N stages, while adjuvant ICI was beneficial for all N stages. CHF was a risk factor for lower N stages but not for higher N stages. Conclusions: ML applied to structured and unstructuredEHRs identified predictors of risk of DR at 2 yrs after surgery in eNSCLC and may identify high-risk pts who would benefit from enhanced surveillance plans and Tx intensification in the eNSCLC setting. The model indicated favorable outcome from adjuvant targeted therapies in EGFR mutated pts. [Table: see text]

Outcomes with immune checkpoint inhibitors (ICI) in patients (pts) with MTAP alterations (alt) in advanced urothelial carcinoma (aUC).

4574 Background: MTAP loss of function alt in aUC has been associated with poor prognosis. MTAP is an enzyme involved in the adenine salvage pathway and deficiency of the protein leads to susceptibility to antifolate agents, e.g., pemetrexed. MTAP loss has also been correlated with immunosuppressive tumor microenvironment, inducing a “cold tumor” that may be less responsive to ICI. Response and outcomes to ICI in pts with MTAP altered aUC need further assessment. We hypothesized that pts with MTAP altered aUC would have lower response and shorter survival on ICI. Methods: We used our database from 26 centers (US/Europe) of pts with aUC treated with ICI. We included pts with available NGS data who received ICI for aUC. We excluded pts with pure non-UC, treated with adjuvant ICI, ICI combinations, or on clinical trials. Outcomes (observed response rate [ORR], progression free survival [PFS] and overall survival [OS]) were compared in pts who received either 1st line [1L] or 2nd line and beyond [2+L] ICI with and without MTAP alt. We compared ORR using logistic regression; PFS and OS were compared using Kaplan-Meier and Cox proportional hazards. We separately describe outcomes in pts with MTAP alt who received avelumab switch maintenance. Results: 211 pts from 8 centers met inclusion criteria with available MTAP alt status; 174 received ICI as distinct aUC treatment line (16% had MTAP alt; n=28) either in 1L or 2+L setting; 37 pts received avelumab switch maintenance (19% had MTAP alt; n=7). Pts with known MTAP status were 72% men, 91% White, 72% pure UC, 25% upper tract UC, 64% ECOG PS 0-1, 56% visceral mets, 18% bone mets, 15% liver mets. Median follow up from starting ICI was 44 months [mo] (IQR 29-51). ORR to ICI (1L + 2+L) in pts with MTAP alt was 25% (95%CI 10-47) vs 47% (95%CI 39-55%) in pts without MTAP alt [OR 3.11 (95%CI 1.15-7.82)]. PFS for pts with MTAP alt was not significantly different vs pts without MTAP alt (median 3 vs 6 mo, respectively: HR 1.46 [95%CI 0.91-2.35]). OS was similar between groups (median 14 vs 15 mo, respectively: HR 0.93 [95%CI 0.53-1.63]). Table describes outcomes by ICI treatment line (1L, 2+L, maintenance) in pts with and without MTAP alt. Conclusions: In pts with aUC receiving ICI, the presence of MTAP alt was significantly associated with lower ORR and a trend towards shorter PFS compared to absence of MTAP alt. Limitations include retrospective nature, small sample size, selection/confounding biases, lack of randomization and central scan review. Findings need external validation and might inform discussion on the optimal therapy sequence in aUC. [Table: see text]

Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis

PurposeTo analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex.MethodsThree databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting.ResultsOverall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55–0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68–0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females.ConclusionsOS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making.

Adjuvant therapy for renal cell carcinoma: 2023 Canadian Kidney Cancer Forum consensus statement.

Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context. An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who received adjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement. A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data. This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation.

Role of lymphadenectomy during primary surgery for kidney cancer.

Lymph node dissection (LND) during radical nephrectomy (RN) for renal cell carcinoma (RCC) is not considered as a standard. The emergence of robot-assisted surgery and effective immune checkpoint inhibitors (ICI) in recent years may change this and lymph node (LN) staging has become easier and has a clinical impact. In this review, we aimed to reconsider the role of LND today. Although the extent of LND has still not been well established, removal of more LN seems to provide better oncologic outcomes for a select group of patients with high-risk factors such as clinical T3-4. Adjuvant therapy using pembrolizumab has been shown to improve disease free survival if complete resection of metastatic lesions as well as the primary site is obtained in combination. Robot assisted RN for localized RCC has been widespread and the studies regarding LND for RCC has been recently appeared. The staging and surgical benefits and its extent of LND during RN for RCC remains unclear, but it is becoming increasingly important. Technologies that allow an easier LND and adjuvant ICI that improve survival in LN-positive patients are engaging the role of LND, a procedure that was needed, but almost never done, is now indicated sometimes. Now, the goal is to identify the clinical and molecular imaging tools that can help identify with sufficient accuracy who needs a LND and which LNs to remove in a targeted personalized approach.

