Association of CD274 (PD-L1) Copy Number Changes with Immune Checkpoint Inhibitor Clinical Benefit in Non-Squamous Non-Small Cell Lung Cancer.

BACKGROUND: We sought to characterize response to immune checkpoint inhibitor (ICI) in non-squamous non-small cell lung cancer (NSCLC) across various CD274 copy number gain and loss thresholds and identify an optimal cutoff. MATERIALS AND METHODS: A de-identified nationwide (US) real-world clinico-genomic database was leveraged to study 621 non-squamous NSCLC patients treated with ICI. All patients received second-line ICI monotherapy and underwent comprehensive genomic profiling as part of routine clinical care. Overall survival (OS) from start of ICI, for CD274 copy number gain and loss cohorts across varying copy number thresholds, were assessed. RESULTS: Among the 621 patients, patients with a CD274 CN greater than or equal to specimen ploidy +2 (N = 29) had a significantly higher median (m) OS when compared with the rest of the cohort (N = 592; 16.1 [8.9-37.3] vs 8.6 [7.1-10.9] months, hazard ratio (HR) = 0.6 [0.4-1.0], P-value = .05). Patients with a CD274 copy number less than specimen ploidy (N = 299) trended toward a lower mOS when compared to the rest of the cohort (N = 322; 7.5 [5.9-11.3] vs 9.6 [7.9-12.8] months, HR = 0.9 [0.7-1.1], P-value = .3). CONCLUSION: This work shows that CD274 copy number gains at varying thresholds predict different response to ICI blockade in non-squamous NSCLC. Considering these data, prospective clinical trials should further validate these findings, specifically in the context of PD-L1 IHC test results.

Association and interplay of surgeon and hospital volume with mortality after open abdominal aortic aneurysm repair in the modern era.

OBJECTIVE: Operative volume has been used as a marker of quality. Research from previous decades has suggested minimum open abdominal aortic aneurysm (AAA) repair volume requirements for surgeons of 9 to 13 open AAA repairs annually and for hospitals of 18 open AAA repairs annually to purportedly achieve acceptable results. Given concerns regarding the decreased frequency of open repairs in the endovascular era, we examined the association of surgeon and hospital volume with the 30- and 90-day mortality in the Vascular Quality Initiative (VQI) registry. METHODS: Patients who had undergone elective open AAA repair from 2013 to 2018 were identified in the VQI registry. We performed a cross-sectional evaluation of the association between the average hospital and surgeon volume and 30-day postoperative mortality using a hierarchical Bayesian model. Cross-level interactions were permitted, and random surgeon- and hospital-level intercepts were used to account for clustering. The mortality results were adjusted by standardizing to the observed distribution of relevant covariates in the overall cohort. The outcomes were compared to the Society for Vascular Surgery guidelines recommended criteria of <5% perioperative mortality. RESULTS: A total of 3078 patients had undergone elective open AAA repair by 520 surgeons at 128 hospitals. The 30- and 90-day risks of postoperative mortality were 4.1% (n = 126) and 5.4% (n = 166), respectively. The mean surgeon volume and hospital volume both correlated inversely with the 30-day mortality. Averaged across all patients and hospitals, we found a 96% probability that surgeons who performed an average of four or more repairs per year achieved <5% 30-day mortality. Substantial interplay was present between surgeon volume and hospital volume. For example, at lower volume hospitals performing an average of five repairs annually, <5% 30-day mortality would be expected 69% of the time for surgeons performing an average of three operations annually. In contrast, at higher volume hospitals performing an average of 40 repairs annually, a <5% 30-day mortality would be expected 96% of the time for surgeons performing an average of three operations annually. As hospital volume increased, a diminishing difference occurred in 30-day mortality between lower and higher volume surgeons. Likewise, as surgeon volume increased, a diminishing difference was found in 30-day mortality between the lower and higher volume hospitals. CONCLUSIONS: Surgeons and hospitals in the VQI registry achieved mortality outcomes of <5% (Society for Vascular Surgery guidelines), with an average surgeon volume that was substantially lower compared with previous reports. Furthermore, when considering the development of minimal surgeon volume guidelines, it is important to contextualize the outcomes within the hospital volumes.

