Response to Capmatinib in a MET Fusion-positive Cholangiocarcinoma.

Cholangiocarcinoma is the second most common liver cancer after hepatocellular carcinoma. In case of metastatic or unresectable disease, the recommended first-line treatment is gemcitabine-based doublet, most commonly gemcitabine and cisplatin. There is no standard treatment for further lines. MET fusions are rare alterations described in many cancers. The efficacy of specific MET inhibitors is poorly studied. We present the case of a patient with chemotherapy-refractory metastatic cholangiocarcinoma harboring a CAPZA-2-MET fusion along with MET amplification who dramatically responded to capmatinib, a specific MET tyrosine kinase inhibitor.

Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer.

Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m2) or S-1 (30 mg/m2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71-1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80-2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.

First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.

BACKGROUND: The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. METHODS: This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m2 or carboplatin AUC 5-6 plus pemetrexed 500 mg/m2] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1-2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099. FINDINGS: Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6-27·2) in the ceritinib group and 8·1 months (5·8-11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42-0·73]; p<0·00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group. INTERPRETATION: First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC. FUNDING: Novartis Pharmaceuticals Corporation.

Real-life feasibility of home-based pulmonary rehabilitation in chemotherapy-treated patients with thoracic cancers: a pilot study.

BACKGROUND: Patients with advanced lung cancer (LC) or malignant pleural mesothelioma (MPM) exhibit limitation of exercise capacities and alteration of quality of life (QoL) induced by cancer and its treatment. Few studies assessed pulmonary rehabilitation (PR) in these chemotherapy-treated patients, and none evaluated a home-based PR program. METHODS: In this prospective uncontrolled observational pilot study, patients treated by chemotherapy for LC or MPM were screened for a home-based PR program combining exercise training with global cares including therapeutic education and psychosocial management. Feasibility and safety were evaluated by attendance and adherence to PR program. Various exercise tolerance tests, including 6-min walk test (6MWT) and 6-min stepper test (6MST), were performed before and after PR associated with, QoL and psychological assessment (VSRQ and HAD, respectively). RESULTS: 243 patients were considered eligible but only 71 (60.6 ± 8.8 years) started a PR and 47 completed the program. Refusals to participate were mostly related to lack of motivation whereas withdrawals to PR were related to cancer-related medical issues. No adverse event related to PR was observed. Baseline 6MWT distance was associated with performance status (r = - 0.45, p = 0.001) and mMRC dyspnea scale (r = - 0.49, p < 0.001) but not with lung cancer stage. Post-PR reassessment showed 6MWT stability and 6MST improvement in patients who completed the program. Daily physical activity (p = 0.007) and anxiety (p = 0.02) scores were significantly improved. CONCLUSIONS: Home-based PR was feasible and safe in patients with advanced LC or MPM. Exercise capacities stability in patients who completed the PR program suggests that PR might be beneficial. Further studies are warranted to confirm and to improve the potential value of PR in these patients.

Perception of Lung Cancer Risk: Impact of Smoking Status and Nicotine Dependence.

BACKGROUND: The general population is nowadays well aware that tobacco smoking dramatically increases the risk of developing lung cancer. We hypothesized that a personal history of smoking and the level of nicotine dependence in current smokers may affect the perception of this risk among healthy individuals. METHODS: The fourth French nationwide observational survey, EDIFICE 4, was conducted by telephone among a representative sample of individuals (N = 1602) aged between 40 and 75 years. Interviewees were asked about their smoking habits, perception of the risk of lung cancer, and nicotine dependence (Fagerström test). RESULTS: Regardless of their smoking status or level of nicotine dependence, the majority (96%) of our study population (N = 1463) acknowledged that tobacco smoking is a major risk factor for lung cancer. For 34% of all respondents, smoking ≤ 10 cigarettes per day does not carry any risk of lung cancer. Only half the current smokers considered themselves to be at higher risk of lung cancer than the average-risk population. The majority of current cigarette smokers with a nicotine dependence considered themselves to be at higher risk for lung cancer while only 37% of non-nicotine-dependent individuals had the same perception (P < 0.01). Current smokers were more likely to consider a screening examination than former smokers and never-smokers. However, the intention to undergo screening was not significantly affected by the level of nicotine dependence. CONCLUSIONS: Awareness campaigns may first have to overcome misconceptions about light smoking and, secondly, to target specific populations (heavy smokers, those with a long history, highly dependent smokers).