MP69-04 KYNURENINE PATHWAY IS STRONGLY ASSOCIATED WITH CLINICOPATHOLOGICAL FEATURES AND RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP69-04 KYNURENINE PATHWAY IS STRONGLY ASSOCIATED WITH CLINICOPATHOLOGICAL FEATURES AND RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA Kenji Zennami, Makoto Sumitomo, Takuhisa Nukaya, Masashi Takenaka, Manabu Ichino, Kiyoshi Takahara, Hitomi Sasaki, Maeda Yasuhiro, and Ryoichi Shiroki Kenji ZennamiKenji Zennami More articles by this author , Makoto SumitomoMakoto Sumitomo More articles by this author , Takuhisa NukayaTakuhisa Nukaya More articles by this author , Masashi TakenakaMasashi Takenaka More articles by this author , Manabu IchinoManabu Ichino More articles by this author , Kiyoshi TakaharaKiyoshi Takahara More articles by this author , Hitomi SasakiHitomi Sasaki More articles by this author , Maeda YasuhiroMaeda Yasuhiro More articles by this author , and Ryoichi ShirokiRyoichi Shiroki More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003332.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Metabolomics offers a potential role for discovering biomarkers and therapeutic targets by comprehensive screening of metabolites from patients with various cancers. However, metabolomic analysis using upper tract urothelial carcinoma (UTUC) tissue has not been reported. Therefore, we aimed to identify metabolites associated with clinicopathological features and response to neoadjuvant chemotherapy (NAC) in patients with UTUC. METHODS: Patients receiving treatment following a clinical diagnosis of UTUC at the Fujita Health University between October 2019 and August 2022 were enrolled in this study. We assessed 47 consecutive patients for whom a tumor tissue sample and nontumor tissue sample. Concentrations of metabolites were determined by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS). For the analysis of the associations of kynurenine (Kyn) /tryptophan (Trp) metabolism with the patients’ clinicopathological characteristics and response to NAC, the Kyn/Trp ratio (KTR) in tissue samples and the tumor/nontumor (T/N) ratio of Kyn and Trp were determined. RESULTS: We first screened tissue concentrations of 58 metabolites and found that Kyn was the key metabolite. Mann-Whitney U tests revealed significant differences in the tissue Kyn T/N ratio and KTR T/N ratio with pathological stage (p=0.03 and p=0.03; Figure 1A and 1B). The tissue Kyn T/N ratio and KTR T/N ratio were also associated with tumor grade (p=0.02 and p=0.01; Figure 1C and 1D). KTR T/N ratio showed significant association with the presence of lymphovascular invasion (LVI) (p=0.01; Figure 1F), while Kyn T/N ratio was not statistically significant although there was a similar tendency (p=0.08; Figure 1E). In addition, the tissue Kyn T/N ratio and KTR T/N ratio were significantly associated with pathological downstaging (pDS) (p=0.003 and p=0.01; Figure 1G and 1H). CONCLUSIONS: Our study found that Try-Kyn pathway has a key role in the clinicopathological features of UTUC including stage, grade, and LVI. Since Kyn and KTR were associated with pDS, evaluation of Try-Kyn pathway using biopsy sample could be a predictive biomarker in NAC sensitivity, as well as appropriate adjuvant immune checkpoint inhibitors (ICIs) in NAC resistant case. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e964 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kenji Zennami More articles by this author Makoto Sumitomo More articles by this author Takuhisa Nukaya More articles by this author Masashi Takenaka More articles by this author Manabu Ichino More articles by this author Kiyoshi Takahara More articles by this author Hitomi Sasaki More articles by this author Maeda Yasuhiro More articles by this author Ryoichi Shiroki More articles by this author Expand All Advertisement PDF downloadLoading ...

Quantifying the Value of Multigene Testing in Resected Early Stage Lung Adenocarcinoma.

Tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs), each requiring testing for precision biomarkers, have recently been approved in the adjuvant setting. We assessed the potential value of multigene testing in early lung adenocarcinoma (LUAD). Using a real-world clinicogenomic database linking deidentified electronic health record-derived clinical data to genomic data, we selected patients with LUAD who underwent tissue comprehensive genomic profiling (CGP). Using a probabilistic decision tree, we estimated the cost implications of the avoidance of adjuvant ICI in patients with programmed death-ligand 1-positive (PD-L1+) LUAD and an ALK, ROS1 or RET driver. The CGP was performed on a specimen collected before advanced disease in 20% (1320 of 6697) of cases and ordered before advanced diagnosis for 12.6% (847 of 6697) of patients. The prevalence of driver alterations in early and advanced-stage specimens was similar, though KRAS mutations were enriched in early disease and drivers including ALK rearrangements in advanced disease. Patients who had CGP results obtained before versus after recurrence had less time between recurrence and the start of any first-line treatment (median 3.6 versus 6 wk, p < 0.001). Through avoidance of ICI in programmed death-ligand 1-positive early LUAD with an ALK, ROS1 or RET driver, we estimated that the universal CGP could reduce expected costs by $1597.23 per patient relative to EGFR single-gene testing. The CGP can identify driver alterations and accelerate the start of first-line therapy at recurrence. It may also represent a cost-effective approach for avoiding futile adjuvant ICI in patients with drivers that have historically lacked activity with ICI in metastatic disease.

