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Despite approximately 40% of patients having Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of at least 2 in the real world, most landmark clinical trials that led to the use of pembrolizumab as standard of care in advanced non-small cell lung cancer (NSCLC) excluded this group. To evaluate whether an ECOG PS score of at least 2 at the start of therapy is associated with progression-free survival (PFS) and overall survival (OS) in advanced NSCLC treated with pembrolizumab monotherapy. This cohort study included all consecutive patients with advanced NSCLC who underwent treatment with palliative pembrolizumab monotherapy from February 2016 to October 2019 at a single academic cancer center, with data censoring on January 15, 2020. ECOG PS score at start of therapy, with 0 and 1 indicating fully active or restricted in strenuous activity and scores of 2 and higher indicating increasing disability. PFS and OS, measured from initiation of pembrolizumab monotherapy. Of 74 patients (median [range] age, 68.5 [33-87] years; 36 [48.7%] women; 53 [71.6%] White individuals) with median follow-up of 19.5 (95% CI, 13.4-27.8) months, 45 (60.8%) had an ECOG PS of 0 or 1, while 29 (39.2%) had an ECOG PS of at least 2. There were no significant differences in the baseline characteristics, except in age. Compared with patients with PS scores of 0 or 1, those with PS scores of at least 2 had significantly lower disease control rates (38 [88.4%] vs 15 [53.6%]; P = .002), shorter median PFS (7.9 [95% CI, 4.6-15.4] months vs 2.3 [95% CI, 1.8-4.8] months; P = .004), and shorter median OS (23.2 [14.0 vs 35.7] months vs 4.1 [95% CI, 2.1-6.9] months; P < .001). Among those potentially eligible for subsequent cancer-directed therapy beyond pembrolizumab monotherapy, patients in the group with PS scores of at least 2 were less likely to receive it than those with PS scores of 0 or 1 (2 [8.3%] vs 14 [45.2%]; P = .003). Multivariable adjustment for baseline characteristics confirmed ECOG PS of at least 2 as an independent risk factor for worse PFS (HR, 2.02; 95% CI, 1.09-3.74; P = .03) and worse OS (HR, 2.87; 95% CI, 1.40-5.89; P = .004). In this cohort study, having an ECOG PS score of at least 2 was associated with poorer prognosis for treatment of advanced NSCLC with palliative pembrolizumab monotherapy. Further prospective studies are needed to evaluate more objective and consistent measures of functional status to facilitate identification of patients with borderline performance status who may achieve durable clinical benefit from treatment with pembrolizumab monotherapy.

AimsFam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved for advanced stage or metastatic solid tumours with human epidermal growth factor receptor 2 (HER2) immunohistochemical (IHC) 3+ staining. Data on HER2 IHC testing and knowledge of genomic correlates in lung cancer are scarce. This study analyses genomic characteristics of HER2-expressing tumours and addresses issues with preanalytical variables for lung cancer specimens.MethodsHER2 IHC staining was performed on selected archival cytology and surgical pathology lung cancer specimens for patients eligible for T-DXd therapy. Patient and tumour characteristics and next-generation sequencing (NGS) data were correlated with HER2 IHC results.Results166 patients with thoracic tumour samples had HER2 expression assessed: 46% were IHC 0, 28% IHC 1+, 13% IHC 2+ and 13% IHC 3+. HER2 IHC scores were overall lower for cytology cell blocks as compared with surgical pathology specimens; 79% of cases with paired specimens had a decrease in their HER2 IHC score from their surgical specimen to their paired cytology specimen. Of specimens with HER2 IHC 3+ and NGS available, only 14% (3/21) had concomitant ERBB2 alterations. Among all specimens, ERBB2 point mutations were noted in 4% (4/110) and ERBB2 amplification in 3% (3/110). The majority of HER2 3+ cases with paired NGS (17/21, 81%) had non-ERBB2 genomic alterations, including: KRAS, TP53, and STK11 mutations.ConclusionsHER2 IHC 3+ is seen in a small but clinically significant proportion of samples and is associated with a variety of co-occurring non-ERBB2 genomic alterations. Preanalytical variables including specimen fixation can significantly impact the assessment of HER2 expression via immunohistochemistry.

Osimertinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that is used for first-line therapy in EGFR mutated non-small cell lung cancer (NSCLC) based on the results of the randomized FLAURA trial (ClinicalTrials.gov number NCT02296125). We performed a retrospective analysis of baseline characteristics and clinical outcomes in 56 real-world patients treated with osimertinib. In total, 45% of patients were determined to be FLAURA-eligible and 55% were FLAURA-ineligible based on the published inclusion/exclusion criteria of the aforementioned trial. For clinical outcomes, the median osimertinib time to treatment discontinuation (TTD) for all patients was 16.9 months (95% CI: 12.6–35.1), whereas the median TTD was 31.1 months (95% CI: 14.9–not reached) in the FLAURA-eligible cohort and the median TTD was 12.2 months (95% CI: 8.1–34.6 months) in the FLAURA-ineligible cohort. Re-biopsy at acquired resistance disclosed both on- and off-target mechanisms. The most common therapies following osimertinib included local therapies followed by post-progression osimertinib, platinum-doublet chemotherapy with or without osimertinib, and osimertinib combinatory targeted therapies. The median overall survival for all patients was 32.0 months (95% CI: 15.7–not reached), the median survival was not reached for the FLAURA-eligible cohort, and it was 16.5 months for the FLAURA-ineligible cohort. Our data support the use of osimertinib in real-word settings and highlight the need for designing registration trials that are more inclusive of patient/disease characteristics seen in routine clinical practice. It is yet to be determined if the use of evolving first-line EGFR inhibitor combination strategies (either platinum-doublet chemotherapy plus osimertinib or amivantamab plus lazertinib) will similarly translate from clinical trials to real-word settings.

Based on preclinical studies showing synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways and based on window of opportunity studies showing that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC), we conduct a non-randomized phase 2 study of letrozole/abemaciclib/metformin in ER positive endometrioid EC (NCT03675893). Primary objectives include objective response rate (ORR) and rate of progression-free survival (PFS) at 6 months (PFS6) while secondary objectives include PFS, overall survival, duration of response and toxicity. Twenty-five patients initiate protocol therapy [letrozole 2.5 mg orally (PO) once a day (qd), abemaciclib 150 mg PO twice a day (bid) and metformin 500 mg PO qd]. ORR is 32% (3 complete and 5 partial responses, 95% CI 14.9%-53.5%), Kaplan Meier estimate of PFS6 is 69.8% (95% CI 46.9%-84.3%) and median PFS is 19.4 months (95% CI 5.7 months–not estimable). No patients discontinue therapy because of toxicity. There are no objective responses among TP53 mutated ECs and among NSMP (no specific molecular profile) tumors with RB1 or CCNE1 alterations; CTNNB1 mutations correlate with clinical benefit. Pharmacokinetic analyses demonstrate that administration of letrozole and abemaciclib with metformin result in a more than 3-fold increase in metformin exposure. Combined hormonal therapy and CDK4/6 inhibition face resistance challenges in endometrial cancer. Here, the authors present a phase 2, one-arm clinical trial, where metformin is combined with letrozole (hormonal therapy) and abemaciclib (a CDK4/6 inhibitor) reporting safety and efficacy in patients with endometrial cancer.

We know little about the neurologic bases of art production. The idea that the right brain hemisphere is the \"artistic brain\" is widely held, despite the lack of evidence for this claim. Artists with brain damage can offer insight into these laterality questions. The authors used an instrument called the Assessment of Art Attributes to examine the work of two individuals with left-brain damage and one with right-hemisphere damage. In each case, their art became more abstract and distorted and less realistic. They also painted with looser strokes, less depth and more vibrant colors. No unique pattern was observed following right-brain damage. However, art produced after left-brain damage also became more symbolic. These results show that the neural basis of art production is distributed across both hemispheres in the human brain.