Dynamic contrast-enhanced MR imaging pharmacokinetic parameters as predictors of treatment response of brain metastases in patients with lung cancer.

OBJECTIVES: To determine the diagnostic accuracy of pharmacokinetic parameters measured by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in predicting the response of brain metastases to antineoplastic therapy in patients with lung cancer. METHODS: Forty-four consecutive patients with lung cancer, harbouring 123 newly diagnosed brain metastases prospectively underwent conventional 3-T MRI at baseline (within 1 month before treatment), during the early (7-10 weeks) and midterm (5-7 months) post-treatment period. An additional DCE MRI sequence was performed during baseline and early post-treatment MRI to evaluate baseline pharmacokinetic parameters (K trans, k ep, v e, v p) and their early variation (∆K trans, ∆k ep, ∆v e, ∆v p). The objective response was judged by the volume variation of each metastasis from baseline to midterm MRI. ROC curve analysis determined the best DCE MRI parameter to predict the objective response. RESULTS: Baseline DCE MRI parameters were not associated with the objective response. Early ∆K trans, ∆v e and ∆v p were significantly associated with the objective response (p = 0.02, p = 0.001 and p = 0.02, respectively). The best predictor of objective response was ∆v e with an area under the curve of 0.93 [95% CI = 0.87, 0.99]. CONCLUSIONS: DCE MRI and early ∆v e may be a useful tool to predict the objective response of brain metastases in patients with lung cancer. KEY POINTS: • DCE MRI could predict the response of brain metastases from lung cancer • ∆v e was the best predictor of response • DCE MRI could be used to individualize patients' follow-up.

Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.

Faecalibaterium prausnitzii strain EXL01 boosts efficacy of immune checkpoint inhibitors.

Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). A high level of Faecalibacterium prausnitzii have been associated with a positive response to ICI in multiple cancer types. Here, based on fecal shotgun metagenomics data, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that a high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In MCA205 tumor-bearing mice, administration of F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain did not induce any change in fecal microbiota diversity or composition, suggesting a direct effect on immune cells in the small intestine. F. prausnitzii strain EXL01 will be evaluated as an adjuvant to ICI in multiple cancers in the near future.

Relevance of an extensive follow-up after surgery for nonsmall cell lung cancer.

There are no international guidelines for an appropriate and cost-effective follow-up for resected nonsmall cell lung cancer (NSCLC). We retrospectively reviewed the outcome of NSCLC patients after curative surgery. Follow-up included physical examination and chest radiography every 3 months, and chest computed tomography (CT) scan, bronchoscopy, abdominal ultrasound, brain CT scan and bone scan every 6 months for 3 years, then every year over the following 2 years. Prognostic factors and costs were analysed. Median overall survival following surgery for NSCLC in 162 patients was 38.5 months. Recurrence occurred in 85 (52.5%) patients including 41 (48%) symptomatic subjects. Disease-free survival was similar between patients with asymptomatic recurrence versus symptomatic patients (11.4 versus 12 months; p=0.41). Recurrence was detected by physical examination or chest radiography in 47 (55.3%) patients. Curative-intent therapy was provided in 18 (41%) out of 44 patients with asymptomatic recurrence and in four (10%) out of 41 symptomatic cases (p=0.001). Median overall survival from time of recurrence was higher in asymptomatic patients than in symptomatic patients (15.5 versus 7.2 months; p=0.001). The cost per year of life gained was USD32 700 (€22 397). An extensive follow-up, with acceptable cost, may improve the outcome of patients with resected NSCLC through detection of asymptomatic recurrences; however, validation by prospective studies is required.

