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Genomic tumour profiling informs targeted treatment options. Entrectinib is a tyrosine kinase inhibitor with efficacy in NTRK fusion-positive (-fp) solid tumours and ROS1-fp non-small cell lung cancer. FoundationOne® Liquid CDx (F1L CDx), a non-invasive in vitro next-generation sequencing (NGS)-based diagnostic, detects genomic alterations in plasma circulating tumour DNA (ctDNA). We evaluated the clinical validity of F1L CDx as an aid in identifying patients with NTRK-fp or ROS1-fp tumours and assessed the genomic landscape pre- and post-entrectinib treatment. Among evaluable pre-treatment clinical samples (N = 85), positive percentage agreements between F1L CDx and clinical trial assays (CTAs) were 47.4% (NTRK fusions) and 64.5% (ROS1 fusions); positive predictive value was 100% for both. The objective response rate for CTA+ F1L CDx+ patients was 72.2% in both cohorts. The median duration of response significantly differed between F1L CDx+ and F1L CDx- samples in ROS1-fp (5.6 vs. 17.3 months) but not NTRK-fp (9.2 vs. 12.9 months) patients. Fifteen acquired resistance mutations were detected. We conclude that F1L CDx is a clinically valid complement to tissue-based testing to identify patients who may benefit from entrectinib and those with acquired resistance mutations associated with disease progression. [ABSTRACT FROM AUTHOR]

• Chemotherapy combinations with ICIs are the standard of care in several tumor types. • Immune related adverse events can mimic cytotoxic agents' toxicity however the management is very different. • Overlapping adverse events can present a challenge to clinicians in daily practice. • Differential work up is essential to determine the culprit drug and thus propose an adequate management strategy adapted for each type of adverse event. Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

Functional Status (FS) is an important domain in Comprehensive Geriatric Assessment (CGA) and is most often evaluated using the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales separately. This secondary analysis of a previous prospective cohort study was conducted between September 2015 and May 2018 at Marseille University Hospital, France, on 613 cancer outpatients aged ≥70 years. The first objective of this study was to determine the prevalence of FS impairment in older outpatients with cancer using a combination of the information collected with the ADL and short IADL scales. Our second objective was to describe the potential impact of this combined FS on three-month unplanned hospitalizations and three-month mortality in this population. The median age was 81 years and 61.2% were men. The most common types of tumours were lung and thoracic (22.3%). Concerning FS, 255 patients (41.6%) had unimpaired ADL-IADL, 131 patients (21.4%) had IADL impairment, 38 patients (6.2%) had ADL impairment, and 189 patients (30.8%) had impaired ADL-IADL. In the multivariate Cox analysis, metastatic stage (adjusted Hazard Ratio (aHR) = 1.79; 95% CI [1.14–2.80]) and impaired ADL-IADL (aHR = 3.46; 95% CI [1.89–6.33]) were independently associated with three-month mortality. In the logistic regression model, impaired ADL-IADL (adjusted Odd ratio (aOR) = 3.64; 95% CI [1.84–7.20]) was the only factor independently associated with three-month unplanned hospitalizations. The combined use of the ADL and IADL scales to evaluate functional status in older patients with cancer is of significant prognostic value regarding the risks of three-month unplanned hospitalizations and mortality. [ABSTRACT FROM AUTHOR]

Key summary points: Aim: Compare G8 scores according to the cancer site and G8 items in older patients with thoracic cancers. Findings: In our sample study, older patients with thoracic and lung cancers presented a lower BMI, less neuropsychological disorders and were younger compared to older patients with other cancer pathologies. Message: Management of frailties in older patients treated for thoracic and lung cancers should consider nutritional status impairment and psychological status maintenance as priorities. Purpose: Assessment of vulnerability with the G8 screening tool according to cancer localization and weight of the G8 items when screening frailty in thoracic and lung cancer (TLC) compared to other cancer localizations. Methods: This study was conducted retrospectively on all G8 data collected for older cancer patients between April 2015 and December 2019 at Marseille University Hospital. Results: One thousand four hundred and thirty-one patients were included; the median age was 80.6 years and 62.3% of the patients were men. The most common type of cancer was thoracic cancer (34.5%). A majority of patients with thoracic cancers (74.4%) had an impaired G8. In a logistic regression model, male gender, age < 80 years, BMI < 23 kg/m2, normal psychological status, and health status perception were independent factors associated with thoracic cancers. Conclusion: Improving nutritional status and maintaining mental health are important issues to consider before treatment initiation in older patients with thoracic cancers. [ABSTRACT FROM AUTHOR]

