BACKGROUND:Molecular testing in NSCLC is essential for treatment selection, yet routine implementation remains inconsistent across institutions. Clinical evidence suggests that variability in testing may not be explained by patient or tumor characteristics but might be driven by institutional factors, potentially leading to adverse outcomes. We examined the extent to which variability in AGA testing is attributable to the treating institution. METHODS:We analyzed 6437 adults with stage IIIB/C or IV NSCLC enrolled in the prospective German real-world registry CRISP (2016-2022). Logistic mixed-effects models with AGA testing as the primary outcome were used to determine institutional variability across 171 institutions. Models included patient, tumor, and treatment-related fixed effects with institutions as random effects. Intraclass correlations (ICC) quantified institutional variability unexplained by other covariates. Institution type was tested in secondary analysis, and overall survival in exploratory analysis. FINDINGS:AGA testing was performed in 77.9 % of patients (n = 5016). Predicted probabilities for testing use ranged from 30.5 % to 93.2 % across institutions. Institutions significantly influenced testing use (p < 0.001), accounting for 21.4 % of the total variance. Variability significantly differed by institution type and was more pronounced in subgroups, e.g., squamous histology (ICC 29.5 %) and KRAS testing (ICC 34.4 %). Absence of AGA testing was independently associated with inferior survival (HRadj 1.11, 95 % CI 1.01-1.23, p = 0.029). INTERPRETATION:Substantial institutional variability exists in AGA testing for NSCLC, which was unexplained by patient or tumor characteristics. This objective evaluation of institution-based variability in testing may emphasize the importance of practice patterns on patient care and may therefore provide an avenue for change.

Perioperative chemoimmunotherapy improves pathological complete response (pCR), EFS, and OS in patients with resectable NSCLC versus chemotherapy, as shown in several phase-III-trials. However, approximately 17-22% of patients did not proceed to surgery, partly due to toxicity, highlighting the need for more efficacious and tolerable regimens. NeoTRACE is a phase II, multicenter, single-arm study to evaluate neoadjuvant sacituzumab govitecan (SG) and the PD-1 inhibitor zimberelimab (ZIM) in resectable stage II to IIIB (N2) NSCLC with no known EGFR/ALK alterations. The trial plans to enroll 50 participants, with neoadjuvant treatment administered for four cycles before resection, followed by adjuvant ZIM with/without SG at the physicians' discretion. The primary endpoint is the rate of pCR in tumor and lymph nodes. Secondary endpoints include major pathological response, surgical resection rate, disease-free survival, OS, safety, and quality of life. The study also explores circulating tumor DNA (ctDNA) dynamics, TROP2 expression, and spatial transcriptomics to identify biomarkers. NeoTRACE assesses a platinum-sparing approach in resectable NSCLC. Previous studies showed ADC and immunotherapy combinations are effective in advanced NSCLC, suggesting potential perioperative benefit. This study aims to improve pCR rate, reduce toxicity, enhance surgical eligibility, and personalize adjuvant treatment to improve long-term outcomes.Clinical Trial Registration: EudraCT: 2024-517561-16.

TPS8120 Background: Phase III trials, including KEYNOTE-671, have established combined neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy (IO) as the standard of care for resectable NSCLC. However, a notable challenge in KEYNOTE-671 and similar studies was that ~17-22% of patients did not proceed to surgery following neoadjuvant chemoimmunotherapy, highlighting the need for more tolerable regimens. Recent data from studies such as NEOpredict (which demonstrated a 100% surgical completion rate with neoadjuvant nivolumab with/without relatlimab), NeoCOAST-2 (which reported a 34% pathological complete response [pCR] rate using a neoadjuvant combination of an anti-TROP2 antibody drug conjugate [ADC], IO, and single-agent platinum, thereby surpassing the ~20% pCR rates achieved with neoadjuvant chemoimmunotherapy), and EVOKE-02 (which showed promising objective response rates of 69% and 44% with the anti-TROP2 ADC sacituzumab govitecan plus pembrolizumab in first-line metastatic NSCLC patients with PD-L1 ≥50% and PD-L1 0-49%, respectively) demonstrate that chemotherapy-sparing approaches may reduce toxicity while maintaining or enhancing efficacy. These findings highlight the potential synergistic effect of ADC plus IO, suggesting this strategy may also be an effective treatment option in the perioperative setting with potentially lower toxicity compared to chemoimmunotherapy. Additionally, long-term adverse events associated with platinum-based chemotherapy, such as neuropathy, may be lower or avoided altogether. This study aims to improve the pCR rate, reduce toxicity, enhance surgical eligibility, and personalize adjuvant treatment. Methods: NeoTRACE is a phase II, multicenter, open-label, single-arm study evaluating the neoadjuvant combination of sacituzumab govitecan (SG) and the PD-1 inhibitor zimberelimab (ZIM) in patients with resectable stage II to IIIB (N2) NSCLC with no known EGFR or ALK alterations. Patients will receive neoadjuvant SG 10 mg/kg IV on days 1 and 8, and ZIM 360 mg IV on day 1, every 3 weeks for 4 cycles, followed by definitive surgery as per local standards. In the adjuvant phase, patients will either continue adjuvant SG plus ZIM for up to 4 cycles, followed by ZIM only for a total of up to 13 cycles, or receive adjuvant ZIM monotherapy (as per physicians’ choice). The primary endpoint is the rate of pCR in tumor and lymph nodes. Secondary endpoints include major pathological response, surgical resection rate, time to surgery, DFS, OS, safety, and quality of life. The study also explores circulating tumor DNA dynamics, TROP2 expression, and spatial transcriptomics and proteomics to identify potential biomarkers. As of June 2025, the NeoTRACE study is recruiting 50 patients across 15 sites in Germany. EudraCT: 2024-517561-16. Clinical trial information: 2024-517561-16 (EudraCT) .

