Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer.

The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 SQLCs with 8p11-p12 amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1-8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain-deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency.

Cost Effectiveness and Budget Impact of Nivolumab Plus Ipilimumab Versus Platinum Plus Pemetrexed (with and Without Bevacizumab) in Patients with Unresectable Malignant Pleural Mesothelioma in Switzerland.

BACKGROUND: Malignant pleural mesotheliomas (MPMs) are aggressive and often unresectable. In the past, chemotherapy was the standard for palliative treatment. However, immunotherapy with nivolumab+ipilimumab has recently received marketing approval. OBJECTIVES: This study evaluated the cost effectiveness of nivolumab+ipilimumab versus pemetrexed+platinum (with/without bevacizumab) for Swiss patients with unresectable MPM, overall and by histological subtype. METHODS: We developed a three-state Markov cohort model with a cycle length of 1 month, a 30-year time horizon, and a discount rate of 3% per year for costs and benefits. The model included the updated survival and treatment-dependent utility results from the Checkmate-743 and MAPS registration trials. A Swiss statutory health insurance perspective was considered with unit costs for 2022 from publicly available and real-world sources. We assumed a willingness-to-pay (WTP) threshold of CHF100,000/QALY. Model robustness was explored in sensitivity and scenario analyses. RESULTS: Compared with chemotherapy, nivolumab+ipilimumab incurred additional costs of CHF109,115 and 0.57 additional quality-adjusted life-years (QALYs), yielding an incremental cost-effectiveness ratio (ICER) of CHF192,585/QALY (i.e. USD201,829/QALY) gained. Relative to their 2022 list price, nivolumab+ipilimumab may be cost effective if priced at 48% across all histologies. Assuming cisplatin-based instead of carboplatin-based chemotherapy reduced the ICER to CHF158,911/QALY (i.e. USD166,539/QALY). For the non-epithelioid subtype, nivolumab+ipilimumab was cost effective compared with chemotherapy (ICER of CHF97,894/QALY, i.e. USD102,593/QALY). Chemotherapy+bevacizumab was often a dominated strategy or would require a bevacizumab cost reduction to 28%. CONCLUSIONS: Our model projected nivolumab+ipilimumab to be cost effective for the non-epithelioid subtype but not for all histologies. Substantial discounts for nivolumab+ipilimumab would be necessary to achieve cost effectiveness for all histologies.

Early Clearance of Plasma Epidermal Growth Factor Receptor Mutations as a Predictor of Outcome on Osimertinib in Advanced Non-Small Cell Lung Cancer; Exploratory Analysis from AURA3 and FLAURA.

PURPOSE: Plasma circulating tumor DNA (ctDNA) analysis is used for genotyping advanced non-small cell lung cancer (NSCLC); monitoring dynamic ctDNA changes may be used to predict outcomes. PATIENTS AND METHODS: This was a retrospective, exploratory analysis of two phase III trials [AURA3 (NCT02151981), FLAURA (NCT02296125)]. All patients had EGFR mutation-positive (EGFRm; ex19del or L858R) advanced NSCLC; AURA3 also included T790M-positive NSCLC. Osimertinib (FLAURA, AURA3), or comparator EGFR-tyrosine kinase inhibitor (EGFR-TKI; gefitinib/erlotinib; FLAURA), or platinum-based doublet chemotherapy (AURA3) was given. Plasma EGFRm was analyzed at baseline and Weeks 3/6 by droplet digital PCR. Outcomes were assessed by detectable/non-detectable baseline plasma EGFRm and plasma EGFRm clearance (non-detection) at Weeks 3/6. RESULTS: In AURA3 (n = 291), non-detectable versus detectable baseline plasma EGFRm had longer median progression-free survival [mPFS; HR, 0.48; 95% confidence interval (CI), 0.33-0.68; P < 0.0001]. In patients with Week 3 clearance versus non-clearance (n = 184), respectively, mPFS (months; 95% CI) was 10.9 (8.3-12.6) versus 5.7 (4.1-9.7) with osimertinib and 6.2 (4.0-9.7) versus 4.2 (4.0-5.1) with platinum-pemetrexed. In FLAURA (n = 499), mPFS was longer with non-detectable versus detectable baseline plasma EGFRm (HR, 0.54; 95% CI, 0.41-0.70; P < 0.0001). For Week 3 clearance versus non-clearance (n = 334), respectively, mPFS was 19.8 (15.1 to not calculable) versus 11.3 (9.5-16.5) with osimertinib and 10.8 (9.7-11.1) versus 7.0 (5.6-8.3) with comparator EGFR-TKI. Similar outcomes were observed by Week 6 clearance/non-clearance. CONCLUSIONS: Plasma EGFRm analysis as early as 3 weeks on-treatment has the potential to predict outcomes in EGFRm advanced NSCLC.