Neural network based ensemble model to predict radiation induced lymphopenia after concurrent chemo-radiotherapy for non-small cell lung cancer from two institutions

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT.In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end of treatment. Multi-institutional data of 139 LA-NSCLC patients from two hospitals were collected for training and validation of our suggested model. Ensemble learning was combined with a bootstrap strategy to stabilize the model, which was evaluated internally using repeated cross validation.The performance of our proposed model was compared to conventional models using the same input features, such as Logistic Regression (LR) and Random Forests (RF), using the Area Under the Curve (AUC) of Receiver Operating Characteristics (ROC) curves. Our suggested model (AUC=0.77) outperformed the comparison models (AUC=0.72, 0.74) in terms of absolute performance, indicating that the convolutional structure of the network successfully abstracts additional information from the differential DVHs, which we studied using Gradient-weighted Class Activation Map.This study shows that clinical factors combined with dDVHs can be used to predict the risk of RIL for an individual patient and shows a path toward preventing lymphopenia using patient-specific modifications of the radiotherapy plan.

Adjuvant immunotherapy in renal cell carcinoma: asystematic review and meta-analysis.

To synthesise available data regarding the disease-free survival (DFS) benefit of adjuvant immune checkpoint inhibitors (ICIs) for patients with renal cell carcinoma (RCC) and evaluate the overall safety profile of ICIs in this setting. We utilised PubMed, Embase, and relevant conference proceedings to identify phase III randomised controlled trials comparing adjuvant ICIs vs placebo/observation for RCC. The primary outcome of interest was DFS. Variables for subgroup analyses were programmed death-ligand 1 (PD-L1) expression, sarcomatoid features, nephrectomy type, and disease-risk category. Secondary outcomes included Grade ≥3 adverse events (AEs), immune-related AEs, and treatment discontinuation due to AEs. All outcomes were analysed using random-effects models owing to inter-study heterogeneity. Among the four included studies, one demonstrated a significant DFS benefit. There was considerable clinical and statistical heterogeneity (I2 = 64%) due to differences in inclusion criteria and interventions. While pooled results across the four studies did not demonstrate a significant benefit in DFS overall (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.69-1.04) there was significant benefit among patients with positive PD-L1 expression (HR 0.72, 95% CI 0.55-0.94) and sarcomatoid features (HR 0.59, 95% CI 0.38-0.91). The evidence base to date regarding ICIs as adjuvant therapy in RCC is mixed - conclusions are limited by considerable heterogeneity between studies. However, pooled analyses suggest that patients with positive PD-L1 expression or sarcomatoid features are most likely to benefit from adjuvant immunotherapy.

Immune Checkpoint Inhibitors for Solid Tumors in the Adjuvant Setting: Current Progress, Future Directions, and Role in Transplant Oncology

The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk-benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice.

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 Therapy for Renal Cell Carcinoma: End Points, Outcomes, and Risk Assessments.

Targeted tyrosine kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs) revolutionized the treatment of metastatic renal cell carcinoma (RCC). Efforts to translate these therapies into the adjuvant setting for local and locoregional RCC have been pursued over the past decade. We sought to provide an updated review of the literature regarding adjuvant therapy in RCC, as well as an analysis of patient characteristics that may portend the most favorable responses. Using PubMed, Google Scholar, and Wiley Online Library, we reviewed articles between 2000 and 2022. Search terms included "tyrosine kinase inhibitors," "adjuvant," "immunotherapy," and "renal cell carcinoma." The articles included were original and published in English. Information on clinical trials was collected from ClinicalTrials.gov, accessed in June 2022. Landmark trials investigating adjuvant vascular endothelial growth factor (VEGF) inhibitors produced conflicting results, with only a single trial of sunitinib (S-TRAC) resulting in US Food and Drug Administration-approval on the basis of a slightly prolonged progression-free survival (PFS). Subsequent meta-analyses failed to show a benefit for adjuvant VEGF inhibitors. Several trials evaluating ICIs are currently ongoing, with pembrolizumab (KEYNOTE-564) earning US Food and Drug Administration-approval for a prolonged PFS, although overall survival data are not yet mature. Preliminary results from other adjuvant ICI trials have been conflicting. There remains a lack of clear benefit for the use of adjuvant VEGF inhibitors in local and locoregional RCC. Adjuvant ICI investigations are ongoing, with promising results from KEYNOTE-564. It remains to be seen if PFS is an adequate surrogate end point for overall survival. Selection of patients at greatest risk for recurrence, and identification of those at greatest risk of rare but serious adverse events, may improve outcomes.

