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• Use of surgery increased while use of both chemo- & radiotherapy decreased in stage I. • The rate of both chemo- & radiotherapy increased in stage III up to 70% in 2019. • Use of concurrent versus sequential chemoradiation increased over time (stage II-III) • 2013–2019: concurrent radiotherapy was most often accelerated fractionated. • (Possibly unwarranted) variation in treatment between patients, hospitals and regions. Recent treatment patterns for small cell lung cancer (SCLC) in the Netherlands were unknown. This nationwide population-based study describes trends and variations in the treatment of stage I-III SCLC in the Netherlands over the period 2008–2019. Patients were selected from the population-based Netherlands Cancer Registry. Treatments were studied stratified for clinical stage. In stage II-III, factors associated with the use of concurrent (cCRT) versus sequential chemoradiation (sCRT) and accelerated versus conventionally fractionated radiotherapy in the context of cCRT were identified. In stage I (N = 535), 29% of the patients underwent surgery in 2008–2009 which increased to 44% in 2018–2019. Combined use of chemotherapy and radiotherapy decreased in stage I from 47% to 15%, remained constant (64%) in stage II (N = 472), and increased from 57% (2008) to 70% (2019) in stage III (N = 5,571). Use of cCRT versus sCRT in stage II-III increased over time (odds ratio (OR) 2008-2011 vs 2016-2019 : 0.53 (95%-confidence interval (95%CI): 0.41–0.69)) and was strongly associated with lower age, WHO performance status 0, and diagnosis in a hospital with in-house radiotherapy. Forty-six percent of patients with stage III received cCRT in 2019. Until 2012, concurrent radiotherapy was mainly conventionally fractionated, thereafter a hyperfractionated accelerated scheme was administered more frequently (57%). Accelerated radiotherapy was strongly associated with geographic region (OR south vs north : 4.13 (95%CI: 3.00–5.70)), WHO performance (OR 1 vs 0 : 0.50 (95%CI: 0.35–0.71)), and radiotherapy facilities treating ≥ 16 vs < 16 SCLC patients annually (OR: 3.01 (95%CI: 2.38–3.79)). The use of surgery increased in stage I. In stages II and III, the use of cCRT versus sCRT increased over time, and since 2012 most radiotherapy in cCRT was accelerated. Treatment regimens and radiotherapy fractionation schemes varied between patient groups, regions and hospitals. Possible unwarranted treatment variation should be countered. [ABSTRACT FROM AUTHOR]

• Proton-therapy in stage III NSCLC was associated with a lower incidence of grade 3 lymphopenia and anemia. • Patients treated with concurrent chemotherapy and proton-therapy had better performance status after the treatment. • Patients treated with concurrent chemotherapy and proton-therapy had a higher probability of receiving adjuvant durvalumab. Concurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab is standard-of-care for fit patients with unresectable stage III NSCLC. Intensity modulated proton therapy (IMPT) results in different doses to organs than intensity modulated photon therapy (IMRT). We investigated whether IMPT compared to IMRT reduce hematological toxicity and whether it affects durvalumab treatment. Prospectively collected series of consecutive patients with stage III NSCLC receiving CCRT between 06.16 and 12.22 (staged with FDG-PET-CT and brain imaging) were retrospectively analyzed. The primary endpoint was the incidence of lymphopenia grade ≥ 3 in IMPT vs IMRT treated patients. 271 patients were enrolled (IMPT: n = 71, IMRT: n = 200) in four centers. All patients received platinum-based chemotherapy. Median age: 66 years, 58 % were male, 36 % had squamous NSCLC. The incidence of lymphopenia grade ≥ 3 during CCRT was 67 % and 47 % in the IMRT and IMPT group, respectively (OR 2.2, 95 % CI: 1.0–4.9, P = 0.03). The incidence of anemia grade ≥ 3 during CCRT was 26 % and 9 % in the IMRT and IMPT group respectively (OR = 4.9, 95 % CI: 1.9–12.6, P = 0.001). IMPT was associated with a lower rate of Performance Status (PS) ≥ 2 at day 21 and 42 after CCRT (13 % vs. 26 %, P = 0.04, and 24 % vs. 39 %, P = 0.02). Patients treated with IMPT had a higher probability of receiving adjuvant durvalumab (74 % vs. 52 %, OR 0.35, 95 % CI: 0.16–0.79, P = 0.01). IMPT was associated with a lower incidence of severe lymphopenia and anemia, better PS after CCRT and a higher probability of receiving adjuvant durvalumab. [ABSTRACT FROM AUTHOR]

Synchronous oligometastatic non-small cell lung cancer (NSCLC) definition varies from 1 metastasis in 1 organ (tumour-node-metastasis 8 [TNM8]), 1–3 metastases (European Society for Medical Oncology [ESMO]), ≤3 metastases (including mediastinal nodes [MLN]) after systemic treatment to 3–5 metastases in ongoing trials. A single definition is however needed to design/compare trials. To assess oligometastatic NSCLC definitions used by clinical experts in daily practice and its evolution, we redistributed a 2012 case-based survey (Dooms, the World Congress of Lung Cancer 2013). In December 2017, 10 real-life multidisciplinary team (MDT) discussed patients (good condition, no significant comorbidities, 18F-fluorodeoxyglucose positron emission tomography/brain magnetic resonance imaging staged, all < 5 metastases, 9/10 ≤ 3 metastases, oncogene-addicted or wild-type) were distributed to 33 international NSCLC experts involved in the European Organisation for Research and Treatment of Cancer oligometastatic NSCLC consensus group, questioning is this oligometastatic disease and if oligometastatic, which treatment proposal. The answers provided in 2017 were compared with the 2012 answers; real-life treatment and survival of the patients was added. Twenty-six of 33 experts (24 centres) replied: 8 medical oncologists, 7 pulmonologists, 7 radiation oncologists, 4 thoracic surgeons. Sixty-two percent of respondents discussed the cases with their MDT. One case had 100% oligometastatic consensus, and 3 cases had >90% consensus; the number of treatment proposals varied between 3 and 8. Radical treatment was more often offered in case of single metastasis or N0. Compared with 2012, there was a trend towards a more conservative oligometastatic definition and chemotherapy was more frequently included in the treatment proposal. Oligometastatic NSCLC definition was conservative. The number of organs, MLN status and radical treatment possibility seem to be components of daily practice oligometastatic definition. • Oligometastatic non-small cell lung cancer definition was conservative in this case-based survey. • Organ number, mediastinal lymph nodes and radical treatment options are important. • Chemotherapy was more often incorporated in the treatment compared with 2012. [ABSTRACT FROM AUTHOR]

Synchronous oligometastatic disease (sOM) has been described as a distinct disease entity; however, there is no consensus on OM definition (OM-d) in non–small-cell lung cancer (NSCLC). A consensus group was formed aiming to agree on a common OM-d that could be used in future clinical trials. A European survey was circulated to generate questions and input for the consensus group meeting. A European Organisation for Research and Treatment of Cancer Lung Cancer Group (LCG)/sOM-d consensus group survey was distributed to LCG, sOM-d consensus group, and several European thoracic oncology societies' members. 444 responses were analysed (radiation oncologist: 55% [n = 242], pulmonologist: 15% [n = 66], medical oncologist: 14% [n = 64]). 361 physicians (81%) aimed to cure sOM NSCLC patients and 82% (n = 362) included the possibility of radical intent treatment in their sOM-d. The maximum number of metastases considered in sOM-d varied: 12% replied 1 metastasis, 42% ≤ 3, and 17% ≥ 5 metastases. 79% (n = 353) stated that number of organs involved was important for sOM-d, and most (80%, n = 355) considered that only ≤3 involved organs (excluding primary) should be included. 317 (72%) included mediastinal lymph node involvement in the sOM-d and 22% (n = 70/317) counted mediastinal lymph node as a metastatic site. Most physicians completed sOM staging with brain magnetic resonance imaging (91%, n = 403) and positron emission tomography/computed tomography (98%, n = 437). Pathology proof of metastatic disease was a requirement to define sOM for 315 (71%) physicians. The preferred primary outcome for sOM clinical trials was overall survival (73%, n = 325). Although consensual answers were obtained, several issues remain unresolved and will require further research to agree on a sOM-d. • The majority aimed to cure sOM NSCLC patients. • The maximum number of metastases considered in sOM-d was 42% ≤ 3 and 17% ≥ 5. • Most considered only ≤3 involved organs (excluding primary). • Few counted mediastinal lymph node as a metastatic site. • The preferred primary outcome for sOM clinical trials was overall survival. [ABSTRACT FROM AUTHOR]