Lung cancer affects older and older old adults and is the leading cause of death by cancer. Comprehensive Geriatric Assessment (CGA) is recommended before and during cancer treatment to guide therapy management in this population. This study was conducted between September 2015 and January 2019 at Marseille University Hospital (AP-HM). During this period, all consecutive outpatients 70 years or older referred for a CGA before initiation of lung cancer treatment were enrolled. The objective of this study was to compare lung and thoracic cancer management of octogenarians (≥80 years) and their geriatric profile versus patients aged 70 to 79 years (<80 years). In our study, 228 patients were recruited. The median age was 78.7 ± 5 years. There were 94 octogenarians (41.2%), 36.2% of them were diagnosed with stage IV neoplasm and the most common treatment was chemotherapy (43.6%). The logistic regression analysis highlights that handgrip strength was the most commonly impaired domain (OR 2.3; 95% CI [1.3–4.3]) in octogenarians and that they are more likely than their younger counterparts to be treated by targeted therapy (OR 9.8; 95% CI [1.0–92.9]). Overall survival (OS) was similar in both age groups (log rank = 0,95). In our study, octogenarians and patients <80 years had equivalent survival, across the different thoracic cancer treatments and tumor stages. Measure of muscle strength in CGA could be very useful in a clinical setting to help improve the management of older old patients treated for lung or thoracic cancer. • Octogenarians have the same survival than younger patients in thoracic cancers. • Impaired muscle strength is an important factor to help improve the management of octogenarians. • Some geriatric assessments domains may predict outcomes in older patients with thoracic cancers. [ABSTRACT FROM AUTHOR]

Comprehensive Geriatric Assessment (CGA), is used in older patients with cancer to identify frailties, which can interfere with specialized treatment, and to help with therapeutic care. Functional Status (FS) is a domain of CGA in which Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) are evaluation tools. Our study reviewed the data available on the most frequently used tools to assess ADL and IADL in a geriatric oncology setting and their predictive values on overall survival (OS), toxicity, treatment feasibility or decision and postoperative complications. This review was based on a systematic search of the MEDLINE® database for articles published in English and French between January 1, 2010, and December 31, 2017. In the final analysis, 40 out of 4061 studies were included. The most common ADL and IADL scales used are the Katz ADL (KL-ADL) in 25 studies and the Lawton IADL (IADL 8) in 22 studies. FS is predictive of OS in 11 out of 24 studies, chemotoxicity in 2 out of 7 studies, treatment feasibility in 2 out of 5 studies, treatment decisions in 2 out of 3 studies, and postoperative complications in 4 out of 6 studies. FS is of prognostic value in a geriatric oncology setting despite heterogeneous methodology and inclusion criteria, in the studies included. Additional research is needed to explore more precisely the prognostic value of FS in overall survival, toxicity, treatment feasibility or decision and postoperative complications, in older cancer patients. [ABSTRACT FROM AUTHOR]

• Oligoprogression is an emergent pattern of relapse in the current NSCLC landscape. • Local radical treatments could remove resistant clones before systemic progression. • Literature supporting this strategy is promising but remains heterogeneous. • Biomarkers such as ctDNA should be ideally integrated for optimal patient selection. Progresses of systemic treatments in advanced non-small cell lung cancer (NSCLC), such as immune checkpoint blockers (ICB) and targeted therapies, led to the increased incidence of oligoprogressive disease (OPD). The OPD is a subtype of oligometastatic disease (OMD) defined as a progression of a limited number of lesions during systemic treatment exposure. The hypothesis was formulated that local radical treatments (LRT) could eradicate progressive lesions resulting from resistant clones, ultimately leading to systemic treatment sensitivity restoration. Recently published international consensuses and guidelines aim to obtain a uniform definition of OMD NSCLC, to standardize the inclusion of these patients in future clinical trials, as well as their management in daily practice. Although there is no specific definition of OPD, LRT strategies in OPD are supported after reporting promising results. Both retrospective and preliminary prospective randomized data of LRT for patients with OPD NSCLC are encouraging. More clinical and translational data are needed for selecting best scenarios where LRT should be delivered. In this review, we analyze the current available literature on LRT for patients with OPD in advanced NSCLC and discuss about future trial design and challenges. [ABSTRACT FROM AUTHOR]