Background In patients with unresectable, stage III non-small cell lung cancer (NSCLC), durvalumab maintenance after concurrent chemoradiotherapy (cCRT) was shown to improve survival over placebo. As subgroup analyses indicated better outcomes with earlier start of durvalumab, several trials evaluated concomitant checkpoint inhibition (CPI) with cCRT. However, this may introduce an increased risk of treatment-related pulmonary toxicity. Methods We conducted a systematic review and meta-analysis of clinical trials of combined cCRT plus CPI followed by CPI maintenance in patients with stage III NSCLC. Endpoints included incidence of pneumonitis by any cause, objective response rate (ORR), progression-free (PFS), and overall survival (OS). Results A total of 7 trials comprising 653 patients were included. In trials of single-agent CPI with cCRT, pneumonitis occurred in 33% of patients (95% confidence interval [CI], 28-39) with 7% (5-9) having CTCAE grade 3-5. In one trial, double CPI (PD-1 and CTLA4) plus cCRT was associated with excessive pneumonitis-related mortality of 16% (4-40). Across all trials, ORR was 69% (63-76). Median PFS and OS were 16.3 (95% CI, 14.0-20.5) and 39.5 months (35.3-45.9), respectively. Three-year PFS and OS were 36.8% (95% CI, 32.7-41.4) and 53.1% (49.1-57.4). Sensitivity analysis showed that induction chemoimmunotherapy prior cCRT plus CPI was associated with improved PFS of 48.0% at 3 years (95% CI, 40.7-56.7) in one trial. Discussion Addition of single-agent CPI to cCRT is manageable in selected patients with stage III NSCLC. Efficacy outcomes appear to be in line with previous data of cCRT followed by CPI maintenance.

Purpose: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification. Methods: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] >= 2) or polysomy (gene copy number >= 5, MET-CEP7 < 2). Results: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54). Conclusion: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response.

PURPOSE:To evaluate whether intraoperative ventilation using lower driving pressure decreases the risk of nonhome discharge.METHODS:We conducted a historical cohort study of patients aged ≥ 60 yr who were living at home before undergoing elective, noncardiothoracic surgery at two tertiary healthcare networks in Massachusetts between 2007 and 2018. We assessed the association of the median driving pressure during intraoperative mechanical ventilation with nonhome discharge using multivariable logistic regression analysis, adjusted for patient and procedural factors. Contingent on the primary association, we assessed effect modification by patients' baseline risk and mediation by postoperative respiratory failure.RESULTS:Of 87,407 included patients, 12,584 (14.4%) experienced nonhome discharge. In adjusted analyses, a lower driving pressure was associated with a lower risk of nonhome discharge (adjusted odds ratio [aOR], 0.88; 95% confidence interval [CI], 0.83 to 0.93, per 10 cm H2O decrease; P < 0.001). This association was magnified in patients with a high baseline risk (aOR, 0.77; 95% CI, 0.73 to 0.81, per 10 cm H2O decrease, P-for-interaction < 0.001). The findings were confirmed in 19,518 patients matched for their baseline respiratory system compliance (aOR, 0.90; 95% CI, 0.81 to 1.00; P = 0.04 for low [< 15 cm H2O] vs high [≥ 15 cm H2O] driving pressures). A lower risk of respiratory failure mediated the association of a low driving pressure with nonhome discharge (20.8%; 95% CI, 15.0 to 56.8; P < 0.001).CONCLUSIONS:Intraoperative ventilation maintaining lower driving pressure was associated with a lower risk of nonhome discharge, which can be partially explained by lowered rates of postoperative respiratory failure. Future randomized controlled trials should target driving pressure as a potential intervention to decrease nonhome discharge.

RATIONALE AND OBJECTIVES:To investigate the diagnostic value of radiomics features and dual-source dual-energy CT (DECT) based material decomposition in differentiating low-risk thymomas, high-risk thymomas, and thymic carcinomas. MATERIALS AND METHODS:This retrospective study included 32 patients (16 males, mean age 66 ± 14 years) with pathologically confirmed thymic masses who underwent contrast-enhanced DECT between 10/2014 and 01/2023. Two experienced readers evaluated all patients regarding conventional radiomics features, as well as DECT-based features, including attenuation (HU), iodine density (mg/mL), and fat fraction (%). Data comparisons were performed using analysis of variance and chi-square statistic tests. Receiver operating characteristic curve analysis and Cox-regression tests were used to discriminate between low-risk/high-risk thymomas and thymic carcinomas. RESULTS:Of the 32 thymic tumors, 12 (38%) were low-risk thymomas, 11 (34%) were high-risk thymomas, and 9 (28%) were thymic carcinomas. Values differed significantly between low-risk thymoma, high-risk thymoma, and thymic carcinoma regarding DECT-based features (p ≤ 0.023) and 30 radiomics features (p ≤ 0.037). The area under the curve to differentiate between low-risk/high-risk thymomas and thymic cancer was 0.998 (95% CI, 0.915-1.000; p < 0.001) for the combination of DECT imaging parameters and radiomics features, yielding a sensitivity of 100% and specificity of 96%. During a follow-up of 60 months (IQR, 35-60 months), the multiparametric approach including radiomics features, DECT parameters, and clinical parameters showed an excellent prognostic power to predict all-cause mortality (c-index = 0.978 [95% CI, 0.958-0.998], p = 0.003). CONCLUSION:A multiparametric approach including conventional radiomics features and DECT-based features facilitates accurate, non-invasive discrimination between low-risk/high-risk thymomas and thymic carcinomas.