Overall survival and role of programmed death ligand 1 expression in patients with metastatic non-small-cell lung cancer and immunotherapy: an observational study from central Switzerland.

BACKGROUND: In clinical trials, therapy with immune checkpoint inhibitors has improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). These trials were important for drug approval and for defining new treatment standards but the effect of checkpoint inhibitors in patients treated outside of clinical trials is not well known. The goal of this study was to assess the effect of immunotherapy on the overall survival of patients with metastatic NSCLC in the region of central Switzerland. MATERIALS AND METHODS: The study included 274 patients with histologically confirmed metastatic (stage IV) NSCLC in central Switzerland in the years 2015 to 2018. Patients with NSCLC and actionable driver mutations were excluded. Patients with checkpoint inhibitor treatment (immuno-oncology [IO] group, n = 122) were compared with patients without checkpoint inhibitor treatment (no-IO group, n = 152). Baseline demographics, disease characteristics and therapies applied were collected retrospectively. The primary endpoint was median overall survival calculated either from diagnosis or from the start of checkpoint inhibitor therapy to death or data cut-off (21 July 2021). We used the Kaplan-Meier method and an adjusted Cox proportional-hazards regression model. The expression of programmed-death ligand 1 (PD-L1) on tumour cells was used for exploratory analysis. RESULTS: Patients had a median age of 68.4 years, most were male (61.7%) and more than half were current or former smokers (65%). A test for PD-L1 expression was available for 55.8% of the tumours. Patients in the IO group were younger than patients in the no-IO group. Among the 122 patients in the IO group, the median overall survival was 15 months (95% confidence interval [CI] 12-20). In the no-IO group, the median overall survival was 4 months (95% CI 3-7) with chemotherapy and 2 months (95% CI 1-2) with best supportive care. Patients with high (≥50%) PD-L1 expression and checkpoint inhibitor therapy had a slightly longer overall survival than patients with low PD-L1 and checkpoint inhibitor therapy. CONCLUSION: These results suggest that treatment with checkpoint inhibitors improves overall survival in patients with metastatic NSCLC and that PD-L1 expression could have a predictive value in patients treated outside of clinical trials. Further studies are needed to study the magnitude of the benefit of checkpoint inhibitors according to molecular NSCLC subtype.

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial.

PURPOSE: Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with RET fusion-positive non-small-cell lung cancer (NSCLC). We provide a registrational data set update in more than double (n = 316) of the original reported population (n = 144) and better characterization of long-term efficacy and safety. METHODS: Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm, open-label study of selpercatinib in patients with RET-altered cancers. An analysis of patients with RET fusion-positive NSCLC, including 69 treatment-naive and 247 with prior platinum-based chemotherapy, was performed. The primary end point was objective response rate (ORR; RECIST v1.1, independent review committee). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival, and safety. RESULTS: In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up of 21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was 61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI, 20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free (median follow-up of 24.7 months). Of 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety population (n = 796), the median treatment duration was 36.1 months. The safety profile of selpercatinib was consistent with previous reports. CONCLUSION: In a large cohort with extended follow-up, selpercatinib continued to demonstrate durable and robust responses, including intracranial activity, in previously treated and treatment-naive patients with RET fusion-positive NSCLC.