MET Exon 14 Skipping in NSCLC: A Systematic Literature Review of Epidemiology, Clinical Characteristics, and Outcomes.

INTRODUCTION: MET exon 14 (METex14) skipping is a rare oncogenic driver in non-small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was recently approved. Given the heterogeneity in published data of METex14 skipping NSCLC, we conducted a systematic literature review to evaluate its frequency, patient characteristics, and outcomes. METHODS: On June 13, 2022 we conducted a systematic literature review of publications and conference abstracts reporting frequency, patient characteristics, or outcomes of patients with METex14 skipping NSCLC. RESULTS: We included 139 studies reporting frequency or patient characteristics (350,997 patients), and 39 studies reporting clinical outcomes (3989 patients). Median METex14 skipping frequency was 2.0% in unselected patients with NSCLC, with minimal geographic variation. Median frequency was 2.4% in adenocarcinoma or nonsquamous subgroups, 12.0% in sarcomatoid, and 1.3% in squamous histology. Patients with METex14 skipping NSCLC were more likely to be elderly, have adenocarcinoma histology; there was no marked sex or smoking status distribution. In first line of treatment, median objective response rate ranged from 50.7% to 68.8% with targeted therapies (both values correspond to MET TKIs), was 33.3% with immunotherapy, and ranged from 23.1% to 27.0% with chemotherapy. CONCLUSIONS: Patients with METex14 skipping are more likely to have certain characteristics, but no patient subgroup can be ruled out; thus, it is crucial to test all patients with NSCLC to identify suitable candidates for MET inhibitor therapy. MET TKIs appeared to result in higher efficacy outcomes, although no direct comparison with chemotherapy or immunotherapy regimens was found.

Histo-Molecular Factors of Response to Combined Chemotherapy and Immunotherapy in Non-Small Cell Lung Cancers.

BACKGROUND: Chemo-immunotherapy (CIT) is the standard of care for advanced non-small cell lung cancer (NSCLC), but the impact of routinely available histo-molecular biomarkers on its efficacy has not yet been fully assessed. OBJECTIVE: The purpose of this multicenter study was to evaluate the clinical activity of CIT according to oncogenic drivers, STK11 and TP53 mutations, and MET overexpression. PATIENTS AND METHODS: Patients receiving CIT for advanced NSCLC with available comprehensive molecular profile were included. The primary endpoint was progression-free survival (PFS), adjusted on main confounding factors, and secondary endpoints were overall survival (OS) and objective response rate. RESULTS: Among the 195 patients included between September 2018 and October 2021, 88 (41%) had a KRAS mutation, 16 (8.2%) an EGFR mutation or an ALK, ROS1, or RET rearrangement, 11 (5.6%) a BRAF mutation, 6 (3.1%) a MET exon 14 mutation or MET amplification, and 5 (2.6%) a HER2 mutation. Seventy-seven patients (39.5%) had none of these alterations. The median PFS was 6.4 months (95% CI 5.3-7.3). Per subgroup, the median PFS was 7.1 months (5.4-8.9) for KRAS, 5.5 months (2.5-15.3) for EGFR/ALK/ROS1/RET, 12.9 months (2.6-not reached [NR]) for BRAF, 1.5 months (0.6-NR) for MET, 3.9 months (2.6-NR) for HER2, and 5.6 months (4.7-7.8) for patients without any oncogenic alteration. No difference in PFS was observed between the KRAS, BRAF, EGFR/ALK/ROS1/RET, and no-driver subgroups. STK11 mutations were associated with poor PFS (HR 1.59 [95% CI 1.01-2.51]) whereas TP53 mutations had no impact. MET overexpression was associated with longer PFS (HR 0.59 [95% CI 0.35-0.99]). CONCLUSION: This study suggests that the efficacy of combining pembrolizumab with pemetrexed and platinum-based chemotherapy differs according to the histo-molecular biomarkers, which may help to identify patients liable to benefit from CIT.