Patients with non-small cell lung cancer (NSCLC) experience leptomeningeal metastases (LM) in 3–9% of cases. Because overall survival (OS) and performance status are very poor, they are mostly excluded from clinical trials. Here, we evaluated survival of patients with NSCLC having LM treated with immune checkpoint inhibitors (ICIs). A prospectively collected list of patients with advanced NSCLC treated with ICIs between November 2012 and July 2018 in 7 European centres was merged. All patients with LM before ICI start were selected, data were retrospectively added and patients were classified according to the National Comprehensive Cancer Network (NCCN) LM prognostic classification (good/poor). Progression-free survival (PFS) and OS on ICIs were evaluated. Nineteen of 1288 (1.5%) patients had LM; 73.7% had synchronous brain metastases; 73.7% had neurological symptoms at the start of ICIs and 52.6% were in the NCCN LM good prognosis group. Programmed death ligand-1 (PD-L1) expression was known for 42.1% of patients (87.5% positive). Median follow-up was 13 months from the start of ICIs, and median (95% confidence interval [CI]) PFS on ICIs was 2.0 (1.8–2.2) months. Six-month PFS rate was 21.0% and was significantly higher in the NCCN good versus poor prognostic group: 40% vs 0% (p = 0.05). Twelve-month PFS rate was 0%. Median (95% CI) OS from the start of ICIs was 3.7 (0.9–6.6) months. Six-month OS rate was 36.8%, and 12-month OS rate was 21.1%; both were not statistically significantly different for the good versus poor NCCN prognostic group (p = 0.40 and p = 0.56, respectively). Some patients with NSCLC having LM do benefit from ICI treatment; specifically, those in the NCCN LM good prognosis group can obtain a long survival. • Survival is poor for patients with non-small cell lung cancer (NSCLC) having leptomeningeal metastases (LM). • Some patients with NSCLC having LM do benefit from immune checkpoint inhibition. • Some, especially in the NCCN LM good prognosis group, can obtain a long survival. [ABSTRACT FROM AUTHOR]

Medical images are an integral part of oncological patient records and they are reviewed by many different specialists. Therefore, it is important that besides imaging experts, other clinicians are also aware that the diagnostic value of a scan is influenced by the applied imaging protocol. Based on two clinical lung cancer trials, we experienced that, even within a study protocol, there is a large variability in imaging parameters, which has direct impact on the interpretation of the image. These two trials were: 1) the NTR3628 in which the added value of gadolinium magnetic resonance imaging (Gd-MRI) to dedicated contrast enhanced computed tomography (CE-CT) for detecting asymptomatic brain metastases in stage III non-small cell lung cancer (NSCLC) was investigated and 2) a sub-study of the NVALT 12 trial (NCT01171170) in which repeated 18 F-fludeoxyglucose positron emission tomography ( 18 F-FDG-PET) imaging for early response assessment was investigated. Based on the problems encountered in the two trials, we provide recommendations for non-radiology clinicians, which can be used in daily interpretation of imaging. Variations in image parameters cannot only influence trial results, but sub-optimal imaging can also influence treatment decisions in daily lung cancer care, when a physician is not aware of the scanning details. [ABSTRACT FROM AUTHOR]

• Cognitive impairment is dynamic in individuals. • Cognitive impairment has 4 types: sustained, reversible, recurring, alternating. • Baseline cognitive impairment is the most important risk factor. • Cognitive functioning should be assessed at multiple time points. • Patients who have sustained cognitive impairment should avoid neurotoxic treatments. To identify risk factors for self-reported cognitive impairment in radically treated stage III non-small cell lung cancer (NSCLC). Cognitive functioning was assessed using the EORTC-QLQ-C30 at seven pre-specified time points in the phase III NVALT-11 trial (observation versus prophylactic cranial irradiation [PCI] in stage III NSCLC treated with chemo-radiotherapy ± surgery). Cognition was analyzed as binary (impairment or not) and continuous outcome, respectively, using generalized estimating equation (GEE) before and after multiple imputation. A score < 75 was defined as cognitive impairment. A mean difference by < 10, 10-<20, ≥ 20 points was regarded as of no, moderate, and large clinical effect, respectively. We categorized the cognitive impairment into four types based on changes over time: sustained, reversible, recurring, and alternating. In the no-PCI arm, 43/84 [51.2%] reported cognitive impairment at least once, of which 31.4% were sustained, 25.7% reversible, 28.6% recurring, and 14.3% alternating. Results were similar in the PCI arm. Cognitive functioning at baseline was comparable in two arms and a score < 75 was a significant risk factor with large effect for subsequent cognitive impairment (no-PCI: β = –23.30, p < 0.001; PCI arm: β = –22.34, p < 0.001; All: β = –23.47, p < 0.001). Younger age (≤60y), squamous histology, and PCI were risk factors without clinical relevance (β > -10, p < 0.05). Cognitive functioning declined over time (β = -0.26, p = 0.001) except for patients with cognitive impairment at baseline (β = 0.141, p = 0.33). Cognitive impairment is dynamic over time with four types. Baseline cognitive impairment (score < 75) is the most important risk factor for subsequent cognitive impairment in stage III NSCLC. Note: This work has been partly reported as an oral presentation at the ESTRO 2021 meeting (OC-0176). [ABSTRACT FROM AUTHOR]

• 198 responses (56% radiation oncologists) to this European survey were analysed. • OD RT is the most commonly used regimen. • BD RT increased after the CONVERT trial publication (32% before; 42% after). • Future research questions: integrating systemic therapies, and PCI vs MRI surveillance. The CONVERT trial showed that twice-daily (BD) concurrent chemoradiotherapy should continue to be considered the standard of care in localised LS-SCLC. A survey was conducted to assess the impact of the CONVERT trial in clinical practice and to identify any relevant research questions for future trials in this setting. An EORTC Group online survey of LS-SCLC practice was distributed to the EORTC LCG and to members of several European thoracic oncology societies between April and December 2018. 198 responses were analysed. The majority of respondents (88%, n = 174) were aware of the CONVERT trial. Radiation oncologists comprised 56% of all respondents. Once-daily (OD) radiotherapy is still the most commonly used regimen, however the use of concurrent BD radiotherapy increased after the publication of CONVERT (n = 59/186, 32% prior to and n = 78/187, 42% after the publication, p = 0.053). The main reasons for not implementing BD after the CONVERT publication were logistical issues (n = 88, 44%), inconvenience for patients (n = 56, 28%), and the absence of a statistical survival difference between the two arms in CONVERT (n = 38, 19%). Brain MRI was used by 28% during staging but more than half (60%) of the respondents did not routinely image the brain during follow-up. The main research questions of interest in LS-SCLC were 1) integrating novel targeted therapies-immunotherapies (n = 160, 81%), 2) PCI (+/- hippocampal sparing) vs. MRI surveillance (n = 140, 71%) and, 3) biomarker driven trials (n = 92, 46%). Once daily radiotherapy (60–66 Gy in 30–33 fractions) remains the most prescribed radiotherapy fractionation, despite the findings suggested by the CONVERT trial. [ABSTRACT FROM AUTHOR]

Objectives Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development. Materials and methods Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC–polychemotherapy subgroups of ≥50 patients. Results Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% ( p = 0.904). In cyclic dose cCRT ( N = 346) and LDC ( N = 391) BM were found in 18.8% and 17.9%, respectively ( p = 0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse ( p = 0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 ( p = 0.669), OR 0.93 ( p = 0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 ( p = 0.819), OR 1.21 ( p = 0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane ( N = 277) and cyclic dose taxane regimens ( N = 69) and for cCRT regimens with ≥50 patients (LDC versus cisplatin/etoposide ( N = 188), cisplatin/vinorelbin ( N = 65), weekly cisplatin/docetaxel ( N = 60)). Conclusion approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment. [ABSTRACT FROM AUTHOR]