Expanding the indications for measurement of objective functional impairment in spine surgery: A pilot study of four patients with diseases affecting the spinal cord.

•The TUG test and the 6WT are feasible to apply in ambulatory patients with spinal cord affection.•The objective measurement of functional impairment resembled the functional status of four patients in this pilot study.•The TUG test and the 6WT may detect and quantify functional decline and/or improvement resulting from spinal cord affection.•Modern smartphone app-based technology may help to accurately quantify impairment, which is key for decision-making and evaluating the efficacy of interventions.

Clinical Activity of Mitogen-Activated Protein Kinase-Targeted Therapies in Patients With Non-V600 BRAF-Mutant Tumors.

PURPOSE: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established. METHODS: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival. RESULTS: A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors. CONCLUSION: This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.

A prognostic score for patients with malignant pleural mesothelioma (MPM) receiving second-line immunotherapy or chemotherapy in the ETOP 9-15 PROMISE-meso phase III trial.

INTRODUCTION: Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy. METHODS: Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients. These consisted of immune-inflammatory indexes (neutrophil-lymphocyte ratio [NLR], systemic immune-inflammatory index [SII], lactate dehydrogenase [LDH]) along with other already known prognostic baseline characteristics and laboratory values. Cut-offs were chosen independently of outcome. Based on Cox multivariable analysis for PFS in the whole cohort, a risk factor model was built to illustrate the prognostic stratification of patients by the combination of the derived independent prognostic factors, taking into account the EORTC score, a validated prognostic score in MPM. All models were stratified by histology and adjusted by treatment. RESULTS: In the stratified multivariable analysis in the whole cohort, high SII (hazard ratio (HR) 2.06; 95%CI 1.39-3.05) and low haemoglobin (HR 1.62; 95%CI 1.06-2.50) were associated with worse PFS. Based on these two prognostic factors, a mesothelioma risk score (MRS) was constructed with three PFS risk prognosis categories: favourable, intermediate and poor with 0, 1 and 2 risk factors, respectively (corresponding percent of cohort: 24%, 34% and 42% and median PFS: 5.8, 4.2 and 2.1 months). The derived MRS stratified the prognosis for PFS and OS, overall and within each of the EORTC groups. No significant predictors of treatment benefit were identified. CONCLUSIONS: The proposed MRS is prognostic of patient outcome and it fine-tunes the prognosis of patients with pre-treated MPM alone or when used with the already established EORTC score.

Distance to first symptoms measured by the 6-min walking test differentiates between treatment success and failure in patients with degenerative lumbar disorders.

PURPOSE: The smartphone-based 6-min walking test (6WT) is an established digital outcome measure in patients undergoing surgery for degenerative lumbar disorders (DLD). In addition to the 6WTs primary outcome measure, the 6-min walking distance (6WD), the patient's distance to first symptoms (DTFS) and time to first symptoms (TTFS) can be recorded. This is the first study to analyse the psychometric properties of the DTFS and TTFS. METHODS: Forty-nine consecutive patients (55 ± 15.8 years) completed the 6WT pre- and 6 weeks (W6) postoperative. DTFS and TTFS were assessed for reliability and content validity using disease-specific patient-reported outcome measures. The Zurich Claudication Questionnaire patient satisfaction subscale was used as external criterion for treatment success. Internal and external responsiveness for both measures at W6 was evaluated. RESULTS: There was a significant improvement in DTFS and TTFS from baseline to W6 (p < 0.001). Both measures demonstrated a good test-retest reliability (ß = 0.86, 95% CI 0.81-0.90 and ß = 0.83, 95% CI 0.76-0.87, both p < 0.001). The DTFS exceeded the 6WD capability to differentiate between satisfied (82%) and unsatisfied patients (18%) with an AUC of 0.75 (95% CI 0.53-0.98) vs. 0.70 (95% CI 0.52-0.90). The TTFS did not demonstrate meaningful discriminative abilities. CONCLUSION: Change in DTFS can differentiate between satisfied and unsatisfied patients after spine surgery. Digital outcome measures on the 6WT metric provide spine surgeons and researchers with a mean to assess their patient's functional disability and response to surgical treatment in DLD.