To evaluate whether intraoperative ventilation using lower driving pressure decreases the risk of nonhome discharge.We conducted a historical cohort study of patients aged ≥ 60 yr who were living at home before undergoing elective, noncardiothoracic surgery at two tertiary healthcare networks in Massachusetts between 2007 and 2018. We assessed the association of the median driving pressure during intraoperative mechanical ventilation with nonhome discharge using multivariable logistic regression analysis, adjusted for patient and procedural factors. Contingent on the primary association, we assessed effect modification by patients' baseline risk and mediation by postoperative respiratory failure.Of 87,407 included patients, 12,584 (14.4%) experienced nonhome discharge. In adjusted analyses, a lower driving pressure was associated with a lower risk of nonhome discharge (adjusted odds ratio [aOR], 0.88; 95% confidence interval [CI], 0.83 to 0.93, per 10 cm H2O decrease; P < 0.001). This association was magnified in patients with a high baseline risk (aOR, 0.77; 95% CI, 0.73 to 0.81, per 10 cm H2O decrease, P-for-interaction < 0.001). The findings were confirmed in 19,518 patients matched for their baseline respiratory system compliance (aOR, 0.90; 95% CI, 0.81 to 1.00; P = 0.04 for low [< 15 cm H2O] vs high [≥ 15 cm H2O] driving pressures). A lower risk of respiratory failure mediated the association of a low driving pressure with nonhome discharge (20.8%; 95% CI, 15.0 to 56.8; P < 0.001).Intraoperative ventilation maintaining lower driving pressure was associated with a lower risk of nonhome discharge, which can be partially explained by lowered rates of postoperative respiratory failure. Future randomized controlled trials should target driving pressure as a potential intervention to decrease nonhome discharge.RéSUMé: OBJECTIF: Évaluer si la ventilation peropératoire utilisant une pression motrice plus faible diminue le risque de congé hors domicile. MéTHODE: Nous avons réalisé une étude de cohorte historique de patients âgés de ≥ 60 ans vivant à la maison avant de bénéficier d’une chirurgie non cardiothoracique non urgente dans deux réseaux de soins de santé tertiaires du Massachusetts entre 2007 et 2018. Nous avons évalué l’association entre la pression motrice médiane pendant la ventilation mécanique peropératoire et le congé ailleurs qu’au domicile à l’aide d’une analyse de régression logistique multivariable, ajustée pour tenir compte des facteurs liés aux patients et à l’intervention. En fonction de l’association primaire, nous avons évalué la modification de l’effet par le risque initial des patients et la médiation par l’insuffisance respiratoire postopératoire. RéSULTATS: Sur les 87 407 patients inclus, 12 584 (14,4 %) ont reçu leur congé ailleurs qu’au domicile. Dans les analyses ajustées, une pression motrice plus faible était associée à un risque réduit de congé hors domicile (rapport de cotes ajusté [RCa], 0,88; intervalle de confiance [IC] à 95 %, 0,83 à 0,93, par diminution de 10 cm H2O; P < 0,001). Cette association a été amplifiée chez les patients présentant un risque initial élevé (RCa, 0,77; IC 95 %, 0,73 à 0,81, par diminution de 10 cm H2O, P-pour-interaction < 0,001). Les résultats ont été confirmés chez 19 518 patients appariés pour la compliance initiale de leur système respiratoire (RCa, 0,90; IC 95 %, 0,81 à 1,00; P = 0,04 pour des pressions motrices faibles [< 15 cm H2O] vs élevées [≥ 15 cm H2O]). Un risque plus faible d’insuffisance respiratoire a entraîné une association entre une faible pression motrice et un congé à l’extérieur du domicile (20,8 %; IC 95 %, 15,0 à 56,8 ; P < 0,001). CONCLUSION: La ventilation peropératoire maintenant une pression motrice plus faible a été associée à un risque plus faible de congé hors domicile, ce qui peut s’expliquer en partie par des taux réduits d’insuffisance respiratoire postopératoire. Les futures études randomisées contrôlées devraient cibler la pression motrice comme intervention potentielle pour réduire les congés hors domicile.