Transforming properties of MET receptor exon 14 skipping can be recapitulated by loss of the CBL ubiquitin ligase binding site.

MET is a receptor tyrosine kinase that is activated in many cancers through various mechanisms. MET exon 14 (Ex14) skipping occurs in 3% of nonsmall cell lung tumors. However, the contribution of the regulatory sites lost upon this skipping, which include a phosphorylated serine (S985) and a binding site for the E3 ubiquitin ligase CBL (Y1003), remains elusive. Sequencing of 2808 lung tumors revealed 71 mutations leading to MET exon 14 skipping and three mutations affecting Y1003 or S985. In addition, MET exon 14 skipping and MET Y1003F induced similar transcriptional programs, increased the activation of downstream signaling pathways, and increased cell mobility. Therefore, the MET Y1003F mutation is able to fully recapitulate responses induced by MET exon 14 skipping, suggesting that loss of the CBL binding site is the main contributor of cell transformation induced by MET Ex14 mutations.

MET variants with activating N-lobe mutations identified in hereditary papillary renal cell carcinomas still require ligand stimulation.

In hereditary papillary renal cell carcinoma (HPRCC), the MET receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations recently identified in non-small cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: in this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed ten uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, further enhanced by HGF stimulation: His1086Leu, Ile1102Thr, Leu1130Ser, and Cis1125Gly. Similar to the variant resulting in MET exon14 skipping, the two N-lobe MET variants His1086Leu, Ile1102Thr further characterized were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation displayed also transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET TKIs opens the way for use of targeted therapies for patients harboring the corresponding mutations.

Characterization of 164 patients with NRAS mutated non-small cell lung cancer (NSCLC).

BACKGROUND: NRAS mutations are observed in less than 1% of non-small cell lung cancer (NSCLC). Clinical data regarding this rare subset of lung cancer are scarce and response to systemic treatment such as chemotherapy or immune checkpoint inhibitors (ICI) has never been reported. METHODS: All consecutive patients with an NRAS mutated NSCLC, diagnosed between August 2014 and November 2020 in 14 French centers, were included. Clinical and molecular data were collected and reviewed from medical records. RESULTS: Out of the 164 included patients, 106 (64.6%) were men, 150 (91.5%) were current or former smokers, and 104 (63.4%) had stage IV NSCLC at diagnosis. The median age was 62 years, and the most frequent histology was adenocarcinoma (81.7%). NRAS activating mutations were mostly found in codon 61 (70%), while codon 12 and 13 alterations were observed in 16.5% and 4.9% of patients, respectively. Programmed death ligand-1 expression level <1%/1-49%/≥50% were respectively found in 30.8%/27.1%/42.1% of tumors. With a median follow-up of 12.5 months, median overall survival (OS) of stage IV patients was 15.3 months (95% CI 9.9-27.6). No significant difference in OS was found according to the type of mutation (codon 61 vs. other), HR = 1.12 (95% CI 0.65-1.95). Among stage IV patients treated with platinum-based doublet (n = 66), ICI (n = 48), or combination of both (n = 10), objective response rate, and median progression free survival were respectively 45% and 5.8 months, 35% and 6.9 months, 70% and 8.6 months. CONCLUSION: NRAS mutated NSCLC are characterized by a high frequency of smoking history and codon 61 mutations. Further studies are needed to confirm the encouraging outcome of immunotherapy in combination with chemotherapy.

Tepotinib Treatment in Patients With MET Exon 14-Skipping Non-Small Cell Lung Cancer: Long-term Follow-up of the VISION Phase 2 Nonrandomized Clinical Trial.

