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Highlights d Pre-treatment ctDNA features are associated with checkpoint blockade response d Pre-treatment peripheral T cell levels are associated with checkpoint blockade response d Early on-treatment ctDNA dynamics are associated with checkpoint blockade response d Multiparameter noninvasive models can predict checkpoint blockade response in NSCLC

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Purpose: Treatment with PD-(L)1 blockade can produce remarkably durable responses in nonsmall cell lung cancer (NSCLC) patients. However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. Experimental Design: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (PFS≥12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). Tumor tissue was available for 24 patients and was profiled by wholeexome sequencing (n=18) or by targeted sequencing (n=6).Results: 31 NSCLC patients with long-term benefit to PD-(L)1 blockade were identified and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; by contrast, all four patients with detectable ctDNA eventually progressed (Fisher's p<0.0001; PPV 1 [95% CI 0.51-1]; NPV 0.93 [95% CI 0.80-0.99]).Conclusions: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.

Abstract1. Understanding how animals perceive, learn and remember stimuli is critical for understanding both how cognition is shaped by natural selection, and how ecological factors impact behaviour. However, the majority of studies on cognition involve captive animals in laboratory settings. While controlled settings are required to accurately measure aspects of cognition, they may not yield realistic estimates of learning performance in natural environments. Wild bees offer a useful system in which to study cognitive ecology and comparative cognition more broadly: they encompass around 20,000 species globally, varying in characteristics such as lifehistory strategy, degree of sociality and dietary specialization. Yet, the limited number of protocols currently available for studying insect cognition has restricted research to a few commercially available bee species, in almost exclusively laboratory settings. We present a protocol (Free-Moving Proboscis Extension Response [FMPER]) tomeasure wild bees' colour preferences, learning performance and memory.3. We first used laboratory-reared bumblebees Bombus impatiens to establish that FMPER yielded results consistent with learning theory. We then successfully tested wild honeybees Apis mellifera in the laboratory and Bombus vosnesenskii at field sites. Free-Moving Proboscis ExtensionResponse is straightforward to implement, is low cost, and may be readily adapted to other flower-visiting insects. We believe it will be useful to a broad range of evolutionary biologists, behavioural ecologists and pollination ecologists interested in measuring cognitive performance in the wild and across a broader range of species.