Approximately 10% to 25% of patients with stage IV NSCLC present with brain metastases (BMs) at disease onset which can severely affect quality of life and cause morbidity.1Waqar S.N. Samson P.P. Robinson C.G. et al.Non-small-cell lung cancer with brain metastasis at presentation.Clin Lung Cancer. 2018; 19: e373-e379Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Local treatment options for BM include neurosurgical resection, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS).2Vogelbaum M.A. Brown P.D. Messersmith H. et al.Treatment for brain metastases: ASCO-SNO-ASTRO guideline.J Clin Oncol. 2022; 40: 492-516Crossref PubMed Scopus (189) Google Scholar Compared with SRS, WBRT results in improved local and distant intracerebral disease control, but even with modern techniques such as hippocampal avoidance and co-administration of memantine,3Brown P.D. Gondi V. Pugh S. et al.Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: phase III trial NRG oncology CC001.J Clin Oncol. 2020; 38: 1019-1029Crossref PubMed Scopus (429) Google Scholar it is still associated with worsening quality of life and neurocognitive function and loss of functional independence.2Vogelbaum M.A. Brown P.D. Messersmith H. et al.Treatment for brain metastases: ASCO-SNO-ASTRO guideline.J Clin Oncol. 2022; 40: 492-516Crossref PubMed Scopus (189) Google Scholar Long-term neurotoxicity is an evolving issue in the era of precision medicine with a relevant proportion of patients living longer than five years even in a metastatic setting. A small retrospective study in patients who received a median WBRT dose of 30 Gy found symptoms of late radiation toxic in 49% of patients after 2 years and 83% after 5 years.4Nieder C. Leicht A. Motaref B. Nestle U. Niewald M. Schnabel K. Late radiation toxicity after whole-brain radiotherapy: the influence of antiepileptic drugs.Am J Clin Oncol. 1999; 22: 573Crossref PubMed Scopus (63) Google Scholar Nevertheless, not all patients are suitable for SRS. The ASCO-SNO-ASTRO guidelines recommend SRS in case of one BM to four BMs because patients with a higher number of central nervous system (CNS) lesions were excluded from clinical trials investigating SRS.2Vogelbaum M.A. Brown P.D. Messersmith H. et al.Treatment for brain metastases: ASCO-SNO-ASTRO guideline.J Clin Oncol. 2022; 40: 492-516Crossref PubMed Scopus (189) Google Scholar In contrast, according to the EANO ESMO guidelines, SRS is a considerable option for up to 10 CNS lesions.5Rhun E.L. Guckenberger M. Smits M. et al.EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours☆.Ann Oncol. 2021; 32: 1332-1347Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar In addition to the number of BM, the choice of radiation modality should be based on the patient's performance status, size and location of BM, and the availability of close follow-up with brain imaging. Of course, local treatment should be followed or accompanied by optimal systemic treatment depending on the presence or absence of targetable molecular alterations. In this issue, Hou et al. report on results of a trial that investigated a different approach omitting any local treatment of BM.6Hou X. Zhou C. Wu G. et al.Efficacy, safety, and health-related quality of life with camrelizumab plus pemetrexed and carboplatin as first-line treatment for advanced nonsquamous non-small-cell lung cancer with brain metastases (CAP-BRAIN): a multicentre, open-label, single-arm, phase 2 study.J Thorac Oncol. 2023; 18: 769-779Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar CAP-BRAIN is a national, multicenter, single-arm phase 2 trial evaluating the efficacy of the programmed cell death protein-1 inhibitor camrelizumab in combination with carboplatin and pemetrexed in a Chinese patient population looking at the intracranial response rate. Patients newly diagnosed with having advanced nonsquamous NSCLC with BM were eligible if they had not received prior local treatment and BM was either asymptomatic or controlled with the use of either dexamethason or additional mannitol. Of note, 13 of 45 enrolled patients belonged to the latter group of patients with initially symptomatic but controlled BM. In the intention-to-treat population, the intracranial objective response rate (ORR) was 46.7% (95% confidence interval [CI]: 31.7–62.1) with an intracranial disease control rate of 77.8% (62.9–88.8). Median intracranial progression-free survival (PFS) was 7.6 months (4.6–not reached) with a 1-year intracranial PFS of 41.9% (23.0–60.9). Median overall survival (OS) was 21.0 months (15.9–not reached) with 71.2% (56.6–85.8) of patients alive after 1 year. How can the results of CAP-BRAIN be put into perspective? In nononcogene-addicted NSCLC, there is limited evidence on the intracerebral efficacy of first-line immune checkpoint inhibitor (ICI)–based therapies as most trials included only patients with asymptomatic or treated BM. Nevertheless, the efficacy of ICI with or without chemotherapy seems similar in the CNS and other compartments as indicated by subgroup analyses from pivotal trials7Powell S.F. Rodríguez-Abreu D. Langer C.J. et al.Outcomes with pembrolizumab plus platinum-based chemotherapy for patients with NSCLC and stable brain metastases: pooled analysis of KEYNOTE-021, -189, and -407.J Thorac Oncol. 2021; 16: 1883-1892Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 8Mansfield A.S. Herbst R.S. de Castro G. et al.Outcomes with pembrolizumab monotherapy in patients with programmed death-ligand 1-positive NSCLC with brain metastases: pooled analysis of KEYNOTE-001, 010, 024, and 042.JTO Clin Res Rep. 2021; 2100205PubMed Google Scholar, 9Paz-Ares L.G. Ciuleanu T.E. Cobo M. et al.First-line nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone for metastatic NSCLC in CheckMate 9LA: 3-year clinical update and outcomes in patients with brain metastases or select somatic mutations.J Thorac Oncol. 2023; 18: 204-222Abstract Full Text Full Text PDF Scopus (20) Google Scholar and real-world data.10Crinò L. Bronte G. Bidoli P. et al.Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer.Lung Cancer. 2019; 129: 35-40Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar,11Hendriks L.E.L. Henon C. Auclin E. et al.Outcome of patients with non–small cell lung cancer and brain metastases treated with checkpoint inhibitors.J Thorac Oncol. 2019; 14: 1244-1254Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar Regarding systemic responses and survival, results of CAP-BRAIN align with previous data on ICI and platinum doublet combinations.7Powell S.F. Rodríguez-Abreu D. Langer C.J. et al.Outcomes with pembrolizumab plus platinum-based chemotherapy for patients with NSCLC and stable brain metastases: pooled analysis of KEYNOTE-021, -189, and -407.J Thorac Oncol. 2021; 16: 1883-1892Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar But how about the intracranial efficacy? In ATEZO-BRAIN (NCT03526900), another multicenter, single-arm, phase 2 trial, patients with previously untreated nonsquamous NSCLC with BM (no prior SRS or WBRT, maximum daily dexamethasone dose of 4 mg) received atezolizumab in combination with carboplatin and pemetrexed.12Nadal E. Rodriguez-Abreu D. Massuti B. et al.Updated analysis from the ATEZO-BRAIN trial: atezolizumab plus carboplatin and pemetrexed in patients with advanced nonsquamous non–small cell lung cancer with untreated brain metastases.J Clin Oncol. 2022; 40 (9010–9010)PubMed Google Scholar Here, 16 of 40 patients (40%) had confirmed CNS response on the basis of RANO-BM criteria. Median intracranial PFS was 6.9 months (95% CI: 4.7–11.9). Goldberg et al.13Goldberg S.B. Schalper K.A. Gettinger S.N. et al.Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.Lancet Oncol. 2020; 21: 655-663Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar published a single-center phase 2 trial (NCT02085070) of pembrolizumab monotherapy in patients with or without previous systemic treatment but naive to programmed cell death protein-1 and programmed death-ligand 1 (PD-L1) inhibitors. Intracranial response to single-agent ICI was lower with 11 of 37 (29.7%, 95% CI: 15.9%–47.0%) PD-L1–positive patients having a confirmed CR or PR according to modified Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Furthermore, 50% of the patients had received prior local treatment (SRS 38%, WBRT 19%, resection 10%). Similarly, among patients with melanoma with untreated BM who received single-agent ICI, intracranial response rates were overall moderate ranging from 20% to 26%.14Kluger H.M. Chiang V. Mahajan A. et al.Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a phase II trial.J Clin Oncol. 2019; 37: 52-60Crossref PubMed Scopus (181) Google Scholar,15Long G.V. Atkinson V. Lo S. et al.Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study.Lancet Oncol. 2018; 19: 672-681Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar Subsequent studies have found higher rates of durable responses with a double ICI combination of nivolumab plus ipilimumab particularly in patients with asymptomatic BM. The recent phase 2 CheckMate 204 trial evaluated the intracranial efficacy of nivolumab plus ipilimumab (four cycles followed by nivolumab maintenance) in patients with either asymptomatic BM (cohort A) or stable symptoms with or without low-dose dexamethasone (cohort B).16Tawbi H.A. Forsyth P.A. Hodi F.S. et al.Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.Lancet Oncol. 2021; 22: 1692-1704Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar At least one BM had to remain unirradiated for response assessment, whereas SRS or excision of up to three lesions was permitted. Intracranial ORR was high with 53.5% (95% CI: 47.2–67.2) for cohort A and moderate with 16.7% (3.6–41.4) for cohort B. Intracranial PFS at 36 months was 52.5% (95% CI: 41.4–62.4) and 18.9% (4.6–40.5), respectively. Consistent results were reported in an Australian phase 2 study and a small phase 3 study.15Long G.V. Atkinson V. Lo S. et al.Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study.Lancet Oncol. 2018; 19: 672-681Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar,17Di Giacomo A.M. Chiarion-Sileni V. Del Vecchio M. et al.Primary analysis and 4-year follow-up of the phase III NIBIT-M2 trial in melanoma patients with brain metastases.Clin Cancer Res. 2021; 27: 4737-4745Crossref PubMed Scopus (26) Google Scholar On the basis of these data, nivolumab plus ipilimumab is considered standard of care among eligible patients with asymptomatic melanoma BM. Treatment of symptomatic BM remains challenging with worse response, early progression, and no data on high-risk patients presenting with unstable symptoms, having recent seizures, or receiving higher steroid doses. The CAP-BRAIN results are interesting, and we thank the authors for providing important data on this relevant patient population, which is continuously underrepresented in clinical trials. Nevertheless, evidence is too little to allow definite conclusions regarding the current standard of care to treat every BM locally. Indeed, it is a relevant question as to whether radiotherapy (RT) (especially WBRT) can be initially omitted in certain patient populations to reduce the associated risk of neurocognitive deterioration, while still maintaining local tumor control. This is particularly important when considering that SRS, a radiation technique that, unlike WBRT, can spare tissue neighboring the targeted BM, is still not accessible in many regions of the world.18Pannullo S.C. Julie D.A.R. Chidambaram S. et al.Worldwide access to stereotactic radiosurgery.World Neurosurg. 2019; 130: 608-614Crossref PubMed Scopus (11) Google Scholar Even across high-income countries, there are fundamental disparities in access to modern radiation technologies.19Ascha M.S. Funk K. Sloan A.E. Kruchko C. Barnholtz-Sloan J.S. Disparities in the use of stereotactic radiosurgery for the treatment of lung cancer brain metastases: a SEER-Medicare study.Clin Exp Metastasis. 2020; 37: 85-93Crossref PubMed Scopus (7) Google Scholar Moreover, the attempt to reduce treatment-related neurologic impairment is becoming more relevant because with ICI more patients achieve long-term survival than ever before. For instance, in the KEYNOTE-024 trial, the 5-year OS of first-line pembrolizumab monotherapy in patients with PD-L1 greater than or equal to 50% was 31.9% versus 16.3% with chemotherapy.20Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50.J Clin Oncol. 2021; 39: 2339-2349Crossref PubMed Scopus (389) Google Scholar In patients with nonsquamous (KEYNOTE-189) and squamous (KEYNOTE-407) NSCLC and PD-L1 greater than or equal to 50%, 5-year OS rates with pembrolizumab combined with a platinum doublet were 29.6% and 23.3%, respectively.21Garassino M.C. Gadgeel S.M. Speranza G. et al.973MO KEYNOTE-189 5-year update: first-line pembrolizumab (pembro) + pemetrexed (pem) and platinum vs placebo (pbo) + pem and platinum for metastatic nonsquamous NSCLC.Ann Oncol. 2022; 33: S992-S993Abstract Full Text Full Text PDF PubMed Google Scholar,22Novello S. Kowalski D.M. Luft A. et al.Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study.J Clin Oncol. 2023; 41: 1999-2006https://doi.org/10.1200/JCO.22.01990Crossref PubMed Scopus (40) Google Scholar For these patients, advanced NSCLC starts to resemble more of a chronic disease, where long-term side effects of brain radiation that occur from several months to years after treatment are more significant. Withholding upfront brain radiation has already been achieved as common practice in patients with targetable molecular alterations, such as ALK fusions. The second- and third-generation ALK inhibitors alectinib, brigatinib, and lorlatinib confer excellent intracerebral activity allowing for local treatment to be omitted if close monitoring of lesions is possible.2Vogelbaum M.A. Brown P.D. Messersmith H. et al.Treatment for brain metastases: ASCO-SNO-ASTRO guideline.J Clin Oncol. 2022; 40: 492-516Crossref PubMed Scopus (189) Google Scholar In the respective first-line phase 3 trials (NCT02737501, NCT02075840, NCT03052608), intracranial ORR ranged between 59% and 67% in patients with asymptomatic or controlled BM (78% and 82% in patients with measurable BM).23Camidge D.R. Kim H.R. Ahn M.J. et al.Brigatinib versus crizotinib in ALK-positive non–small-cell lung cancer.N Engl J Med. 2018; 379: 2027-2039Crossref PubMed Scopus (648) Google Scholar, 24Shaw A.T. Bauer T.M. de Marinis F. et al.First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer.N Engl J Med. 2020; 383: 2018-2029Crossref PubMed Scopus (506) Google Scholar, 25Peters S. Camidge D.R. Shaw A.T. et al.Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer.N Engl J Med. 2017; 377: 829-838Crossref PubMed Scopus (1702) Google Scholar Considering the higher incidence of BMs among patients with ALK-positive NSCLC, these studies have been practice changing for many cases. Albeit intracranial efficacy of immunochemotherapy combinations in the current CAP-BRAIN trial or the ATEZO-BRAIN trial was not as good as with the targeted therapies mentioned previously, it may be good enough for initially postponing RT with close follow-up and salvaging CNS involvement in cases of treatment failure. Of course, this approach should be limited to cases with asymptomatic metastases (with or without the use of corticosteroids) and without imminent threat of severe neurologic deterioration. In the pre-ICI era, a randomized phase 3 trial has found that this was possible with chemotherapy alone.26Lim S.H. Lee J.Y. Lee M.Y. et al.A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer.Ann Oncol. 2015; 26: 762-768Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar In CAP-BRAIN, only eight of 45 patients (18%) received subsequent brain RT at data cutoff. Several trials further investigating RT-free approaches are already underway (Table 1), and it will be relevant to identify patient populations where withholding upfront radiation to the brain is feasible. From the CAP-BRAIN data, patients with a high PD-L1 expression of greater than or equal to 50% and asymptomatic BM at baseline (ORR 80% and 54%, respectively) seemed to derive the most benefit. Therefore, the hypothesis that these patients can be safely treated without local therapy deserves being further evaluated in an international randomized controlled trial. In contrast, treatment of PD-L1–negative, symptomatic patients should definitely include early local therapy.Table 1Nonexhaustive List of Ongoing Trials Investigating on ICI-Based Therapies in NSCLC With Locally Untreated Brain Metastases Not Qualifying for Targeted TherapiesName/IdentifierPatient PopulationPlanned Number of ParticipantsStudy DesignNIke, LOGiK200427Tsuchiya-Kawano Y. Shiraishi Y. Kiyomi F. Okamoto I. Phase II study of nivolumab plus ipilimumab with platinum-based chemotherapy for treatment-naïve advanced non-small cell lung cancer with untreated brain metastases: Nike trial (LOGiK2004).Cancer Manag Res. 2021; 13: 8489-8493Crossref PubMed Scopus (3) Google ScholarStage IV or recurrent chemotherapy-naive NSCLC with untreated symptomatic or asymptomatic BM30Single-arm phase 2Nivolumab + ipilimumab + platinum-based chemotherapy (2 cycles) followed by nivolumab + ipilimumab maintenanceNIVIPI-BRAINNCT05012254Cohort A: previously untreated stage IV NSCLC with untreated asymptomatic BMCohort B: previously untreated stage IV NSCLC with at least one untreated symptomatic BM controlled with corticosteroids71Single-arm phase 2Nivolumab + ipilimumab + platinum-based chemotherapy (2 cycles) followed by nivolumab + ipilimumab maintenanceNCT02681549Metastatic NSCLC or melanoma with at least one untreated BM53Single-arm phase 2Pembrolizumab + bevacizumabNCT04967417Previously untreated stage IV NSCLC with untreated BM50Single-arm phase 2Pembrolizumab + platinum-based chemotherapy (4 cycles) followed by pembrolizumab maintenanceNCT05207904Previously untreated stage IV NSCLC with asymptomatic BM with or without dehydration therapy41Single-arm phase 2Tislelizumab + carboplatin + paclitaxel (4–6 cycles) followed by tislelizumab maintenanceBM, brain metastases; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; PS, performance status. Open table in a new tab BM, brain metastases; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; PS, performance status. Fabian Acker, Friederike C. Althoff, Martin Sebastian: Writing—reviewing and editing.