Association of Medical Comorbidities With Objective Functional Impairment in Lumbar Degenerative Disc Disease.

STUDY DESIGN: Analysis of a prospective 2-center database. OBJECTIVES: Medical comorbidities co-determine clinical outcome. Objective functional impairment (OFI) provides a supplementary dimension of patient assessment. We set out to study whether comorbidities are associated with the presence and degree of OFI in this patient population. METHODS: Patients with degenerative diseases of the spine preoperatively performed the timed-up-and-go (TUG) test and a battery of questionnaires. Comorbidities were quantified using the Charlson Comorbidity Index (CCI) and the American Society of Anesthesiology (ASA) grading. Crude and adjusted linear regression models were fitted. RESULTS: Of 375 included patients, 97 (25.9%) presented at least some degree of medical comorbidity according to the CCI, and 312 (83.2%) according to ASA grading. In the univariate analysis, the CCI was inconsistently associated with OFI. Only patients with low-grade CCI comorbidity displayed significantly higher TUG test times (p = 0.004). In the multivariable analysis, this effect persisted for patients with CCI = 1 (p = 0.030). Regarding ASA grade, patients with ASA = 3 exhibited significantly increased TUG test times (p = 0.003) and t-scores (p = 0.015). This effect disappeared after multivariable adjustment (p = 0.786 and p = 0.969). In addition, subjective functional impairment according to ODI, and EQ5D index was moderately associated with comorbidities according to ASA (all p < 0.05). CONCLUSION: The degree of medical comorbidities appears only weakly and inconsistently associated with OFI in patients scheduled for degenerative lumbar spine surgery, especially after controlling for potential confounders. TUG testing may be valid even in patients with relatively severe comorbidities who are able to complete the test.

External Validation of the Minimum Clinically Important Difference in the Timed-up-and-go Test After Surgery for Lumbar Degenerative Disc Disease.

STUDY DESIGN: Prospective observational cohort study. OBJECTIVE: The aim of this study was to provide external validation of the minimum clinically important difference (MCID) of the Timed-up-and-go (TUG) test. SUMMARY OF BACKGROUND DATA: The TUG test is one of the best explored and most frequently applied objective task-based functional outcome measure in patients with lumbar degenerative disc disease (DDD). The increased use of the TUG test is based on its solid psychometric properties; however, an external validation of the originally determined MCID is lacking. METHODS: Forty-nine patients with lumbar DDD, scheduled for elective spine surgery, were assessed pre- and 6-weeks (W6) postoperative. MCID values were calculate for raw TUG test times (seconds) and standardized TUG z scores using three different computation methods and the following established patient-reported outcome measures (PROMs) as anchors: Visual Analog Scales (VAS), Core Outcome Measures Index Back, Zurich Claudication Questionnaire (ZCQ). RESULTS: The three computation methods generated a range of MCID values, depending on the PROM used as anchor, from 0.9 s (z score of 0.3) based on the VAS leg pain to 3.0 seconds (z score of 2.7) based on the ZCQ physical function scale. The average MCID of the TUG test across all anchors and computation methods was 2.1 s (z score of 1.5). According to the average MCID of raw TUG test values or TUG z scores, 41% and 43% of patients classified as W6 responders to surgery, respectively. CONCLUSION: This study confirms the ordinally reported TUG MCID values in patients undergoing surgery for lumbar. A TUG test time change of 2.1 seconds (or TUG z score change of 1.5) indicates an objective and clinically meaningful change in functional status. This report facilitates the interpretation of TUG test results in clinical routine as well as in research.Level of Evidence: 3.

PD-1/PD-L1 inhibitor activity in patients with gene-rearrangement positive non-small cell lung cancer-an IMMUNOTARGET case series.