Objectives Development of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC)-patients is associated with a poor prognosis. It has been suggested that LM-patients with epidermal growth factor receptor mutated ( EGFR +) NSCLC have a superior prognosis compared to EGFR -wild type NSCLC. Studies in EGFR + NSCLC-patients with LM are scarce. We retrospectively evaluated a multi-institutional cohort of EGFR + NSCLC-patients for LM to assess clinical outcome in relation to patient characteristics and treatment modalities. Material and methods Medical records of advanced-stage EGFR + NSCLC-patients (diagnosed between August 2000 and June 2014) from 11 Dutch hospitals were evaluated for LM as diagnosed by MRI and/or cytopathological liquor analysis. Data on patient characteristics, treatment and outcome were collected. Results Thirty-two of 356 (9.0%) advanced-stage EGFR + NSCLC-patients (median follow-up 21.0 months), were diagnosed with LM between 2006 and 2014. LM was diagnosed by MRI (59.4%), liquor analysis (9.4%) or by both MRI and liquor analysis (31.3%). Median survival after LM-diagnosis was 3.1 months (95% CI: 0.0–7.3). Six- and 12-month survival rates were 43.8% and 18.8%, respectively. Patients with performance status (PS) 0–1 at time of diagnosis of LM had a significantly higher chance to be alive after 6 months and had a significantly longer survival after diagnosis of LM compared to patients with PS ≥ 2. Age, treatment with high-dose EGFR-TKI, radiotherapy and whether LM was the only site of progressive disease did not influence survival after LM-diagnosis. Conclusion Although median survival after LM-diagnosis in EGFR -mutated NSCLC-patients was poor, a substantial part of the patients had a prolonged survival of more than 6 months. PS of 0–1 at time of diagnosis of LM was associated with prolonged survival. No other patient- or treatment-related characteristics were identified. Further research is warranted to identify treatment strategies that improve survival in EGFR + NSCLC-patients with LM. [ABSTRACT FROM AUTHOR]

Background. Median survival after diagnosis of brain metastases is, depending on the Recursive Partitioning Analysis (RPA) classes, 7.1 (class I) to 2.3 months (class III). In 2011 the Dutch guideline on brain metastases was revised, advising to withhold whole brain radiotherapy (WBRT) in RPA class III. In this large retrospective study, we evaluated the guideline's use in daily practice. Material and methods. Data of 428 lung cancer patients undergoing WBRT for brain metastases (2004-2012) referred from three Dutch hospitals were retrospectively analyzed. Details on Karnofsky performance score (KPS), age, control of primary tumor, extracranial metastases, histology, and survival after diagnosis of brain metastases were collected. RPA class was determined using the first four items. Results. In total 327 patients had non-small cell lung cancer (NSCLC) and 101 small cell lung cancer (SCLC). For NSCLC, 6.1%, 71.9%, and 16.2% were classified as RPA I, II, and III, respectively, and 5.8% could not be classified. For SCLC this was 8.9%, 66.3%, 14.9%, and 9.9%, respectively. Before the revised guideline was implemented, 11.3-21.3% of WBRT patients were annually classified as RPA III. In the year thereafter, this was 13.0% (p = 0.646). Median survival (95% CI) for NSCLC RPA class I, II, and III was 11.4 (9.9-12.9), 4.0 (3.4-4.7), and 1.7 (1.3-2.0) months, respectively. For SCLC this was 7.9 (4.1-11.7), 4.7 (3.3-6.1), and 1.7 (1.5-1.8) months. Conclusions. Although it is advised to withhold WBRT in RPA class III patients, in daily practice 11.3-21.3% of WBRT-treated patients were classified as RPA III. The new guideline did not result in a decrease. Reasons for referral of RPA III patients despite a low KPS were not found. Despite WBRT, survival of RPA III patients remains poor and this poor outcome should be stressed in practice guidelines. Therefore, better awareness amongst physicians would prevent some patients from being treated unnecessarily. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Stage III NSCLC patients are candidates for treatment with curative intent. Current guidelines advise post contrast magnetic resonance imaging (MRI) or contrast enhanced computed tomography (CE-CT) of the brain in these patients to exclude brain metastases (BM). In previous small studies MRI was reported to be superior to CE-CT. However, CT and MR technology have evolved and 18F-deoxyglucose-positron-emission-tomography (18FDG-PET) has been implemented in staging of NSCLC. If CE-CT, performed together with 18FDG-PET-CT shows the same yield of BM detection as an additionally performed MRI, substantial gain in time and resources is expected. Methods: All NSCLC patients who underwent a staging 18FDG-PET-CT between January 2008 and September 2011 were reviewed. Neurological asymptomatic patients with stage III NSCLC who were eligible for treatment with curative intent were selected, without taking into account the results of brain MRI. CT was compared to MRI to investigate whether additional BM were detected on MRI. Development of BM within a year after negative MRI was recorded. Results: 97/429 NSCLC patients who underwent a PET-CT had stage III disease. Three otherwise stage III patients already had occult BM on CE-CT. 77/97 (79%) patients underwent MRI, 45/77 (58%) CE-CT and 32/77 (42%) LD-CT. In none of the CE-CT, but in 5/32 (16%) LD-CT patients BM were detected on MRI. 9/72 patients (13%) without BM on MRI at diagnosis developed BM within a year. Conclusions: This retrospective study suggests that there is no additive value of MRI to 18FDG-PET-CT with CE-CT in screening for BM in neurological asymptomatic patients with stage III NSCLC. [Copyright &y& Elsevier]

• Addition of cobicistat increased osimertinib exposure in all NSCLC patients. • Addition of cobicistat to osimertinib did not lead to unexpected or severe adverse events. • The osimertinib boosting effect of cobicistat was stable over time. Exposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor. This was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (≤195 ng/mL). On day 1, the area under the plasma curve (AUC 0-24,ss) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22–26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still ≤ 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2–4 months) of the boosting effect. The mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC 0-24ss (AUC osimertinib + AUC AZ5104) was 60%, (range 19%–192%). The boosting effect was consistent over time. No grade ≥ 2 toxicity was observed. Pharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable. [ABSTRACT FROM AUTHOR]