Adjuvant ICIs Plus Targeted Therapies Reduce HCC Recurrence after Hepatectomy in Patients with High Risk of Recurrence.

The high recurrence rate of hepatocellular carcinoma (HCC) after hepatectomy usually results in poor prognosis. To the best of our knowledge, no study has reported the efficacy of immune checkpoint inhibitors (ICIs) plus targeted therapies on preventing HCC recurrence after hepatectomy. Thus, the aim of this study was to investigate the benefits and safety of applying adjuvant ICIs plus targeted therapies after hepatectomy for patients at high risk of HCC recurrence. A total of 196 patients with any risk factors for recurrence who underwent hepatectomy for HCC were reviewed in this retrospective study. Compared with the control group (n = 158), ICIs plus targeted therapies (n = 38) had a significantly higher recurrence-free survival (RFS) rate in univariate analysis (HR, 0.46; 95% confidence interval [CI], 0.24-0.90; p = 0.020), multivariate analysis (adjusted HR, 0.62; 95%CI, 0.49-0.79; p < 0.001) and propensity score-matched analysis (HR, 0.35; 95%CI, 0.16-0.75; p = 0.005). Subgroup analyses also showed that postoperative adjuvant ICIs plus targeted therapies might reduce HCC recurrence in patients with the most of risk factors. Postoperative adjuvant ICI plus targeted therapies may reduces early HCC recurrence in patients with a high risk of recurrence, and the treatments are well tolerated.

Role of Immunotherapy in Breast Cancer.

The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of solid tumor malignancies. In breast cancer, the most robust data to date for ICI exist for triple-negative breast cancer (TNBC). Preclinical studies suggested increased antitumoral immune response in patients with TNBC undergoing ICI treatment. Early clinical trials investigated the use of ICI monotherapy in patients with metastatic TNBC with promising results, particularly in the first-line setting and for those patients whose tumors had high programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) expression. Subsequent trials evaluated the use of ICI in combination with conventional chemotherapy to enhance the host immune response. Pembrolizumab combined with chemotherapy in the KEYNOTE-355 study resulted in improved progression-free survival and overall survival benefits for patients with PD-L1 combined positive score > 10 metastatic TNBC. In early-stage disease, two phase III trials demonstrated increased rates of pathologic complete response at the time of surgery with the addition of neoadjuvant ICI to standard chemotherapy. The large KEYNOTE-522 trial showed improved event-free survival with neoadjuvant and adjuvant ICI. Several biomarkers have been identified, which may be predictive of response to ICI therapy including PD-1/PD-L1 expression, tumor mutational burden, tumor-infiltrating lymphocytes, and multigene assays capturing favorable immune cell signatures. For hormone receptor-positive and human epidermal growth factor receptor-positive breast cancer, there are ongoing studies evaluating ICI therapy in combination with chemotherapy and targeted agents. Finally, across all subtypes, several novel immunotherapeutic agents are under investigation including novel ICIs, cancer vaccines, adoptive cellular therapy, and oncolytic viruses.

What is the ideal endpoint in early-stage immunotherapy neoadjuvant trials in lung cancer?

Numerous clinical trials investigating neoadjuvant immune checkpoint inhibitors (ICI) have been performed over the last 5 years. As the number of neoadjuvant trials increases, attention must be paid to identifying informative trial endpoints. Complete pathologic response has been shown to be an appropriate surrogate endpoint for clinical outcomes, such as event-free survival or overall survival, in breast cancer and bladder cancer, but it is less established for non-small-cell lung cancer (NSCLC). The simultaneous advances reported with adjuvant ICI make the optimal strategy for early-stage disease debatable. Considering the long time required to conduct trials, it is important to identify optimal endpoints and discover surrogate endpoints for survival that can help guide ongoing clinical research. Endpoints can be grouped into two categories: medical and surgical. Medical endpoints are measures of survival and drug activity; surgical endpoints describe the feasibility of neoadjuvant approaches at a surgical level as well as perioperative attrition and complications. There are also several exploratory endpoints, including circulating tumor DNA clearance and radiomics. In this review, we outline the advantages and disadvantages of commonly reported endpoints for clinical trials of neoadjuvant regimens in NSCLC.