Importance: MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non-small cell lung cancer (NSCLC); however, data with longer follow-up and in larger populations are needed to further optimize therapeutic approaches. Objective: To assess the long-term efficacy and safety of tepotinib, a potent and highly selective MET inhibitor, in patients with METex14-skipping NSCLC in the VISION study. Design, Setting, and Participants: The VISION phase 2 nonrandomized clinical trial was a multicohort, open-label, multicenter study that enrolled patients with METex14-skipping advanced/metastatic NSCLC (cohorts A and C) from September 2016 to May 2021. Cohort C (>18 months' follow-up) was an independent cohort, designed to confirm findings from cohort A (>35 months' follow-up). Data cutoff was November 20, 2022. Intervention: Patients received tepotinib, 500 mg (450 mg active moiety), once daily. Main Outcomes and Measures: The primary end point was objective response by independent review committee (RECIST v1.1). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Cohorts A and C included 313 patients (50.8% female, 33.9% Asian; median [range] age, 72 [41-94] years). The objective response rate (ORR) was 51.4% (95% CI, 45.8%-57.1%) with a median (m)DOR of 18.0 (95% CI, 12.4-46.4) months. In cohort C (n = 161), an ORR of 55.9% (95% CI, 47.9%-63.7%) with an mDOR of 20.8 (95% CI, 12.6-not estimable [NE]) months was reported across treatment lines, comparable to cohort A (n = 152). In treatment-naive patients (cohorts A and C; n = 164), ORR was 57.3% (95% CI, 49.4%-65.0%) and mDOR was 46.4 (95% CI, 13.8-NE) months. In previously treated patients (n = 149), ORR was 45.0% (95% CI, 36.8%-53.3%) and mDOR was 12.6 (95% CI, 9.5-18.5) months. Peripheral edema, the most common treatment-related adverse event, occurred in 210 patients (67.1%) (35 [11.2%] experienced grade ≥3 events). Conclusions and Relevance: The findings from cohort C in this nonrandomized clinical trial supported the results from original cohort A. Overall, the long-term outcomes of VISION demonstrated robust and durable clinical activity following treatment with tepotinib, particularly in the treatment-naive setting, in the largest known clinical trial of patients with METex14-skipping NSCLC, supporting the global approvals of tepotinib and enabling clinicians to implement this therapeutic approach for such patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02864992.

MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanised HGF knock-in mice.

Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3-4% of non-small-cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment with MET-tyrosine kinase inhibitors (TKIs), underlying the need to understand the mechanism of METex14 oncogenicity and sensitivity to TKIs. Whether METex14 is a driver mutation and whether it requires hepatocyte growth factor (HGF) for its oncogenicity in a range of in vitro functions and in vivo has not been fully elucidated from previous preclinical models. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in nontransformed human lung cells and report that the METex14 single alteration was sufficient to drive MET-dependent in vitro anchorage-independent survival and motility and in vivo tumorigenesis, sensitising tumours to MET-TKIs. However, we also show that human HGF (hHGF) is required, as demonstrated in vivo using a humanised HGF knock-in strain of mice and further detected in tumour cells of METex14 NSCLC patient samples. Our results also suggest that METex14 oncogenicity is not a consequence of an escape from degradation in our cell model. Thus, we developed a valuable model for preclinical studies and present results that have potential clinical implication.

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.

Safety of Tepotinib in Patients With MET Exon 14 Skipping NSCLC and Recommendations for Management.

INTRODUCTION: The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors. PATIENTS AND METHODS: Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial. RESULTS: Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks. CONCLUSION: Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population.

Paclitaxel-bevacizumab combination in advanced non-squamous non-small-cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel-bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19-82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2-9.6] and 10.8 [IQR: 5.3-19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI-): 7.0 [IQR: 4.2-11.0] versus 5.2 [IQR: 2.9-8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0-1. Only a performance status of 0-1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.