• Osimertinib 160 mg showed modest antitumor activity in EGFR exon 20 mutated NSCLC. • Confirmed overall response was 28%. • The median duration of response was 5.3 months. • Osimertinib 160 mg can be beneficial, particularly if CNS disease is present. • Approved and newer drugs in clinical trials should be considered first for this patient group. Patients with life-threatening advanced non-small cell lung cancer (NSCLC) who harbor an exon 20 deletion and/or insertion mutation (EGFRex20 +) have limited effective treatment options. The high dose 3rd generation tyrosine kinase inhibitor (TKI) osimertinib shows promising in vitro activity in EGFRex20 + NSCLC tumors. The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC. We allowed patients to be treatment naïve and to have asymptomatic brain metastases. The primary endpoint was overall response rate (ORR). Secondary outcomes were duration of response (DoR), progression free survival (PFS), overall survival (OS), and treatment related adverse events (trAEs). From June 2018 to October 2021, 25 patients were enrolled across five centers in the Netherlands. The median age was 70 years (range, 47–87), 20 patients (80%) were women, and the median number of previous lines of therapy was 1 (range, 0–3). The exon 20 mutations were clustered between A763 and L777. The most common exon 20 mutations were p.(N771_H773dup) (n = 3) and p.(A767_V769dup) (n = 3). The ORR was 28% (95% CI, 12–49%), including seven partial responses, with a median DoR of 5.3 months (range, 2.7–27.6). The median PFS was 6.8 months (95% CI, 4.6–9.1) and the median OS was 15.2 months (95% CI, 14.3–16.0). The most common trAEs were diarrhea (72%), dry skin (44%), and fatigue (44%). The primary reason for discontinuation was progressive disease in 14 patients (56%). The POSITION20 study showed modest antitumor activity in patients with EGFRex20 + NSCLC treated with 160 mg osimertinib, with a confirmed ORR of 28% and acceptable toxicity. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the most lethal cancer, and 85% of cases are classified as non-small cell lung cancer (NSCLC). Metabolic rewiring is a cancer hallmark that causes treatment resistance, and lacks insights into serine/glycine pathway adaptations upon radiotherapy. Methods: We analyzed radiotherapy responses using mass-spectrometry-based metabolomics in NSCLC patient's plasma and cell lines. Efficacy of serine/glycine conversion inhibitor sertraline with radiotherapy was investigated by proliferation, clonogenic and spheroid assays, and in vivo using a serine/glycine dependent NSCLC mouse model by assessment of tumor growth, metabolite and cytokine levels, and immune signatures. Results: Serine/glycine pathway metabolites were significantly consumed in response to radiotherapy in NSCLC patients and cell models. Combining sertraline with radiotherapy impaired NSCLC proliferation, clonogenicity and stem cell self-renewal capacity. In vivo, NSCLC tumor growth was reduced solely in the sertraline plus radiotherapy combination treatment group. Tumor weights linked to systemic serine/glycine pathway metabolite levels, and were inhibited in the combination therapy group. Interestingly, combination therapy reshaped the tumor microenvironment via cytokines associated with natural killer cells, supported by eradication of immune checkpoint galectin-1 and elevated granzyme B levels. Conclusion: Our findings highlight that targeting serine/glycine metabolism using sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutations in patients with non–small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). There is evidence of activity of combining EGFR TKIs with monoclonal antibodies. This study reports on the efficacy and safety of afatinib in combination with cetuximab. Methods: In this single‐arm phase 2 trial, patients with advanced NSCLC harboring an EGFR ex20ins mutation were treated with afatinib 40 mg once daily in combination with cetuximab 500 mg/m2 every 2 weeks. The primary end point was disease control rate (DCR) at 18 weeks of treatment. Results: Thirty‐seven patients started treatment, with a median age of 65 years (range, 40–80 years), 78% female, and 95% White. The study achieved its primary end point with a DCR of 54% at 18 weeks, an overall response rate (ORR) of 43%, and a 32% confirmed ORR. Best responses were partial (n = 16), stable (n = 16), progressive disease (n = 2), or not evaluable (n = 3). Median progression‐free survival was 5.5 months (95% CI, 3.7–8.3 months) and median overall survival was 16.8 months (95% CI, 10.7–25.8 months). The most common treatment‐related adverse events (TRAEs) were diarrhea (70%), rash (65%), dry skin (59%), paronychia (54%), and erythema (43%). Grade 3 TRAEs were reported in 54% of all patients. Conclusions: Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 54% at 18 weeks and a 32% confirmed ORR. Toxicity was significant, although manageable, after dose reduction. Combination treatment with afatinib and cetuximab in patients with non–small cell lung cancer harboring an EGFR exon 20 insertion mutation demonstrated antitumor activity with a disease control rate of 54% at 18 weeks of treatment and a 32% confirmed overall response rate. [ABSTRACT FROM AUTHOR]

• Radiotherapy use in stage I increased while use of surgery decreased over time. • 2015-2018: radiotherapy (mainly SBRT/SABR) is used more often than surgery in stage I. • Combined chemo- & radiotherapy use in stage III only marginally increased over time. • 2008–2018: low use of concurrent chemoradiotherapy in stage III (23 %). • (Possibly unwarranted) variation in treatment between patients, hospitals and regions. This Dutch population-based study describes nationwide treatment patterns and its variations for stage I-III non-small cell lung cancer (NSCLC). Patients diagnosed with clinical stage I-III NSCLC in the period 2008–2018 were selected from the Netherlands Cancer Registry. Treatment trends were studied over time and age groups. Use of radiotherapy versus surgery (stage I-II), and concurrent versus sequential chemoradiotherapy (stage III) were analyzed by logistic regression. In stage I, the rate of surgery decreased from 58 % (2008) to 40 % (2018) while radiotherapy use increased over time (from 31 % to 52 %), which mostly concerned stereotactic body radiotherapy (74 %). In stage II, 54 % of patients received surgery, and use of radiotherapy alone increased from 18 % to 25 %. The strongest factors favoring radiotherapy over surgery were WHO performance status (OR ≥ 2 vs 0: 23.39 (95% CI: 18.93−28.90)), increasing age (OR ≥ 80 vs <60 years: 14.52 (95% CI: 13.02−16.18)) and stage (OR stage II vs I: 0.61 (95% CI: 0.57−0.65)). In stage III, the combined use of chemotherapy and radiotherapy increased from 35 % (2008) to 39 % (2018). In all years, 23 % received concurrent chemoradiotherapy, 9 % sequential chemoradiotherapy, 23 % radiotherapy or chemotherapy alone, and 25 % best supportive care. The strongest factors favoring concurrent over sequential chemoradiotherapy were age (OR ≥ 80 vs <60 years: 0.14 (95% CI: 0.10−0.19)), WHO Performance status (OR ≥ 2 vs 0: 0.33 (95% CI: 0.24−0.47)) and region (OR east vs north: 0.39 (95% CI: 0.30−0.50)). The use of radiotherapy became more prominent over time in stage I NSCLC. Combined use of chemotherapy and radiotherapy marginally increased in stage III: only one third of patients received chemoradiotherapy, mainly concurrently. Treatment variation seen between patient groups suggests tailored treatment decision, while variation between hospitals and regions indicate differences in clinical practice. [ABSTRACT FROM AUTHOR]

• Idiopathic pulmonary fibrosis (IPF) has a poor prognosis. • IPF and radiation induced lung injury share many similarities in pathogenesis. • IPF increases complication risk in patients receiving thoracic radiotherapy. • Multidisciplinary evaluation is required regarding thoracic radiotherapy for patients with IPF. • Proton beam therapy seems to be a safer thoracic radiotherapy technique for patients with IPF. Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease with an unknown cause. Uncertainties still remain regarding the pathogenesis of IPF, and the prognosis of this disease is poor despite some recent improvements in treatment. Radiation induced lung injury (RILI) is a common complication and a dose-limiting toxicity of thoracic radiotherapy. Importantly, IPF is a crucial risk factor for pulmonary toxicity after thoracic radiotherapy. Although IPF is not universally accepted as a definite contraindication for thoracic radiotherapy at present, it has been shown that IPF can increase the risk of severe and fatal complications after thoracic radiotherapy. Proton beam therapy has shown promising results in reducing the incidence of thoracic radiotherapy related life-threatening complications in IPF patients, but the current evidence is not sufficient to recommend the standard use of it. Many similarities are noticeable between IPF and RILI in terms of pathogenesis and underlying mechanisms. Better understanding of the mechanisms of IPF and RILI may enable clinicians to provide safer and more effective thoracic radiotherapy treatments in cancer patients with IPF. In this review, we summarize the current knowledge of IPF, present the importance of IPF in radiation oncology practice, and highlight the similarities and relationship between IPF and RILI. [ABSTRACT FROM AUTHOR]

The article focuses on the ethical considerations surrounding the design of the phase 3 LIBRETTO-431 trial, which compared selpercatinib to platinum-based chemotherapy with or without pembrolizumab in patients with advanced RET fusion-positive non-small-cell lung cancer. Topics include the Declaration of Helsinki's guidelines on conclusive proof, the necessity of equipoise before initiating a randomized clinical trial.