Cancer drug approvals are based on clinical trials with strict inclusion and exclusion criteria, and more often than not, the patient population encountered in real-world settings is different (with additional comorbidities or different patient-disease characteristics) than the one that led to regulatory approval. Oral inhibitors of the EGFR oncogene are approved for use in EGFR mutated lung cancers. We sought to evaluate if the EGFR inhibitor osimertinib would perform in real-word populations in a manner expected by the registration trial of this anti-cancer agent. We were able to identify cases in our real-world cohort that had durations of both cancer control and overall survival that were in line with the data from the registration clinical trial named FLAURA. The real-world data presented here support the translation of results from clinical trials to routine clinical care for targeted therapy in EGFR mutated lung cancer but also highlight the need for clinical trials that are more inclusive. Osimertinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that is used for first-line therapy in EGFR mutated non-small cell lung cancer (NSCLC) based on the results of the randomized FLAURA trial (ClinicalTrials.gov number NCT02296125). We performed a retrospective analysis of baseline characteristics and clinical outcomes in 56 real-world patients treated with osimertinib. In total, 45% of patients were determined to be FLAURA-eligible and 55% were FLAURA-ineligible based on the published inclusion/exclusion criteria of the aforementioned trial. For clinical outcomes, the median osimertinib time to treatment discontinuation (TTD) for all patients was 16.9 months (95% CI: 12.6–35.1), whereas the median TTD was 31.1 months (95% CI: 14.9–not reached) in the FLAURA-eligible cohort and the median TTD was 12.2 months (95% CI: 8.1–34.6 months) in the FLAURA-ineligible cohort. Re-biopsy at acquired resistance disclosed both on- and off-target mechanisms. The most common therapies following osimertinib included local therapies followed by post-progression osimertinib, platinum-doublet chemotherapy with or without osimertinib, and osimertinib combinatory targeted therapies. The median overall survival for all patients was 32.0 months (95% CI: 15.7–not reached), the median survival was not reached for the FLAURA-eligible cohort, and it was 16.5 months for the FLAURA-ineligible cohort. Our data support the use of osimertinib in real-word settings and highlight the need for designing registration trials that are more inclusive of patient/disease characteristics seen in routine clinical practice. It is yet to be determined if the use of evolving first-line EGFR inhibitor combination strategies (either platinum-doublet chemotherapy plus osimertinib or amivantamab plus lazertinib) will similarly translate from clinical trials to real-word settings.

Little about the neuropsychology of art perception and evaluation is known. Most neuropsychological approaches to art have focused on art production and have been anecdotal and qualitative. The field is in desperate need of quantitative methods if it is to advance. Here, we combine a quantitative approach to the assessment of art with modern voxel-lesion-symptom-mapping methods to determine brain-behavior relationships in art perception. We hypothesized that perception of different attributes of art are likely to be disrupted by damage to different regions of the brain. Twenty participants with right hemisphere damage were given the Assessment of Art Attributes, which is designed to quantify judgments of descriptive attributes of visual art. Each participant rated 24 paintings on 6 conceptual attributes (depictive accuracy, abstractness, emotion, symbolism, realism, and animacy) and 6 perceptual attributes (depth, color temperature, color saturation, balance, stroke, and simplicity) and their interest in and preference for these paintings. Deviation scores were obtained for each brain-damaged participant for each attribute based on correlations with group average ratings from 30 age-matched healthy participants. Right hemisphere damage affected participants' judgments of abstractness, accuracy, and stroke quality. Damage to areas within different parts of the frontal parietal and lateral temporal cortices produced deviation in judgments in four of six conceptual attributes (abstractness, symbolism, realism, and animacy). Of the formal attributes, only depth was affected by inferior prefrontal damage. No areas of brain damage were associated with deviations in interestingness or preference judgments. The perception of conceptual and formal attributes in artwork may in part dissociate from each other and from evaluative judgments. More generally, this approach demonstrates the feasibility of quantitative approaches to the neuropsychology of art.