Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.

BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded. RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS. CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

An evaluation of the impact of missing deaths on overall survival analyses of advanced non-small cell lung cancer patients conducted in an electronic health records database.

PURPOSE: The aim of this study was to assess the impact of missing death data on survival analyses conducted in an oncology EHR-derived database. METHODS: The study was conducted using the Flatiron Health oncology database and the National Death Index (NDI) as a gold standard. Three analytic frameworks were evaluated in advanced non-small cell lung cancer (aNSCLC) patients: median overall survival [mOS]), relative risk estimates conducted within the EHR-derived database, and "external control arm" analyses comparing an experimental group augmented with mortality data from the gold standard to a control group from the EHR-derived database only. The hazard ratios (HRs) obtained within the EHR-derived database (91% sensitivity) and the external control arm analyses, were compared with results when both groups were augmented with mortality data from the gold standard. The above analyses were repeated using simulated lower mortality sensitivities to understand the impact of more extreme levels of missing deaths. RESULTS: Bias in mOS ranged from modest (0.6-0.9 mos.) in the EHR-derived cohort with (91% sensitivity) to substantial when lower sensitivities were generated through simulation (3.3-9.7 mos.). Overall, small differences were observed in the HRs for the EHR-derived cohort across comparative analyses when compared with HRs obtained using the gold standard data source. When only one treatment arm was subject to estimation bias, the bias was slightly more pronounced, but increased substantially when lower sensitivities were simulated. CONCLUSIONS: The impact on survival analysis is minimal with high mortality sensitivity with only modest impact associated within external control arm applications.

Elaboration over a Discourse Facilitates Retrieval in Sentence Processing.

Language comprehension requires access to stored knowledge and the ability to combine knowledge in new, meaningful ways. Previous work has shown that processing linguistically more complex expressions ('Texas cattle rancher' vs. 'rancher') leads to slow-downs in reading during initial processing, possibly reflecting effort in combining information. Conversely, when this information must subsequently be retrieved (as in filler-gap constructions), processing is facilitated for more complex expressions, possibly because more semantic cues are available during retrieval. To follow up on this hypothesis, we tested whether information distributed across a short discourse can similarly provide effective cues for retrieval. Participants read texts introducing two referents (e.g., two senators), one of whom was described in greater detail than the other (e.g., 'The Democrat had voted for one of the senators, and the Republican had voted for the other, a man from Ohio who was running for president'). The final sentence (e.g., 'The senator who the {Republican/Democrat}had voted for…') contained a relative clause picking out either the Many-Cue referent (with 'Republican') or the One-Cue referent (with 'Democrat'). We predicted facilitated retrieval (faster reading times) for the Many-Cue condition at the verb region ('had voted for'), where readers could understand that 'The senator' is the object of the verb. As predicted, this pattern was observed at the retrieval region and continued throughout the rest of the sentence. Participants also completed the Author/Magazine Recognition Tests (ART/MRT; Stanovich and West, 1989), providing a proxy for world knowledge. Since higher ART/MRT scores may index (a) greater experience accessing relevant knowledge and/or (b) richer/more highly structured representations in semantic memory, we predicted it would be positively associated with effects of elaboration on retrieval. We did not observe the predicted interaction between ART/MRT scores and Cue condition at the retrieval region, though ART/MRT interacted with Cue condition in other locations in the sentence. In sum, we found that providing more elaborative information over the course of a text can facilitate retrieval for referents, consistent with a framework in which referential elaboration over a discourse and not just local linguistic information directly impacts information retrieval during sentence processing.

Distinctiveness and encoding effects in online sentence comprehension.

In explicit memory recall and recognition tasks, elaboration and contextual isolation both facilitate memory performance. Here, we investigate these effects in the context of sentence processing: targets for retrieval during online sentence processing of English object relative clause constructions differ in the amount of elaboration associated with the target noun phrase, or the homogeneity of superficial features (text color). Experiment 1 shows that greater elaboration for targets during the encoding phase reduces reading times at retrieval sites, but elaboration of non-targets has considerably weaker effects. Experiment 2 illustrates that processing isolated superficial features of target noun phrases-here, a green word in a sentence with words colored white-does not lead to enhanced memory performance, despite triggering longer encoding times. These results are interpreted in the light of the memory models of Nairne, 1990, 2001, 2006, which state that encoding remnants contribute to the set of retrieval cues that provide the basis for similarity-based interference effects.

The source ambiguity problem: Distinguishing the effects of grammar and processing on acceptability judgments.

Judgments of linguistic unacceptability may theoretically arise from either grammatical deviance or significant processing difficulty. Acceptability data are thus naturally ambiguous in theories that explicitly distinguish formal and functional constraints. Here, we consider this source ambiguity problem in the context of Superiority effects: the dispreference for ordering a wh-phrase in front of a syntactically "superior" wh-phrase in multiple wh-questions, e.g. What did who buy? More specifically, we consider the acceptability contrast between such examples and so-called D-linked examples, e.g. Which toys did which parents buy? Evidence from acceptability and self-paced reading experiments demonstrates that (i) judgments and processing times for Superiority violations vary in parallel, as determined by the kind of wh-phrases they contain, (ii) judgments increase with exposure while processing times decrease, (iii) reading times are highly predictive of acceptability judgments for the same items, and (iv) the effects of the complexity of the wh-phrases combine in both acceptability judgments and reading times. This evidence supports the conclusion that D-linking effects are likely reducible to independently motivated cognitive mechanisms whose effects emerge in a wide range of sentence contexts. This in turn suggests that Superiority effects, in general, may owe their character to differential processing difficulty.

Representational Complexity and Memory Retrieval in Language Comprehension.

Mental representations formed from words or phrases may vary considerably in their feature-based complexity. Modern theories of retrieval in sentence comprehension do not indicate how this variation and the role of encoding processes should influence memory performance. Here, memory retrieval in language comprehension is shown to be influenced by a target's representational complexity in terms of syntactic and semantic features. Three self-paced reading experiments provide evidence that reading times at retrieval sites (but not earlier) decrease when more complex phrases occur as filler-phrases in filler-gap dependencies. The data also show that complexity-based effects are not dependent on string length, syntactic differences, or the amount of processing the stimuli elicit. Activation boosting and reduced similarity-based interference are implicated as likely sources of these complexity-based effects.

Cognitive Constraints and Island Effects.

Competence-based theories of island effects play a central role in generative grammar, yet the graded nature of many syntactic islands has never been properly accounted for. Categorical syntactic accounts of island effects have persisted in spite of a wealth of data suggesting that island effects are not categorical in nature and that non-structural manipulations that leave island structures intact can radically alter judgments of island violations. We argue here, building on work by Deane, Kluender, and others, that processing factors have the potential to account for this otherwise unexplained variation in acceptability judgments.We report the results of self-paced reading experiments and controlled acceptability studies which explore the relationship between processing costs and judgments of acceptability. In each of the three self-paced reading studies, the data indicate that the processing cost of different types of island violations can be significantly reduced to a degree comparable to that of non-island filler-gap constructions by manipulating a single non-structural factor. Moreover, this reduction in processing cost is accompanied by significant improvements in acceptability. This evidence favors the hypothesis that island-violating constructions involve numerous processing pressures that aggregate to drive processing difficulty above a threshold so that a perception of unacceptability ensues. We examine the implications of these findings for the grammar of filler-gap dependencies.