Simple Summary: Synchronous oligometastatic non-small cell lung cancer (NSCLC) represents an intermediate state of metastatic disease with a limited number of metastases. It has been suggested that adding local radical treatment (LRT) in this setting may improve the survival outcomes, but there are no validated tools to better select those patients who are most likely to benefit from LRT. The presence of cachexia and sarcopenia at diagnosis seems to be linked to poorer outcomes in local or advanced NSCLC, but it is not clear if these factors can be used to guide the treatment decisions in oligometastatic NSCLC and to preclude a possible radical treatment in patients with baseline cachexia or sarcopenia. For this reason, we evaluated the impact of cachexia and sarcopenia on survival outcomes and toxicities in a group of patients with synchronous oligometastatic NSCLC on an intention-to-treat basis. Considering the different definitions of sarcopenia used among different studies, we used the Psoas Muscle Index (PMI) as a surrogate of sarcopenia. Progression-free survival was longer for patients without cachexia and sarcopenia compared to those with cachexia and/or sarcopenia. Among patients with advanced NSCLC, there is a group of patients with synchronous oligometastatic disease (sOMD), defined as a limited number of metastases detected at the time of diagnosis. As cachexia and sarcopenia are linked to poor survival, incorporating this information could assist clinicians in determining whether a radical treatment should be administered. In a retrospective multicenter study, including all patients with adequately staged (FDG-PET, brain imaging) sOMD according to the EORTC definition, we aimed to assess the relationship between cachexia and/or sarcopenia and survival. Of the 439 patients that were identified between 2015 and 2021, 234 met the criteria for inclusion and were included. The median age of the cohort was 67, 52.6% were male, and the median number of metastasis was 1. Forty-six (19.7%) patients had cachexia, thirty-four (14.5%) had sarcopenia and twenty-one (9.0%) had both. With a median follow-up of 49.7 months, median PFS and OS were 8.6 and 17.3 months, respectively. Moreover, a trend toward longer PFS was found in patients without cachexia and sarcopenia compared to those with cachexia and/or sarcopenia. In multivariate analysis, cachexia and sarcopenia were not associated with an inferior survival, irrespective of receiving radical treatment. High CRP was associated with inferior survival and could be a prognostic factor, helping the decision of clinicians in selecting patients who may benefit from the addition of LRT. However, despite the homogeneous definition of oligometastatic disease and the adequate staging, our subgroups were small. Therefore, further studies are needed to better understand our hypothesis and generating findings. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic strategy and prognosis of advanced non-small cell lung cancer (NSCLC) patients. Nowadays, ICIs as monotherapy or in combination with chemotherapy are the standard of care treatment in advanced NSCLC, and in stage III, durvalumab (a programmed death ligand 1 inhibitor) is the unique drug approved as consolidation treatment after chemo-radiotherapy. This article reviews the pharmacological properties, clinical activity and safety of durvalumab as monotherapy or in combination with chemotherapy or other ICIs in the therapeutic strategy of NSCLC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 30% of patients with stage III non-small cell lung cancer (NSCLC) receiving radical chemoradiotherapy will develop symptomatic brain metastases (BM) during the disease course. Identifying risk factors for BM can help improve the management of these patients. The aim of this current study was to identify clinical risk factors, including gross tumor volume (GTV) radiomics features, for developing BM in patients with radically treated stage III NSCLC. We found that age, NSCLC subtype, and GTV of lymph nodes (GTVn) were significant factors for BM. GTVn radiomics features provided higher predictive value than GTV of primary tumor (GTVp) and GTV. Therefore, GTVp and GTVn should be separated in clinical and research practice. Purpose: To identify clinical risk factors, including gross tumor volume (GTV) and radiomics features, for developing brain metastases (BM) in patients with radically treated stage III non-small cell lung cancer (NSCLC). Methods: Clinical data and planning CT scans for thoracic radiotherapy were retrieved from patients with radically treated stage III NSCLC. Radiomics features were extracted from the GTV, primary lung tumor (GTVp), and involved lymph nodes (GTVn), separately. Competing risk analysis was used to develop models (clinical, radiomics, and combined model). LASSO regression was performed to select radiomics features and train models. Area under the receiver operating characteristic curves (AUC-ROC) and calibration were performed to assess the models' performance. Results: Three-hundred-ten patients were eligible and 52 (16.8%) developed BM. Three clinical variables (age, NSCLC subtype, and GTVn) and five radiomics features from each radiomics model were significantly associated with BM. Radiomic features measuring tumor heterogeneity were the most relevant. The AUCs and calibration curves of the models showed that the GTVn radiomics model had the best performance (AUC: 0.74; 95% CI: 0.71–0.86; sensitivity: 84%; specificity: 61%; positive predictive value [PPV]: 29%; negative predictive value [NPV]: 95%; accuracy: 65%). Conclusion: Age, NSCLC subtype, and GTVn were significant risk factors for BM. GTVn radiomics features provided higher predictive value than GTVp and GTV for BM development. GTVp and GTVn should be separated in clinical and research practice. [ABSTRACT FROM AUTHOR]

Adjuvant durvalumab is the standard of care for patients with stage III unresectable non-small cell lung cancer (NSCLC), without progression after concurrent chemo-radiation (CCRT). Patients with stage III NSCLC harbouring epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase rearrangements do not seem to benefit from durvalumab. Data are lacking about patients harbouring other driver genomic alterations (dGA). We performed a multicentre (N = 4, Netherlands and Italy) retrospective study including consecutive patients with unresectable stage III NSCLC and treated with CCRT—with or without adjuvant durvalumab—between 2016 and 2022. We enrolled 271 patients; 130 of which received adjuvant durvalumab. Sixty-six patients had dGA (41 KRAS mutations, 4 EGFR common mutations and 21 uncommon dGA). In the entire population, the median PFS was 24.9 months (95% CI 17.5–32.4) and 12.6 months (95% CI 9.0–16.1) with and without durvalumab (p = 0.001). In the dGA group (excluding common EGFR), mPFS was 12.3 months (95% CI 7.8–16.8) with and 7.6 (95% CI 3.4–11.9) without durvalumab (p = 0.038). For patients with KRAS mutations, mPFS was 12.3 months (95% CI 3.6–20.9) with and 7.2 months (95% CI 1.8–12.6) without durvalumab (p = 0.12). Among patients with uncommon dGA, mPFS was 12.9 months (95% CI 8.4–17.4) with and 7.6 months (95% CI 1.4–14) without durvalumab (p = 0.23). We have shown a meaningful survival benefit of adjuvant durvalumab in patients harbouring KRAS mutations and uncommon dGA. This is the largest stage III NSCLC cohort showing the efficacy of durvalumab in patients with uncommon dGA. Further prospective studies are needed to confirm our results. • Largest cohort of patients with stage III NSCLC and uncommon genomic alterations. • Adjuvant durvalumab improved survival in patients with uncommon genomic alterations. • Adjuvant durvalumab improved survival in patients with KRAS mutations. • Molecular testing should be mandatory for patients with stage III NSCLC. • Clinical trials should investigate the best adjuvant treatment in this setting. [ABSTRACT FROM AUTHOR]

Immunotherapy-induced pneumonitis (IIP) is a serious side-effect which requires accurate diagnosis and management with high-dose corticosteroids. The differential diagnosis between IIP and other types of pneumonitis (OTP) remains challenging due to similar radiological patterns. This study was aimed to develop a prediction model to differentiate IIP from OTP in patients with stage IV non-small cell lung cancer (NSCLC) who developed pneumonitis during immunotherapy. Consecutive patients with metastatic NSCLC treated with immunotherapy in six centres in the Netherlands and Belgium from 2017 to 2020 were reviewed and cause-specific pneumonitis events were identified. Seven regions of interest (segmented lungs and spheroidal/cubical regions surrounding the inflammation) were examined to extract the most predictive radiomic features from the chest computed tomography images obtained at pneumonitis manifestation. Models were internally tested regarding discrimination, calibration and decisional benefit. To evaluate the clinical application of the models, predicted labels were compared with the separate clinical and radiological judgements. A total of 556 patients were reviewed; 31 patients (5.6%) developed IIP and 41 patients developed OTP (7.4%). The line of immunotherapy was the only predictive factor in the clinical model (2nd versus 1st odds ratio = 0.08, 95% confidence interval:0.01–0.77). The best radiomic model was achieved using a 75-mm spheroidal region of interest which showed an optimism-corrected area under the receiver operating characteristic curve of 0.83 (95% confidence interval:0.77–0.95) with negative and positive predictive values of 80% and 79%, respectively. Good calibration and net benefits were achieved for the radiomic model across the entire range of probabilities. A correct diagnosis was provided by the radiomic model in 10 out of 12 cases with non-conclusive radiological judgements. Radiomic biomarkers applied to computed tomography imaging may support clinicians making the differential diagnosis of pneumonitis in patients with NSCLC receiving immunotherapy, especially when the radiologic assessment is non-conclusive. • There is no gold-standard to make the differential diagnosis of pneumonitis. • The best radiomic model was developed using the 75-mm spheroidal region of interest. • The proposed radiomic model had area under the receiver operating characteristic curve = 0.83 with good calibration and net benefits. • The radiomic model diagnosed 83% of cases with non-conclusive radiological judgement. [ABSTRACT FROM AUTHOR]

