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Pretreatment prognostication, on-treatment monitoring, and early detection of physiological symptoms are considerable challenges in cancer. We describe the feasibility of high-resolution wearable data (steps per day, walking speed) to longitudinally profile physiological trajectories extracted from Apple Health data in three patients with lung cancer from diagnosis through cancer treatment after obtaining informed consent. We used descriptive statistics to describe our approach of building longitudinal physiological profiles. The wearable data monitoring period ranged from 58 to 135 weeks, with between 34,319 and 103,535 distinct digital physiological measures collected during this period—the equivalent to 41 measures per day/patient. Longitudinal profiling revealed that wearable data accurately captured physiological changes linked with clinical events such as surgery and hospitalizations as well as initiation (and cessation) of systemic cancer treatment in all three patients. These findings suggest that wearable devices could play a critical role in the management of lung cancer, although larger studies are needed to confirm these preliminary observations and validate their generalizability. Wearable devices hold significant promise for the development of personalized “digital biomarkers,” which may enhance risk stratification and management in oncology.

Introduction: ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring. Methods: The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma. Results: A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants. Conclusions: ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.

Abstract Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression.

Introduction: Patients with EGFR-mutant NSCLC have a high incidence of brain metastases. The EGFR-directed tyrosine kinase inhibitor osimertinib has intracranial activity, making the role of local central nervous system (CNS)-directed therapies, such as radiation and surgery, less clear. Methods: Patients with EGFR-mutant NSCLC and brain metastases who received osimertinib as initial therapy after brain metastasis diagnosis were included. Individual lesion responses were assessed using adapted RANO-BM criteria. CNS progression and local progression of brain metastasis from osimertinib start were analyzed using cumulative incidence treating death as a competing risk. Overall survival was estimated using Kaplan-Meier methodology. Results: There were 36 patients who had a median interval from brain metastasis diagnosis to first-line osimertinib initiation of 25 days. In total, 136 previously untreated brain metastases were tracked from baseline. Overall, 105 lesions (77.2%) had complete response and 31 had partial response reflecting best objective response of 100%. Best response occurred at a median of 96 days (range: 28–1113 d) from baseline magnetic resonance imaging. This reflects a best objective response rate of 100%. Two-year overall survival was 80%. CNS progression rates at 1-, 2-, and 3-years post-osimertinib were 21%, 32%, and 41%, respectively. Lesion-level local failure was estimated to be 0.7% and 4.7% at 1- and 2-years post-osimertinib, respectively. No clinicodemographic factors including brain metastasis number were associated with post-osimertinib progression. Conclusions: Intracranial response to osimertinib is excellent for patients with EGFR-mutant NSCLC with de novo, previously untreated brain metastases. Very low local failure rates support a strategy of upfront osimertinib alone in selected patients.

BackgroundSensitive and reliable biomarkers for early detection of recurrence are needed to improve post-definitive radiation risk stratification, disease management, and outcomes for patients with unresectable early-stage or locally advanced non-small cell lung cancer (NSCLC) who are treated with definitive radiation therapy (RT). This prospective, multistate single-center, cohort study investigated the association of circulating tumor DNA (ctDNA) status with recurrence in patients with unresectable stage I-III NSCLC who underwent definitive RT.MethodsA total of 70 serial plasma samples from 17 NSCLC patients were collected before, during, and after treatment. A personalized, tumor-informed ctDNA assay was used to track a set of up to 16 somatic, single nucleotide variants in the associated patient’s plasma samples.ResultsPre-treatment ctDNA detection rate was 82% (14/17) and varied based on histology and stage. ctDNA was detected in 35% (6/17) of patients at the first post-RT timepoint (median of 1.66 months following the completion of RT), all of whom subsequently developed clinical progression. At this first post-RT time point, patients with ctDNA-positivity had significantly worse progression-free survival (PFS) [hazard ratio (HR): 24.2, p=0.004], and ctDNA-positivity was the only significant prognostic factor associated with PFS (HR: 13.4, p=0.02) in a multivariate analysis. All patients who developed clinical recurrence had detectable ctDNA with an average lead time over radiographic progression of 5.4 months, and post-RT ctDNA positivity was significantly associated with poor PFS (p

Liquid biopsies allow the non-invasive detection of somatic mutations from tumours. Here, the authors develop and test MSK-ACCESS, an NGS-based clinical assay for identifying low frequency mutations in 129 genes and describe how it benefits patients in the clinic.

Abstract Background Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e., cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth. Methods Plasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z-score statistics. Plasma samples with no somatic alterations detected by cf-IMPACT were triaged based on sWGS-estimated tumor fraction for analysis with either a less comprehensive but more sensitive assay (MSK-ACCESS) or broader whole exome sequencing (WES). Results cfDNA profiling using cf-IMPACT identified somatic mutations in 55/76 (72%) patients for whom MSK-IMPACT tumor profiling data were available. A significantly higher concordance of mutational profiles and tumor mutational burden (TMB) was observed between plasma and tumor profiling for plasma samples with a high tumor fraction (z-score≥5). In the 42 patients from whom tumor data was not available, cf-IMPACT identified mutations in 16/42 (38%). In total, cf-IMPACT analysis of plasma revealed mutations in 71/118 (60%) patients, with clinically actionable alterations identified in 30 (25%), including therapeutic targets of FDA-approved drugs. Of the 47 samples without alterations detected and low tumor fraction (z-score