IntroductionSmall cell lung cancer (SCLC) is a rapidly growing malignancy with early distant metastases. Up to 70% will develop brain metastases, and the poor prognosis of these patients has not changed considerably. The potential of checkpoint inhibitors (CPI) in treating recurrent (r/r) SCLC and their effect on brain metastases remain unclear.MethodsIn this retrospective multicenter study, we analyzed r/r SCLC patients receiving second or further-line CPI versus chemotherapy between 2010 and 2020. We applied multivariable-adjusted Cox regression analysis to test for differences in 1-year mortality and real-world progression. We then used interaction analysis to evaluate whether brain metastases (BM) and/or cranial radiotherapy (CRT) modified the effect of CPI versus chemotherapy on overall survival.ResultsAmong 285 patients, 99 (35%) received CPI and 186 (65%) patients received chemotherapy. Most patients (93%) in the CPI group received nivolumab/ipilimumab. Chemotherapy patients were entirely CPI-naïve and only one CPI patient had received atezolizumab for first-line treatment. CPI was associated with a lower risk of 1-year mortality (adjusted Hazard Ratio [HRadj] 0.59, 95% CI 0.42 to 0.82, p=0.002). This benefit was modified by BM and CRT, indicating a pronounced effect in patients without BM (with CRT: HRadj 0.34, p=0.003; no CRT: HRadj 0.50, p=0.05), while there was no effect in patients with BM who received CRT (HRadj 0.85, p=0.59).ConclusionCPI was associated with a lower risk of 1-year mortality compared to chemotherapy. However, the effect on OS was significantly modified by intracranial disease and radiotherapy, suggesting the benefit was driven by patients without BM.