• No standard of care exists for L2 treatment after L1 chemo-immunotherapy in NSCLC. • Platinum rechallenge and taxane + antiangiogenic are valuable regimens in this setting. • Patients resistant to L1 treatment (PFS < 6mo) have poorer outcomes in L2. • Patients with high PD-L1 expressing tumors had better outcomes in L2. Chemotherapy plus immunotherapy is the standard of care for patients with metastatic NSCLC. No study has evaluated the outcomes of second-line chemotherapy treatments after progression following first-line chemo-immunotherapy. This multicenter retrospective study evaluated the efficacy of second line (2L) chemotherapies after progression under first-line (1L) chemo-immunotherapy, measured by overall survival (2L-OS) and progression free survival (2L-PFS). A total of 124 patients were included. The mean age was 63.1 years, 30.6 % of the patients were female, 72.6 % had an adenocarcinoma and 43.5 % had a poor ECOG-performance status prior to 2L initiation. Sixty-four (52.0 %) patients were considered resistant to first line chemo-immunotherapy. (1L-PFS < 6 months). In 2L treatments, 57 (46.0 %) patients received taxane monotherapy, 25 (20.1 %) taxane plus anti-angiogenic, 12 (9.7 %) platinum-based chemotherapy and 30 (24.2 %) other chemotherapy. At a median follow-up of 8.3 months (95 %CI: 7.2–10.2), post initiation of 2L treatment, the median 2L-OS was 8.1 months (95 % CI: 6.4–12.7) and the median 2L-PFS was 2.9 months (95 %CI: 2.4–3.3). Overall, the 2L-objective response and 2L-disease control rates were 16.0 %, and 42.5 %, respectively. Taxane plus anti-angiogenic and platinum rechallenge achieved longest median 2L-OS: not reached (95 %CI: 5.8-NR) and 17.6 months (95 %CI 11.6-NR), respectively (p = 0.05). Patients resistant to the 1L treatment had inferior outcomes (2L-OS 5.1 months, 2L-PFS 2.3 months) compared with 1L responders (2L-OS 12.7 months, 2L-PFS 3.2 months). In this real-life cohort, 2L chemotherapy achieved modest activity following progression under chemo-immunotherapy. 1L-resistant patients remained a refractory population, highlighting a need for new 2L strategies. [ABSTRACT FROM AUTHOR]

For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice. We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy. Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3–26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6–34.6) and 66.9% (95% CI: 59.6–75.2%), respectively. The incidence of grade 3–5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma. Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity. • Immune checkpoint blockers strategy is feasible in pre-treated thymic carcinomas. • In this population, ICB achieve a RR of 18% and one-year OS of 67%. • Close monitoring of patients is strongly advised to detect severe immune-toxicity. [ABSTRACT FROM AUTHOR]

Background In unselected elderly with stage III Non-Small Cell Lung Cancer (NSCLC), evidence is scarce regarding motives and effects of treatment modalities. Methods Hospital-based multicenter retrospective study including unresectable stage III NSCLC patients aged ⩾70 and diagnosed between 2009 and 2013 ( N = 216). Treatment motives and tolerance (no unplanned hospitalizations and completion of treatment), and survival were derived from medical records and the Netherlands Cancer Registry. Results Patients received concurrent chemoradiation (cCHRT, 33%), sequential chemoradiation (sCHRT, 24%), radical radiotherapy (RT, 16%) or no curative treatment (27%). Comorbidity, performance status (58%) and patient refusal (15%) were the most common motives for omitting cCHRT. Treatment tolerance for cCHRT and sCHRT was worse in case of severe comorbidity (OR 6.2 (95%CI 1.6–24) and OR 6.4 (95%CI 1.8–22), respectively). One-year survival was 57%, 50%, 49% and 26% for cCHRT, sCHRT, RT and no curative treatment, respectively. Compared to cCHRT, survival was worse for no curative treatment ( P = 0.000 ) , but not significantly worse for sCHRT and RT ( P = 0.38). Conclusion Although relatively fit elderly were assigned to cCHRT, treatment tolerance was worse, especially for those with severe comorbidity. Survival seemed not significantly better as compared to sCHRT or RT. Prospective studies in this vital and understudied area are needed. [ABSTRACT FROM AUTHOR]

Purpose: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing. Methods: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration–time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated. Results: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436). Conclusion: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing. Clinical trial number: Clinicaltrials.gov identifier: NCT03655821 [ABSTRACT FROM AUTHOR]

Background: For some patients with advanced cancer not knowing prognosis is essential. Yet, in an era of informed decision-making, the potential protective function of unawareness is easily overlooked. We aimed to investigate 1) the proportion of advanced cancer patients preferring not to know prognosis; 2) the reasons underlying patients' prognostic information preference; 3) the characteristics associated with patients' prognostic information preference; and 4) the concordance between physicians' perceived and patients' actual prognostic information preference.Methods: This is a cross-sectional study with structured surveys (PROSPECT). Medical and thoracic oncologists included patients (n = 524), from seven Dutch hospitals, with metastatic/inoperable cancer and an expected median overall survival of ≤ 12 months. For analysis, descriptive statistics and logistic regression models were used.Results: Twenty-five to 31% of patients preferred not to know a general life expectancy estimate or the 5/2/1-year mortality risk. Compared to patients preferring to know prognosis, patients preferring unawareness more often reported optimism, avoidance and inability to comprehend information as reasons for wanting limited information; and less often reported expectations of others, anxiety, autonomy and a sense of control as reasons for wanting complete information. Females (p < .05), patients receiving a further line of systemic treatment (p < .01) and patients with strong fighting spirit (p < .001) were more likely to prefer not to know prognosis. Concordance between physicians' perceived and patients' actual prognostic information preference was poor (kappa = 0.07).Conclusions: We encourage physicians to explore patients' prognostic information preferences and the underlying reasons explicitly, enabling individually tailored communication. Future studies may investigate changes in patients' prognostic information preferences over time and examine the impact of prognostic disclosure on patients who prefer unawareness. [ABSTRACT FROM AUTHOR]

The recently concluded European Lung Cancer Congress 2022 (ELCC22) showcased some very exciting data, with more than 200 abstracts presented during the meeting. Through this review, we focus on selected clinically relevant abstracts that in our opinion represent significant updates in the current management of non-small cell lung cancer (NSCLC). Here, we summarize the updates in surgical management, adjuvant therapy and therapy for advanced stage NSCLC and put these advances in the context of the current clinical standard of care. [ABSTRACT FROM AUTHOR]

• Exercise is an important supportive care for patients with lung cancer. • Healthcare providers counseling have an impact on exercise level of their patients. • Clinicians have a positive perception of exercise in the lung cancer care context. • Overall, 63% assessed patient's exercise, only 10% referred patients to an exercise program. Exercise has been reported to alleviate disease as well as treatment impact in patients with lung cancer. Nevertheless, there is limited information available regarding the perception of lung cancer dedicated healthcare professionals' and their advice on exercise. An online survey exploring healthcare professionals' practice patterns, perceptions, barriers, and facilitators of exercise in patients with lung cancer was conducted within members of the EORTC Lung Cancer Group (LCG). One hundred forty-one healthcare providers completed the survey, mainly medical and radiation oncologists. Overall, 63% of the study participants declared that they frequently assessed exercise level in their patients, and 43% of them reinforced the importance of exercise. However, only 10% referred patients to an exercise program or specialist. Although the majority of the respondents had a positive perception regarding the benefits and safety of exercise (even in patients with advanced disease and/or bone metastasis), two-thirds of clinicians reported not having adequate training about exercise counselling. Moreover, 53% reported to lack of knowledge of guidelines referring to exercise in patients with cancer. Several obstacles and facilitators to improve exercise promotion in lung cancer care were identified. Healthcare providers recognize the relevance and feasibility of exercise as part of cancer treatment intervention, but specific pathways to do the referral are frequently missing. Future structured and well-designed strategies and initiatives are needed to support an effective referral in order to implement exercise interventions routinely in clinical practice. [ABSTRACT FROM AUTHOR]

