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Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9–20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7–60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. Merck (CrossRef Funder ID: 10.13039/100009945).

Previous trials have shown that the combination of fluorouracil-based chemotherapy and cetuximab is active when used as salvage treatment in patients with metastatic colorectal cancer; the present trial shows activity of this combination as first-line treatment as well. The trial also found that for cetuximab to be active, an unmutated KRAS gene in the tumor was required. This trial shows activity of the combination of fluorouracil-based chemotherapy and cetuximab as first-line treatment. The trial also found that for cetuximab to be active, an unmutated KRAS gene in the tumor was required. Colorectal cancer is the third most common cancer worldwide. 1 Approximately 25% of patients with colorectal cancer present with overt metastatic disease, and metastatic disease develops in 40 to 50% of newly diagnosed patients. Standard first-line treatments include fluorouracil with leucovorin and irinotecan 2 , 3 or oxaliplatin, 4 alone or combined with bevacizumab. 5 The immunoglobulin G1 monoclonal antibody against the epidermal growth factor receptor (EGFR), cetuximab (Erbitux), is effective in combination with irinotecan in patients with metastatic colorectal cancer or as a single agent in patients with metastatic colorectal cancer that progresses even when irinotecan is used. 6 , 7 Phase 1 and 2 studies . . .

Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7–23·4] vs 8·5 months [7·1–10·8], hazard ratio [HR] 0·52 [0·32–0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2–not reached] vs 10·0 months [8·7–11·0], HR 0·35 [0·21–0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6–13·6] vs 6·8 months [5·9–12·7], HR 0·80 [0·55–1·16], p=0·24; chemotherapy alone: 11·0 months [9·2–12·6] vs 9·3 months [7·6–11·9], HR 0·77 [0·54–1·10], p=0·16). The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. Merck KGaA.

Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first‐in‐human (FIH) trial, an efficacy‐driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP‐4 pancreatic cell‐line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model. Further clinical PK and target inhibition data (derived from predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs and target inhibition profiles from the mouse xenograft study to establish a translational PK/pharmacodynamic (PD) model. Preclinical data showed that tumor regression with tepotinib treatment in KP‐4 xenograft tumors corresponded to 95% target inhibition. We therefore concluded that a PD criterion of sustained, near‐to‐complete (>95%) phospho‐MET inhibition in tumors should be targeted for tepotinib to be effective. Simulations of dose‐dependent target inhibition profiles in human tumors that exceeded the PD threshold in more than 90% of patients established an RP2D of tepotinib 500 mg once daily. This translational mathematical modeling approach supports an efficacy‐driven rationale for tepotinib phase II dose selection of 500 mg once daily. Tepotinib at this dose has obtained regulatory approval for the treatment of patients with non‐small cell lung cancer harboring MET exon 14 skipping.

The hepatocyte growth factor (HGF)/MET signaling pathway has been proposed to be involved in the resistance to radiotherapy of glioblastoma via proinvasive and DNA damage response pathways. Here we assessed the role of the MET pathway in the response to radiotherapy in vitro and in vivo in syngeneic mouse glioma models. We find that the murine glioma cell lines GL-261, SMA-497, SMA-540 and SMA-560 express HGF and its receptor MET and respond to exogenous HGF with MET phosphorylation. Glioma cell viability or proliferation are unaffected by genetic or pharmacological MET inhibition using tepotinib or CRISPR/Cas9-engineered Met gene knockout and MET inhibition fails to sensitize glioma cells to irradiation in vitro. In contrast, the combination of tepotinib with radiotherapy prolongs survival of orthotopic SMA-560 or GL-261 glioma-bearing mice compared with radiotherapy or tepotinib treatment alone. Synergy is lost when such experiments are conducted in immunodeficient Rag1 −/− mice, and, importantly, also when Met gene expression is disrupted in the tumor cells. Combination therapy suppresses a set of pro-inflammatory mediators including matrix metalloproteases that are upregulated by radiotherapy alone and that have been linked to poor outcome in glioblastoma. Several of these mediators are positively regulated by transforming growth factor (TGF)-β, and pSMAD2 levels as a surrogate marker of TGF-β pathway activity are suppressed by combination treatment. We conclude that synergistic suppression of experimental syngeneic glioma growth by irradiation and MET inhibition requires MET expression in the tumor as well as an intact immune system. Clinical evaluation of this combined strategy in newly diagnosed glioblastoma is warranted.