The European Society for Medical Oncology (ESMO) annual meeting took place in Paris in September 2022. The conference added a number of relevant study updates and novel treatment concepts. We report on highlights in the field of thoracic oncology. The topics cover oncogene-driven and immunotherapy-based therapeutic concepts in metastatic and non-metastatic NSCLC.

TPS9157 Background: Epidermal growth factor receptor (EGFR) – mutated non-small cell lung cancer (NSCLC) is susceptible to EGFR targeting tyrosine kinase inhibitors (TKI), such as the third generation TKI osimertinib. However, response rate and duration vary between patients. Among others, the specific subtype of EGFR-mutation, its co-occurrence with other genetic alterations, and the detection of phosphorylated EGFR (pEGFR) in the plasma, and its clearance upon treatment were previously identified as markers that predict therapy response. A high proportion of patients with early (3-6 weeks after start) pEGFR clearance from plasma show impressive survival upon single-agent TKI. However, failure to achieve early clearance upon Osimertinib is associated with unfavorable outcome. For these patients, treatment concepts are lacking. Here, we report about the initiation of a clinical trial that evaluates the combination of EGFR-directed TKI and platinum-based chemotherapy as an early treatment escalation strategy for this high-risk patient population. Methods: PACE is a prospective multicenter single-arm investigator-initiated phase II trial. Patients with NSCLC harboring L858R or del19 EGFR mutation, who are treated with first-line Osimertinib are subjected to liquid biopsy-based early response assessment three weeks after start of therapy. Failure to clear pEGFR from plasma at this time point triggers treatment escalation with the addition of platinum-based doublet chemotherapy to the Osimertinib treatment. The primary outcome measure of the trial is progression-free survival (PFS), with the objective to assess the efficacy of biomarker-driven escalation of osimertinib therapy with a combination platinum-based regimen. Secondary outcome measures are the overall response rate (ORR), overall survival (OS), and the Quality of life (QLQ-C30, CTCAE-PROs) of the treated patients. In exploratory analyses, we will assess whether specific patterns of co-mutations are associated with early treatment failure (upon TKI) and pEGFR persistence. Fig. 1 illustrates the trial concept. A sample of 46 subjects achieves 80% power at a 0.05 significance level to detect a PFS of 14.4 months in the experimental treatment group when the PFS of the historic control group is 9.1 months; a total of 400 patients need to be screened within the national Network Genomic Medicine. Enrollment started in 12/2021. The clinical trial is supported by AstraZeneca and Guardant. EudraCT registration number: 2019-004757-88 .

Purpose: To assess the potential of material decomposition in dual-energy CT (DECT) to differentiate intrahepatic cholangiocarcinoma (iCCA) from hepatocellular carcinoma (HCC). Method: In this retrospective study, we included 94 patients (26 female (27.7 %), median age 64.5 (interquartile range 55.5-74.5) years) with either iCCA or HCC who underwent abdominal contrast-enhanced DECT in arterial phase. To test for differences between iCCA (n = 47) and HCC (n = 47), we evaluated mean attenuation and DECT material density values including iodine density (ID), normalized iodine uptake (NIU), fat fraction, and lesion-to-liver parenchyma ratio. Histopathology served as reference standard for all lesions. We used univariate logistic regression models for the outcome iCCA versus HCC. ROC curve analysis was applied to assess discriminative ability of the model. Model accuracy was evaluated by calculating the Brier score. Youden index was applied to establish thresholds to differentiate between iCCA and HCC. Results: Comparison of quantitative image parameters revealed significant differences between iCCA and HCC for ID (1.6 +/- 0.5 mg/ml vs 2.8 +/- 0.8 mg/ml, p < 0.001), NIU (14.5 +/- 4.8 vs 24.8 +/- 10.3, p < 0.001), attenuation (41.9 +/- 10.1 HU vs 47.9 +/- 8.9 HU, p = 0.003), and fat fraction (12.0 +/- 7.8 % vs 9.0 +/- 6.4 %, p = 0.045). ROC curve analysis revealed highest ability to differentiate iCCA from HCC for ID (AUC = 0.93, 95 % CI 0.89-0.98). For ID, an optimal threshold of 2.33 mg/dl was determined to discriminate between iCCA and HCC (sensitivity 89.4 %, specificity 76.6 %). Conclusions: DECT-based iodine quantification can serve as a tool for the differentiation of iCCA and HCC in contrast-enhanced CT. ID yielded the highest diagnostic performance and may assist in clinical routine CT diagnostics.

ObjectiveTo assess variability in the intraoperative use of non-depolarising neuromuscular blocking agents (NMBAs) across individual anaesthesia providers, surgeons and hospitals.DesignRetrospective observational cohort study.SettingTwo major tertiary referral centres, Boston, Massachusetts, USA.Participants265537 adult participants undergoing non-cardiac surgery between October 2005 and September 2017.Main outcome measuresWe analysed the variances in NMBA use across 958 anaesthesia and 623 surgical providers, across anaesthesia provider types (anaesthesia residents, certified registered nurse anaesthetists, attendings) and across hospitals using multivariable-adjusted mixed effects logistic regression. Intraclass correlations (ICC) were calculated to further quantify the variability in NMBA use that was unexplained by other covariates. Procedure-specific subgroup analyses were performed.ResultsNMBAs were used in 183242 (69%) surgical cases. Variances in NMBA use were significantly higher among individual surgeons than among anaesthesia providers (variance 1.32 (95% CI 1.06 to 1.60) vs 0.24 (95% CI 0.19 to 0.28), p<0.001). Procedure-specific subgroup analysis of hernia repairs, spine surgeries and mastectomies confirmed our findings: the total variance in NMBA use that was unexplained by the covariate model was higher for surgeons versus anaesthesia providers (ICC 37.0% vs 13.0%, 69.7% vs 25.5%, 69.8% vs 19.5%, respectively; p<0.001). Variances in NMBA use were also partially explained by the anaesthesia provider's hospital network (Massachusetts General Hospital: variance 0.35 (95% CI 0.27 to 0.43) vs Beth Israel Deaconess Medical Center: 0.15 (95% CI 0.12 to 0.19); p<0.001). Across provider types, surgeons showed the highest variance, and anaesthesia residents showed the lowest variance in NMBA use.ConclusionsThere is wide variability across individual surgeons and anaesthesia providers and institutions in the use of NMBAs, which could not sufficiently be explained by a large number of patient-related and procedure-related characteristics, but may instead be driven by preference. Surgeons may have a stronger influence on a key aspect of anaesthesia management than anticipated.