• The cost-effectiveness of PCI compared to no PCI was assessed in stage III NSCLC. • A cohort partitioned survival model was developed including five health states. • PCI was more effective (0.443 QALYs) and costly (€10,123) than no PCI. • The probability of PCI being cost-effective was 93%. In stage III non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduces the brain metastases incidence and prolongs the progression-free survival without improving overall survival. PCI increases the risk of toxicity and is currently not adopted in routine care. Our objective was to assess the cost-effectiveness of PCI compared with no PCI in stage III NSCLC from a Dutch societal perspective. A cohort partitioned survival model was developed based on individual patient data from three randomized phase III trials (N = 670). Quality-adjusted life years (QALYs) and costs were estimated over a lifetime time horizon. A willingness-to-pay (WTP) threshold of €80,000 per QALY was adopted. Sensitivity and scenario analyses were performed to address parameter uncertainty and to explore what parameters had the greatest impact on the cost-effectiveness results. PCI was more effective and costly (0.443 QALYs, €10,123) than no PCI, resulting in an incremental cost-effectiveness ratio (ICER) of €22,843 per QALY gained. The probability of PCI being cost-effective at a WTP threshold of €80,000 per QALY was 93%. The probability of PCI gaining three and six additional months of life were 76% and 56%. The scenario analysis adding durvalumab increased the ICER to €35,159 per QALY gained. Using alternative survival distributions had little impact on the ICER. Assuming fewer PCI fractions and excluding indirect costs decreased the ICER to €18,263 and €5554 per QALY gained. PCI is cost-effective compared to no PCI in stage III NSCLC, and could therefore, from a cost-effectiveness perspective, be considered in routine care. [ABSTRACT FROM AUTHOR]

Pemetrexed is a cytotoxic drug for first‐line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin‐related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P =.196) or volume of distribution (+7% change, P =.002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin. [ABSTRACT FROM AUTHOR]

Simple Summary: The historical standard treatment of metastatic non-small cell lung cancer (NSCLC) consisted of palliative chemotherapy, with limited influence on survival. With the introduction of immuno- and targeted therapy, the prognosis improved largely. A subset of NSCLC patients with limited metastatic disease, called oligometastatic, might obtain long-term survival by adding a local ablative treatment on all visible disease sites, in addition to the standard systemic treatment. The evidence for this combined treatment is still scarce and comes mainly from the pre-immunotherapy era. As radiotherapy might stimulate the immune system making immunotherapy more efficient, here we review the evidence before and in the era of immunotherapy, and discuss the challenges and prospects of the combined treatment. Oligometastatic cancer is recognized as a separate entity within the spectrum of metastatic disease. It was suggested that patients with oligometastatic disease can obtain long-term survival by giving local ablative therapy (LAT) to all visible disease locations. However, the true extent from which metastatic cancer should be called "oligometastatic" is unknown, although a consensus definition for oligometastatic disease is proposed by research organizations, such as the EORTC (maximum of five metastases in three organs). Different states of the oligometastatic disease are defined, such as synchronous vs. metachronous, oligopersistent vs. oligoprogressive disease. All clinical trials including patients with non-small cell lung cancer (NSCLC) are small and most are not randomized. Two small randomized phase II trials on synchronous disease showed an improvement in progression free survival, with the addition of LAT, and one also demonstrated an overall survival benefit. Immune checkpoint inhibitors (ICI) were not part of the treatment in these trials, while ICI significantly improved long-term outcomes of patients with metastatic NSCLC. Radiotherapy might improve the prognosis of patients treated with ICI because of its immunostimulatory effects and the possibility to eradicate metastatic deposits. Here, we summarize the data for adding ablative radiotherapy to the treatment of oligometastatic NSCLC, especially in the ICI era, and discuss the challenges of combined treatment. [ABSTRACT FROM AUTHOR]

dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non–small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16 low cells (immature) by flow cytometry. About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%. The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance. • Baseline dNLR (B) and its dynamics (C2) associate with ICI outcome in advanced NSCLC. • The dNLR (B+C2) can improve the prediction of ICI outcomes vs. (B). • The impact of dNLR on survival remained significant after PD-L1 adjustment. • The dNLR is a simple biomarker that should be validated in clinical trials. • Circulating immature neutrophils can be key on ICI resistance. [ABSTRACT FROM AUTHOR]

The established role of morphological evaluation of tumour-infiltrating lymphocytes (TILs) with immune checkpoint inhibitors (ICIs) in non–small cell lung cancer (NSCLC) is unknown. We aimed to determine TIL association with the outcome for ICIs and for chemotherapy in advanced NSCLC. This is a multicenter retrospective study of a nivolumab cohort of 221 patients treated between November 2012 and February 2017 and a chemotherapy cohort of 189 patients treated between June 2009 and October 2016. Patients with available tissue for stromal TIL evaluation were analysed. The presence of a high TIL count (high-TIL) was defined as ≥10% density. The primary end-point was overall survival (OS). Among the nivolumab cohort, 64% were male, with median age of 63 years, 82.3% were smokers, 77% had performance status ≤1 and 63% had adenocarcinoma histology. High-TIL was observed in 22% patients and associated with OS (hazard ratio [HR] 0.48; 95% confidence interval [95% CI]: 0.28–0.81) and progression-free survival [PFS] (HR = 0.40; 95% CI: 0.25–0.64). Median PFS was 13.0 months (95% CI: 5.0–not reached) with high-TIL versus 2.2 months (95% CI: 1.7–3.0) with the presence of a low TIL count (low-TIL). Median OS for high-TIL was not reached (95% CI: 12.2–not reached) versus 8.4 months (95% CI: 5.0–11.6) in the low-TIL group. High-TIL was associated with the overall response rate (ORR) and disease control rate (DCR) (both, P <.0001). Among the chemotherapy cohort, 69% were male, 89% were smokers, 86% had performance status ≤1 and 90% had adenocarcinoma histology. High-TIL was seen in 37%. Median PFS and OS were 5.7 months (95% CI: 4.9–6.7) and 11.7 months (95% CI: 9.3–13.0), respectively, with no association with TILs. High-TIL was associated with favourable outcomes in a real-world immunotherapy cohort of patients with NSCLC, but not with chemotherapy, suggesting that TILs may be useful in selecting patients for immunotherapy. • High–tumour infiltrating lymphocyte (TIL) density was associated with immunotherapy benefit in non–small cell lung cancer (NSCLC) patients. • No correlation with outcome was observed in chemotherapy-treated patients with NSCLC. • TILs may be useful in selecting patients for immunotherapy. [ABSTRACT FROM AUTHOR]

• Immunotherapy improves lung cancer survival, but acquired resistance is common. • Hypofractionated radiotherapy is known to stimulate the antitumor immune response. • With added radiotherapy, 94% of resistant patients could continue immunotherapy. • Radioimmunotherapy led to a high (62 %) disease control rate at 3 months. • Radiotherapy can thus reinvigorate immunotherapy activity after disease progression. The current work aimed to investigate the clinical benefit of radiotherapy in patients with metastatic non-small cell lung cancer (NSCLC) developing acquired resistance to immune checkpoint inhibitors. We report on a pooled, two-institution, phase II single-arm prospective cohort study. The study included patients with stage IV NSCLC who showed progression of one or more measurable lesions under anti-PD-(L)1 inhibition alone, after initially having achieved at least stable disease. Hypofractionated radiotherapy (hRT) of one to four metastases was performed, while one or more lesions were kept untreated. Following hRT, treatment with immune checkpoint inhibitors was continued unchanged until further evidence of tumor progression or unacceptable toxicity. Primary endpoint of the pooled analysis was progression-free survival (PFS), secondary endpoints included overall survival (OS) and toxicity. A total of 48 patients were enrolled: mean age was 67.1 ± 9.3 years, 50 % were male and 72.9 % were PD-L1 positive. Immunotherapy was in 95.8 % of patients the first or second line therapy at time of enrollment. hRT was performed to one (93.8 % of cases) or more lesions (median total dose: 27.5 Gy, median 6.5 Gy/fraction). Forty-five patients (93.8 %) were able to continue immunotherapy for a median of 6.2 months following hRT. Median PFS was 4.4 months, with 62.5 % disease control at three months and 37.5 % at six months. Median OS was 14.9 months. Severe adverse events (grade ≥ 2) were reported in 12 cases (25 %), of which none were radiotherapy-related and four were immunotherapy-related. Salvage therapy consisted of chemotherapy (48.8 %) or repeated irradiation (21.9 %). No further tumor treatment was performed in 29.3 % of patients. The current pooled analysis is a prospective evaluation of the role of radiation therapy for metastatic NSCLC in the setting of newly acquired immunotherapy resistance. Hypofractionated radiotherapy can support the outcome of immune checkpoint inhibitors and thus allow continuation of treatment for a relevant amount of time despite initial tumor progression. [ABSTRACT FROM AUTHOR]