Background: Prior IMMUNOTARGET registry data had suggested that responses to immune [anti PD(L)1] monotherapy in gene-arranged non-small cell lung cancer (NSCLC) were rare or absent, depending on the specific oncogene. Methods: IMMUNOTARGET sites reporting prior registry data or new individual cases of gene rearranged NSCLC seeming to benefit from immune monotherapy were explored in detail looking to both validate their diagnosis of a functional gene rearrangement and to look for features potentially differentiating them from other such cases associated with low response rates. Results: Five cases of NSCLC with a gene rearrangement with reported responses or prolonged stabilization from immune monotherapy were identified in total. All had little or no prior smoking history and had programmed death-ligand 1 (PD-L1) values ranging from zero to 100%. A confirmed rearrangement partner was reported in only 2 of the cases (CD74-ROS1 and KIF5B-RET), however in one of the other three cases [analplastic lymophoma kinase (ALK)], significant benefit from a relevant prior targeted therapy was noted, also consistent with the rearrangement status being correctly assigned. Conclusions: Not all driver oncogene subtypes of NSCLC are equally responsive to immune monotherapy, however even among patients with well-validated gene rearranged NSCLC which has traditionally been considered immune hyporesponsive, objective responses can occur. Additional explorations of the features associated with and underlying the immune hypo-responsiveness of most, but not all, cases of gene-rearranged NSCLC are required.

Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer.

Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAFV600E and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAFV600E mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients.

Intracranial Activity of Osimertinib Plus Capmatinib in a Patient With EGFR and MET-Driven Lung Cancer: Case Report.

We previously published in the Journal of Thoracic Oncology the case of a patient with EGFR and MET-driven lung cancer and extracranial response to capmatinib and osimertinib. Here, we report on a second patient treated with the same combination, revealing complete and durable intracranial response. Adding capmatinib to osimertinib seems to be an effective salvage therapy for patients with EGFR-mutant lung cancer and acquired MET amplification.

Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial.

PURPOSE: We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non-small cell lung cancers (NSCLC). PATIENTS AND METHODS: In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed. RESULTS: Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60-95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3-NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9-NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population. CONCLUSIONS: Selpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.

Responsiveness of the self-measured 6-minute walking test and the Timed Up and Go test in patients with degenerative lumbar disorders.

OBJECTIVE: The 6-minute walking test (6WT) and the Timed Up and Go (TUG) test are two of the most commonly applied standardized measures of objective functional impairment that help support clinical decision-making for patients undergoing surgery for degenerative lumbar disorders. This study correlates smartphone-app-based 6WT and TUG results to evaluate their responsiveness. METHODS: In a prospective study, 49 consecutive patients were assessed preoperatively and 6 weeks postoperatively using the 6WT, the TUG test, and commonly used patient-reported outcome measures. Raw values and standardized z-scores of both objective tests were correlated. An external criterion for treatment success was created based on the Zurich Claudication Questionnaire patient satisfaction subscale. Internal and external responsiveness for both functional tests was evaluated. RESULTS: The mean preoperative 6WT results improved from 401 m (SD 129 m), z-score -1.65 (SD 1.6) to 495 m (SD 129 m), z-score -0.71 (SD 1.6, p < 0.001). The mean preoperative TUG test results improved from 10.44 seconds (SD 4.37, z-score: -3.22) to 8.47 seconds (SD 3.38, z-score: -1.93, p < 0.001). The 6WT showed a strong negative correlation with TUG test results (r = -66, 95% CI 0.76-0.53, p < 0.001). The 6WT showed higher internal responsiveness (standardized responsive mean = 0.86) compared to the TUG test (standardized responsive mean = 0.67). Evaluation of external responsiveness revealed that the 6WT was capable of differentiating between patients who were satisfied and those who were unsatisfied with their treatment results (area under the curve = 0.70), whereas this was not evident for the TUG test ( area under the curve = 0.53). CONCLUSIONS: Both tests adequately quantified functional impairment in surgical candidates with degenerative lumbar disorders. The 6WT demonstrated better internal and external responsiveness compared with the TUG test. Clinical trial registration no.: NCT03977961 (clinicaltrials.gov). ABBREVIATIONS: AUC = area under the curve; COMI = Core Outcome Measures Index; DLDs = degenerative lumbar disorders; LDH = lumbar disc herniation; LSS = lumbar spinal stenosis; PROM = patient-reported outcome measure; ROC = receiver operating characteristic; SRM = standardized responsive mean; TUG = Timed Up and Go; VAS = visual analog scale; 6WD = 6-minute walking distance; 6WT = 6-minute walking test; ZCQ = Zurich Claudication Questionnaire.