The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups. IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [ EGFR ] or anaplastic lymphoma kinase [ ALK ] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR -positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR -positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov , number NCT02366143 , and is ongoing. Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR -positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17·0–NE) with ABCP (34 of 400) and 18·7 months (95% CI 13·4–NE) with BCP (45 of 400; hazard ratio [HR] 0·61 [95% CI 0·29–1·28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE–NE] with ABCP [26 of 400] vs 17·5 months [95% CI 11·7–NE] with BCP [32 of 400]; HR 0·31 [95% CI 0·11–0·83]) and in the intention-to-treat population (19·8 months [17·4–24·2] vs 14·9 months [13·4–17·1]; HR 0·76 [0·63–0·93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13·3 months [11·6–NE] with ABCP [52 of 400] vs 9·4 months [7·9–11·7] with BCP [57 of 400]; HR 0·52 [0·33–0·82]). Median overall survival was 21·4 months (95% CI 13·8–NE) with ACP versus 18·7 months (95% CI 13·4–NE) with BCP in EGFR -positive patients (HR 0·93 [95% CI 0·51–1·68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0·90 [95% CI 0·47–1·74]), in the intention-to-treat population (HR 0·85 [0·71–1·03]), or in patients with baseline liver metastases (HR 0·87 [0·57–1·32]). In the intention-to-treat safety-evaluable population, grade 3–4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group. Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study. F. Hoffmann-La Roche, Genentech. [ABSTRACT FROM AUTHOR]

• Novel molecular biomarkers are emerging as promising therapeutic targets in non-oncogene addicted NSCLC, a disease where effective strategies are eagerly needed. • Antibody drug conjugates (ADCs) are a new generation of bio-pharmaceutical compounds, combining the precision of targeted therapy with the cytotoxic effect of chemotherapy. • Trophoblastic Cell Surface Antigen 2 (TROP-2) is a surface glycoprotein currently under study in advanced refractory NSCLC. • TROP-2 is an attractive candidate for targeted therapy in NSCLC, with encouraging antitumor activity in early phase trials, as both monotherapy or combination strategy. Antibody drug conjugates (ADCs) represent a revolutionary drug class in cancer therapy, combining the precision of targeted therapy with the cytotoxic effects of chemotherapy. Promising activity of novel ADCs, namely Trastuzumab Deruxtecan and Patritumab Deruxtecan, has been observed in hard-to treat molecular subtypes, such as HER2 -positive and heavily pretreated EGFR -mutant Non-Small Cell Lung Cancer (NSCLC). However, therapeutic advances are expected in certain subgroups of lung cancer patients, including non-oncogene-addicted NSCLC after failure of current standard of care (e.g., immunotherapy with or without chemotherapy, chemo-antiangiogenic treatment). Trophoblastic Cell Surface Antigen 2 (TROP-2) is a surface transmembrane glycoprotein member of the epithelial cell adhesion molecule (EpCAM) family. TROP-2 represents a promising therapeutic target in refractory non-oncogene-addicted NSCLC. We performed a systematic literature search of the clinical trials about TROP-2 directed ADCs in NSCLC referenced in the pubmed.gov database, Cochrane Library database and clinicaltrial.gov database. First-in-humans ADCs targeting TROP-2, namely Sacituzumab Govitecan (SN-38) and Datopotamab Deruxtecan (Dxd), yielded promising activity signals in NSCLC with a manageable safety profile. Most common grade ≥ 3 adverse events (AEs) of Sacituzumab Govitecan included neutropenia (28 %), diarrhea (7 %), nausea (7 %), fatigue (6 %), and febrile neutropenia (4 %). Nausea and stomatitis were the most common all grade AEs with Datopotamab Deruxtecan; dyspnea, amylase increase, hyperglycemia and lymphopenia were reported as grade ≥ 3 AEs in less than 12 % of patients. As more effective strategies are needed for patients with refractory non-oncogene-addicted NSCLC, the design of novel clinical trials with ADCs targeting TROP-2 is encouraged as both a monotherapy or combination strategy with existing agents (e.g., monoclonal antibodies targeting immune checkpoint inhibitors or chemotherapy). [ABSTRACT FROM AUTHOR]