BACKGROUND:We tested the primary hypothesis that use of general anaesthesia vs sedation increases vulnerability to adverse discharge (in-hospital mortality or new discharge to a nursing facility) after endoscopic retrograde cholangiopancreatography (ERCP).METHODS:In this retrospective cohort study, adult patients undergoing ERCP with general anaesthesia or sedation at a tertiary care hospital were included. We calculated adjusted absolute risk differences between patients receiving general anaesthesia vs sedation using provider preference-based instrumental variable analysis. We also used mediation analysis to determine whether intraoperative hypotension during general anaesthesia mediated its effect on adverse discharge.RESULTS:Among 17 538 patients undergoing ERCP from 2007 through 2018, 16 238 received sedation and 1300 received GA. Rates of adverse discharge were 5.8% (n=938) after sedation and 16.2% (n=210) after general anaesthesia. Providers' adjusted mean predicted probabilities of using general anaesthesia for ERCP ranged from 0.2% to 63.2% of individual caseloads. Utilising provider-related variability in the use of general anaesthesia for instrumental variable analysis resulted in an 8.6% risk increase (95% confidence interval, 4.5-12.6%; P<0.001) in adverse discharge among patients receiving general anaesthesia vs sedation. Intraoperative hypotensive events occurred more often during general anaesthesia and mediated 23.8% (95% confidence interval, 3.9-43.7%: P=0.019) of the primary association.CONCLUSIONS:These results suggest that use of sedation during ERCP facilitates reduced adverse discharge for patients for whom general anaesthesia is not clearly indicated. Intraoperative hypotension during general anaesthesia for ERCP partly mediates the increased vulnerability to adverse discharge.

BackgroundA substantial proportion of patients undergoing inpatient surgery each year is at risk for postoperative institutionalization and loss of independence. Reliable individualized preoperative prediction of adverse discharge can facilitate advanced care planning and shared decision making.MethodsUsing hospital registry data from previously home‐dwelling adults undergoing inpatient surgery, we retrospectively developed and externally validated a score predicting adverse discharge. Multivariable logistic regression analysis and bootstrapping were used to develop the score. Adverse discharge was defined as in‐hospital mortality or discharge to a skilled nursing facility. The model was subsequently externally validated in a cohort of patients from an independent hospital.ResultsIn total, 106 164 patients in the development cohort and 92 962 patients in the validation cohort were included, of which 16 624 (15.7%) and 7717 (8.3%) patients experienced adverse discharge, respectively. The model was predictive of adverse discharge with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI 0.87‐0.88) in the development cohort and an AUC of 0.86 (95% CI 0.86‐0.87) in the validation cohort.ConclusionUsing preoperatively available data, we developed and validated a prediction instrument for adverse discharge following inpatient surgery. Reliable prediction of this patient centered outcome can facilitate individualized operative planning to maximize value of care.

BACKGROUND:We examined the association between emergent postoperative tracheal intubation and the use of supraglottic airway devices (SGAs) vs tracheal tubes.METHODS:We included data from adult noncardiac surgical cases under general anaesthesia between 2008 and 2018. We only included cases (n=59 991) in which both airways were deemed to be feasible options. Multivariable logistic regression, instrumental variable analysis, propensity matching, and mediation analysis were used.RESULTS:Use of a tracheal tube was associated with a higher risk of emergent postoperative intubation (adjusted absolute risk difference [ARD]=0.80%; 95% confidence interval (CI), 0.64-0.97; P<0.001), and a higher risk of post-extubation hypoxaemia (ARD=3.9%; 95% CI, 3.4-4.4; P<0.001). The effect was modified by the use of non-depolarising neuromuscular blocking agents (NMBAs); mediation analyses revealed that 28.9% (95% CI, 14.4-43.4%; P<0.001) of the main effect was attributable to NMBA. Airway management modified the association of NMBA and risk of emergent postoperative intubation (Pinteraction=0.02). Patients managed with an SGA had higher odds of NMBA-associated reintubation compared to patients managed with a tracheal tube (adjusted odds ratio [aOR]=3.65, 95% CI, 1.99-6.67 vs aOR=1.68, 95% CI, 1.29-2.18 [P<0.001], respectively).CONCLUSIONS:In patients undergoing procedures under general anaesthesia that could be managed with either SGA or tracheal tube, use of an SGA was associated with lower risk of emergent postoperative intubation. The effect can partly be explained by use of NMBAs. Use of NMBAs in patients with an SGA appears to increase the risk of emergent postoperative intubation.

General anesthesia (GA) with endotracheal intubation and monitored anesthesia care (MAC) are the most widely used modalities of sedation for endoscopic retrograde cholangiopancreatography (ERCP). Aim of this study was to determine difference in adverse discharge between patients receiving GA versus MAC for ERCP.