Functional Dependence and Mortality in the International Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Patients receiving long-term dialysis have among the highest mortality and hospitalization rates. In the nonrenal literature, functional dependence is recognized as a contributor to subsequent disability, recurrent hospitalization, and increased mortality. A higher burden of functional dependence with progressive worsening of kidney function has been observed in several studies, suggesting that functional dependence may contribute to both morbidity and mortality in dialysis patients. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 7,226 hemodialysis patients from 12 countries in the DOPPS (Dialysis Outcomes and Practice Patterns Study) phase 4 (2009-2011) with self-reported data for functional status. PREDICTOR: Patients' ability to perform 13 basic and instrumental activities of daily living was summarized to create an overall functional status score (range, 1.25 [most dependent] to 13 [functionally independent]). OUTCOME: Cox regression was used to estimate the association between functional status and all-cause mortality, adjusting for several demographic and clinical risk factors for mortality. Median follow-up was 17.2 months. RESULTS: The proportion of patients who could perform each activity of daily living task without assistance ranged from 97% (eating) to 47% (doing housework). 36% of patients could perform all 13 tasks without assistance (functional status = 13), and 14% of patients had high functional dependence (functional status < 8). Functionally independent patients were younger and had many indicators of better health status, including higher quality of life. Compared with functionally independent patients, the adjusted HR for mortality was 2.37 (95% CI, 1.92-2.94) for patients with functional status < 8. LIMITATIONS: Possible nonresponse bias and residual confounding. CONCLUSIONS: We found a high burden of functional dependence across all age groups and across all DOPPS countries. When adjusting for several known mortality risk factors, including age, access type, cachexia, and multimorbidity, functional dependence was a strong consistent predictor of mortality.

Multi-state survival models with treatment effects and biomarkers: Simulations for study design assessment.

BACKGROUND: Comparative effectiveness studies of cancer therapeutics in observational data face confounding by patterns of clinical treatment over time. The validity of survival analysis in longitudinal health records depends on study design choices including index date definition and model specification for covariate adjustment. METHODS: Overall survival in cancer is a multi-state transition process with mortality and treatment switching as competing risks. Parametric Weibull regression quantifies proportionality of hazards across lines of therapy in real-world cohorts of 12 solid tumor types. Study design assessments compare alternative analytic models in simulations with realistic disproportionality. The multi-state simulation framework is adaptable to alternative treatment effect profiles and exposure patterns. RESULTS: Event-specific hazards of treatment-switching and death are not proportional across lines of therapy in 12 solid tumor types. Study designs that include all eligible lines of therapy per subject showed lower bias and variance than designs that select one line per subject. Confounding by line number was effectively mitigated across a range of simulation scenarios by Cox proportional hazards models with stratified baseline hazards and inverse probability of treatment weighting. CONCLUSION: Quantitative study design assessment can inform the planning of observational research in clinical oncology by demonstrating the potential impact of model misspecification. Use of empirical parameter estimates in simulation designs adapts analytic recommendations to the clinical population of interest.

Deletions on 9p21 are associated with worse outcomes after anti-PD-1/PD-L1 monotherapy but not chemoimmunotherapy.

NCCN guidelines for first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC) patients without targetable driver alterations includes either immunotherapy alone or in combination with chemotherapy. In this study, we investigated genomic predictors of survival after immunotherapy to guide this treatment decision. Cox proportional hazards regression was used to identify genomic correlates of survival in a cohort of EGFR/ALK-, non-squamous NSCLC patients treated with first-line pembrolizumab monotherapy (mono-IO) or pembrolizumab in combination with carboplatin/cisplatin and pemetrexed (chemo-IO) within a real-world clinico-genomic database. The effect of deletions on 9p21 was further evaluated in five additional tumor types. Among mono-IO treated non-squamous NSCLC patients, tumors with 9p21.3 gene deletions (CDKN2A, CDKN2B, MTAP) were associated with worse survival compared to the corresponding deletion-negative tumors (CDKN2A deletion HR = 1.8, P = 0.001). However, this association was not observed among chemo-IO treated patients (CDKN2A deletion HR = 1.1, P = 0.4). This finding remained after adjusting for clinical and genomic features including TMB and PD-L1. Deletions at 9p21.3 were not associated with differences in TMB, PD-L1, or tumor inflammation. Due to the high incidence of 9p21.3 deletions across tumor types, we performed a pan-cancer analysis and found CDKN2A deletion-positive tumors had worse survival following first-line immunotherapy treatment in multiple tumor types (HR = 1.4, P < 0.001). These results indicate deletions at 9p21.3 are a putative negative predictor of clinical benefit from first-line immune checkpoint inhibitors and may have utility in choosing between mono-IO vs chemo-IO regimens in NSCLC.

Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response.

Neoantigen presentation arises as a result of tumor-specific mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I (HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non-small cell lung cancer, HLA-I LOH was a significant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefit from ICIs. SIGNIFICANCE: This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected "Goldilocks" relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a significant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development.This article is highlighted in the In This Issue feature, p. 211.