Advances in the treatment of RET-fusion-positive lung cancer.

Ten years ago, RET-fusions were discovered as oncogenic drivers and potential drug targets in approximately 1% of metastatic lung adenocarcinomas. Several multikinase inhibitors were tested in clinical trials, however, their antitumor activity was limited. Recently, two selective and potent RET-inhibitors were approved for the treatment of patients with metastatic RET-fusion-positive lung cancer (RET-NSCLC). Here, we discuss the two RET-inhibitors selpercatinib and pralsetinib, and the management of patients with RET-fusion positive NSCLC.

Binimetinib, pemetrexed and cisplatin, followed by maintenance of binimetinib and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) and KRAS mutations. The phase 1B SAKK 19/16 trial.

BACKGROUND: KRAS mutations are found in 20-25 % of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed a multicenter open-label phase 1B trial to determine the recommended phase 2 dose and early antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed. METHODS: Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3 + 3 design with dose escalation in 2 dose levels (DL) of binimetinib and part 2: expansion cohort at the maximum tolerated dose (MTD). Pts received 4 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2and binimetinib 30 (DL1)/45 mg (DL2) orally twice a day (bid) d1-14 q3w followed by pemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity. RESULTS: From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5 % at codon 12. No DLT occurred in the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33 %) or pts/physicians' decision (27 %). Together with the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25 %), fatigue (19 %), anemia (19 %). Overall response rate among 9 evaluable pts receiving binimetinib at MTD (45 mg bid) was 33 % (7-70 %, 95 % CI). Median progression-free survival was 5.7 months (1.1-14.0, 95 % CI) and overall survival 6.5 months (1.8-NR, 95 % CI). CONCLUSIONS: Pts treated with combination of cisplatin, pemetrexed and binimetinib presented no unexpected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population.

A cost-effectiveness analysis of pembrolizumab with or without chemotherapy for the treatment of patients with metastatic, non-squamous non-small cell lung cancer and high PD-L1 expression in Switzerland.

INTRODUCTION: Pembrolizumab monotherapy or in combination with chemotherapy are two new treatment options for patients with metastatic non-squamous non-small cell lung cancer (NSCLC) and high (≥ 50%) programmed death ligand 1 (PD-L1) expression. We conducted a cost-effectiveness analysis for Switzerland comparing these two options but also pembrolizumab to chemotherapy. METHODS: We constructed a 3-state Markov model with a time horizon of 10 years. Parametric functions were fitted to Kaplan-Meier overall survival (OS) and progression-free survival (PFS) using 2-year follow-up data from the KN-024 and KN-189 registration trials. We included estimated costs for further treatment lines and costs for best supportive care. Costs were assessed from the Swiss healthcare payer perspective. We used published utility values. RESULTS: Combination therapy resulted in an expected gain of 0.17 quality-adjusted life years (QALYs) per patient and incremental costs of Swiss Francs (CHF) 81,085 as compared to pembrolizumab. These estimates led to an incremental cost-effectiveness ratio (ICER) of CHF 475,299/QALY. Pembrolizumab in comparison to chemotherapy was estimated to generate mean incremental QALYs of 0.83 and incremental costs of CHF 56,585, resulting in an ICER of CHF 68,580/QALY. Results were most sensitive to changes in costs of 1L pembrolizumab and combination therapy, together with changes in PFS. In the probabilistic sensitivity analysis, we estimated combination therapy was cost-effective in 4.9% of the simulations and pembrolizumab monotherapy in 82.9%, assuming a willingness-to-pay threshold of CHF 100,000 per QALY gained. CONCLUSIONS: Pembrolizumab is likely to be cost-effective from the Swiss healthcare payer perspective, whereas pembrolizumab plus chemotherapy is not.