Platinum-based chemotherapy combined with anti-PD-1 or PD-L1 monoclonal antibodies (mAbs) is now standard first-line therapy for mNSCLC patients without sensitizing driver mutations. Anti-PD-1 and anti-PD-L1 mAbs are considered to be equivalent in efficacy. In the absence of head-to-head randomized control trials (RCTs), we utilized network meta-analysis (NWM) to provide an indirect comparison of their efficacy. A systematic literature review and NWM were performed using RCTs that investigated anti-PD-1 or PD-L1 mAbs ± chemotherapy in patients with mNSCLC in the first-line setting. The primary outcome was comparative overall survival (OS), while secondary outcomes were comparative progression-free survival (PFS), objective response rate (ORR), and rate of grade 3 and higher toxicities. We identified 24 RCTs. Patients treated with anti-PD-1 mAb + chemotherapy compared with anti-PD-L1 mAb + chemotherapy showed superior mOS, mPFS, and ORR with a similar rate of grade 3 and higher toxicities. This difference in mOS was most pronounced in the PD-L1 TPS 1–49% population. The two mAbs were equivalent as single agents. Anti-PD-1 mAb + chemotherapy improved mOS when compared to anti-PD-1 mAb monotherapy, whereas anti-PD-L1 mAbs + chemotherapy did not when compared to anti-PD-L1 mAb monotherapy. Head-to-head RCTs are warranted in the future.

Purpose: Brain metastases are common in patients with limited-stage small cell lung cancer (LS-SCLC) due to the inability of most chemotherapeutics to penetrate the blood–brain barrier. Prophylactic cranial irradiation (PCI) is therefore recommended for use in patients with a good response to concurrent chemoradiotherapy. However, PCI is not always delivered; therefore, we investigated the reasons for PCI omission in patients who underwent therapy with curative intent. Methods and materials: We retrospectively reviewed all patients with LS-SCLC who were treated with curative intent at our institution. Overall survival and cumulative incidence of brain metastasis were estimated by the Kaplan-Meier method. The Pearson χ2 test and Mann-Whitney U test were used to examine factors associated with PCI use, and prognostic factors were analyzed with Cox proportional hazards modeling. Results: We examined 208 patients who were treated for LS-SCLC at our institution. A total of 115 patients (55%) received PCI. The most common documented reason for PCI omission was patient refusal due to neurotoxicity concerns (38%). Physician assessment of being medically unfit (33%) and of advanced age (8%) were the second and third most common reasons, respectively. Karnofsky performance status and clinical American Joint Committee on Cancer stage but not PCI were significantly associated with overall survival. Only clinical stage remained an independent factor on multivariate analysis. Conclusions: Approximately half of patients with LS-SCLC ultimately receive PCI, generally for guideline-recommended reasons. The most common reason for PCI omission was patient concerns regarding neurotoxicity. Efforts to decrease PCI neurotoxicity, including hippocampal-sparing radiation and memantine use, may increase the use of this survival-improving intervention in eligible patients with LS-SCLC.

In the era of somatostatin analogues and targeted therapies, the role of chemotherapy in NET remains largely undefined. This systematic review aimed to assess the effect of chemotherapy on response rates (RR), progression-free survival (PFS), overall survival (OS) and toxicity compared to other chemotherapies/systemic therapies or best supportive care in patients with advanced or metastatic NET.Randomised controlled trials (RCTs) from 1946 to 2015 were identified from MEDLINE, EMBASE, other databases and conference proceedings. Review of abstracts, quality assessment and data abstraction were performed independently by two investigators. Meta-analyses were conducted using Mantel-Haenszel analysis with random-effects modelling.Six RCTs comparing standard streptozotocin plus 5-fluorouacil (STZ/5FU) chemotherapy to other chemotherapy regimens, and 2 comparing this to interferon (IFN) were included. Only 1 study was considered at low risk of bias. STZ/5-FU was no different to other chemotherapies in response rate [RR 0.96; 95% confidence interval (CI) 0.72-1.27], PFS (RR 0.95; CI 0.81-1.13), or OS (RR 1.03; CI 0.77-1.39). IFN may produce higher response than STZ/5FU (RR 0.20; CI 0.04-1.13), but event rates were small and survival was no different. Interferon was associated with higher overall haematological (RR 0.47; CI 0.27-0.82) and lower overall renal toxicity (RR 3.61; CI 1.24-10.51).Strong evidence is lacking in the area of chemotherapy in neuroendocrine tumors. There is currently no evidence that one chemotherapeutic regimen is significantly better than the other, nor is interferon better than chemotherapy. There is an urgent need to design RCTs comparing modern chemotherapy to other agents in NET.

Lung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown.Serum NSE, CYFRA 21-1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC. Pre-treatment serum biomarker levels as well as age, histology, and epidermal growth factor receptor (EGFR) mutation status were evaluated for association with the baseline presence of brain metastases using logistic regression and multivariable analysis. For patients without brain metastases at baseline, the cumulative incidence of subsequent brain metastases were compared according to baseline biomarkers and clinical factors using Gray's test.A total of 118 patients were enrolled, 31 (26%; 95% CI 0.19-0.35) had brain metastases at baseline and a further 26 (22%; 95% CI 0.15-0.30) developed brain metastases subsequently. Pre-treatment serum biomarker levels were available in 104 patients. There was no significant association between the six serum biomarkers and the baseline presence or subsequent development of brain metastases. Age younger than 65 years was the only clinical factor significantly associated with brain metastasis at baseline (OR 3.00; 95% CI 1.22-7.34, P = 0.02) by multivariable analysis. A trend toward increased cumulative incidence of subsequent brain metastases was observed in patients with EGFR mutation (p = 0.2), but this was not statistically significant possibly due to small sample size.Serum NSE, CYFRA 21-1, Pro-GRP, SCC-Ag, TIMP1, and HE4 are not significantly associated with brain metastases. Our methods taking into account follow-up time may be applied to independent datasets to identify a patient cohort with a higher biologic propensity for developing brain metastases. Such information may be useful for the study of agents targeting the development of brain metastases.