• A quantification method for KRAS-inhibitors Adagrasib and Sotorasib was developed. • This method may support pharmacokinetic research for Adagrasib and Sotorasib. • Revealing overexposure may help reduce treatment toxicity in clinical practice. • The method was co-validated with brigatinib, lorlatinib, pralsetinib & selpercatinib. Recently, two small molecular inhibitors (SMIs) –adagrasib and sotorasib– have been introduced for targeting Kirsten rat sarcoma (KRAS) p.G12C mutations in patients with non-small cell lung cancer (NSCLC). In order to support pharmacokinetic research as well as clinical decision making, we developed and validated a simple and accurate liquid chromatography-tandem mass spectrometry method for the multiplexed quantification of adagrasib and sotorasib. This assay was co-validated with the quantification for brigatinib, lorlatinib, pralsetinib and selpercatinib. Methanol was used for single-step protein precipitation. Chromatographic separation was performed using an Acquity® HSS C18 UPLC column, with an elution gradient of ammonium formate 0.1 % v/ v in water and acetonitrile. In K2-EDTA plasma, adagrasib was found to be stable for at least seven days at room temperature and 4 °C, and at least 3 months at −80 °C. Sotorasib was found to be stable for at least three days at room temperature, seven days at 4 °C and at least 3 months at −80 °C. The method was validated over a linear range of 80–4000 ng/mL for adagrasib and 25–2500 ng/mL for sotorasib. The assay is therefore well-equipped for determining plasma concentrations in clinical practice. [ABSTRACT FROM AUTHOR]

Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered. • Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). • This nationwide study investigated risk factors for fatal outcome of COVID-19. • Among 442 registered patients with cancer, 32.3% of patients died of COVID-19. • Haematological malignancy and lung cancer increased the risk of fatal outcome. • These results can guide treatment and vaccination decisions in patients with cancer. [ABSTRACT FROM AUTHOR]

Background: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR).Methods: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed.Discussion: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023.Trial Registration: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019. [ABSTRACT FROM AUTHOR]

Medical imaging plays a key role in evaluating and monitoring lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. The application of artificial intelligence in medical imaging has transformed medical images into mineable data, by extracting and correlating quantitative imaging features with patients' outcomes and tumor phenotype – a process termed radiomics. While this process has already been widely researched in lung oncology, the evaluation of COPD in this fashion remains in its infancy. Here we outline the main applications of radiomics in lung cancer and briefly review the workflow from image acquisition to the evaluation of model performance. Finally, we discuss the current assessments of COPD and the potential application of radiomics in COPD. [ABSTRACT FROM AUTHOR]

• We reviewed papers up to 2018 to see if CTVI can image regional ventilation. • Voxel-based correlations were moderate (∼0.4), and strong for larger volumes (∼0.8). • CTVI images obstructive COPD well, but may miss restrictive/gas diffusion issues. • CTVI validation methodologies need standardization to help clinical implementation. Computed Tomography Ventilation Imaging (CTVI) is an experimental imaging modality that derives regional lung function information from non-contrast respiratory-correlated CT datasets. Despite CTVI being extensively studied in cross-modality imaging comparisons, there is a lack of consensus on the state of its clinical validation in humans. This systematic review evaluates the CTVI clinical validation studies to date, highlights their common strengths and weaknesses and makes recommendations. We performed a PUBMED and EMBASE search of all English language papers on CTVI between 2000 and 2018. The results of these searches were filtered in accordance to a set of eligibility criteria and analysed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. One hundred and forty-four records were identified, and 66 full text records were reviewed. After detailed assessment, twenty-three full text papers met the selection criteria and were included in the final review. This included thirteen prospective studies, with 579 human subjects. Studies used diverse methodologies, with a large amount of heterogeneity between different studies in terms of the reference ventilation imaging modality (e.g. nuclear medicine, hyperpolarised gas MRI), imaging parameters, DIR algorithm(s) used, and ventilation metric(s) applied. The most common ventilation metrics used deformable image registration to evaluate the exhale-to-inhale motion field Jacobian determinant (DIR-Jac) or changes in air volume content based on Hounsfield Units (DIR-HU). The strength of correlation between CTVI and the reference ventilation imaging modalities was moderate to strong when evaluated at the lobar or global level, with the average ± S.D. (number of studies) linear regression correlation coefficients were 0.73 ± 0.25 (n = 6) and 0.86 ± 0.11 (n = 12) for DIR-Jac and DIR-HU respectively, and the SPC were 0.45 ± 0.31 (n = 6) and 0.41 ± 0.11 (n = 5) for DIR-Jac and DIR-HU respectively. We concluded that it is difficult to make a broad statement about the validity of CTVI due to the diverse methods used in the validation literature. Typically, CTVI appears to show reasonable cross-modality correlations at the lobar/whole lung level but poor correlations at the voxel level. Since CTVI is seeing new implementations in prospective trials, it is clear that refinement and standardization of the clinical validation methodologies are required. CTVI appears to be of relevance in radiotherapy planning, particularly in patients whose main pulmonary impairment is not a gas exchange problem but alternative imaging approaches may need to be considered in patients with other pulmonary diseases (i.e. restrictive or gas exchange problems). [ABSTRACT FROM AUTHOR]

• Patients with KRAS G12C + NSCLC receive the same first-line treatment as the general NSCLC population (i.e. ICI monotherapy or concurrent ICI-chemotherapy) • Baseline brain metastases are common in patients with KRAS G12C + NSCLC. • During (chemo)-ICI treatment, intracranial progression was more frequent in patients with baseline brain metastases. • Presence of known baseline brain metastases did not influence OS or PFS in patients treated with (chemo)-ICI. Few data is available on whether brain metastases (BM) influence survival in patients with stage IV KRAS G12C mutated (KRAS G12C+) non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI) +/- chemotherapy ([chemo]-ICI). Data was retrospectively collected from the population-based Netherlands Cancer Registry. The cumulative incidence of intracranial progression, overall survival (OS) and progression free survival (PFS) was determined for patients with KRAS G12C+ stage IV NSCLC diagnosed January 1 – June 30, 2019, treated with first-line (chemo)-ICI. OS and PFS were estimated using Kaplan-Meier methods and BM+ and BM− groups were compared using log-rank tests. Of 2489 patients with stage IV NSCLC, 153 patients had KRAS G12C+ and received first-line (chemo)-ICI. Of those patients, 35% (54/153) underwent brain imaging (CT and/or MRI), of which 85% (46/54) MRI. Half of the patients with brain imaging (56%; 30/54) had BM, concerning one-fifth (20%; 30/153) of all patients, of which 67% was symptomatic. Compared to BM−, patients with BM+ were younger and had more organs affected with metastasis. Around one-third (30%) of patients with BM+ had ≥5 BM at diagnosis. Three quarters of patients with BM+ received cranial radiotherapy prior to start of (chemo)-ICI. The 1-year cumulative incidence of intracranial progression was 33% for patients with known baseline BM and 7% for those without (p = 0.0001). Median PFS was 6.6 (95% CI 3.0–15.9) and 6.7 (95% CI 5.1–8.5) months for BM+ and BM− (p = 0.80), respectively. Median OS was 15.7 (95% CI 6.2–27.3) and 17.8 (95% CI 13.4–22.0) months for BM+ and BM− (p = 0.77), respectively. Baseline BM are common in patients with metastatic KRAS G12C+ NSCLC. During (chemo)-ICI treatment, intracranial progression was more frequent in patients with known baseline BM, justifying regular imaging during treatment. In our study, presence of known baseline BM did not influence OS or PFS. [ABSTRACT FROM AUTHOR]