Proteinase-activated receptor-2 (PAR2) belongs to a new G protein-coupled receptor subfamily that is activated by various serine proteases. Recent knowledge indicates that PAR2 is involved in cutaneous inflammation and immune response. PAR2 is highly expressed by human keratinocytes (KTC). The underlying mechanisms of PAR2-mediated KTC function and cutaneous immune response are, however, still incomplete. Therefore, we investigated the activation of important signaling cascades in primary human KTC after PAR2-stimulation using specific agonists. Moreover, we compared PAR2-immunoreactivity in the epidermis of inflammatory dermatoses and normal human skin. Electrophoretic mobility shift assays and morphological transduction studies revealed PAR2-induced activation and translocation of nuclear factor kappa B (NF-κB) in primary human KTC with a maximum after 1 h. Supershift analysis demonstrated acivation of the p50/p65 heterodimer complex. PAR2 agonists also induced upregulation of intercellular adhesion molecule-1 (ICAM-1) RNA, as shown by RT-PCR. Use of NF-κB inhibitors prevented upregulation of the cell adhesion molecule ICAM-1 in KTC indicating a direct role of NF-κB in PAR2-mediated upregulation of ICAM-1. Fluorescence-activated cell sorter analysis confirmed PAR2-induced and NF-κB-mediated upregulation of ICAM-1 protein after 13 h. Moreover, increased expression of PAR2 was detected in KTC of patients with atopic dermatitis suggesting a role of PAR2 in human skin inflammation. In conclusion, PAR2 induces upregulation of cell adhesion molecules such as ICAM-1 in primary human KTC via NF-κB activation, and is upregulated in KTC during cutaneous inflammation. Thus, PAR2 may play an important regulatory role of human KTC during inflammation and immune response.

Caspase-8 plays an essential role in apoptosis triggered by death receptors. Through the cleavage of Bid, a proapoptotic Bcl-2 member, it further activates the mitochondrial cytochrome c/Apaf-1 pathway. Because caspase-8 can be processed also by anticancer drugs independently of death receptors, we investigated its exact role and order in the caspase cascade. We show that in Jurkat cells either deficient for caspase-8 or overexpressing its inhibitor c-FLIP apoptosis mediated by CD95, but not by anticancer drugs was inhibited. In the absence of active caspase-8, anticancer drugs still induced the processing of caspase-9, -3 and Bid, indicating that Bid cleavage does not require caspase-8. Overexpression of Bcl-x(L) prevented the processing of caspase-8 as well as caspase-9, -6 and Bid in response to drugs, but was less effective in CD95-induced apoptosis. Similar responses were observed by overexpression of a dominant-negative caspase-9 mutant. To further determine the order of caspase-8 activation, we employed MCF7 cells lacking caspase-3. In contrast to caspase-9 that was cleaved in these cells, anticancer drugs induced caspase-8 activation only in caspase-3 transfected MCF7 cells. Thus, our data indicate that, unlike its proximal role in receptor signaling, in the mitochondrial pathway caspase-8 rather functions as an amplifying executioner caspase.

In a study involving patients with non–small-cell lung cancer with a MET exon 14 skipping mutation, the use of tepotinib (a selective MET inhibitor) was associated with a partial response in approximately half the patients. The main adverse event was peripheral edema.

Monoclonal antibodies like cetuximab, targeting the epidermal growth factor receptor (EGFR), and bevacizumab, targeting the vascular endothelial growth factor (VEGF), are an integral part of treatment regimens for metastasized colorectal cancer. However, inhibition of the EGFR has been shown to protect human glioma cells from cell death under hypoxic conditions. In colon carcinoma cells, the consequences of EGFR blockade in hypoxia (e.g., induced by bevacizumab) have not been evaluated yet. LIM1215 and SW948 colon carcinoma and LNT-229 glioblastoma cells were treated with cetuximab, PD153035, and erlotinib and analyzed for cell density and viability. The sequential administration of either cetuximab followed by bevacizumab (CET->BEV) or bevacizumab followed by cetuximab (BEV->CET) was investigated in a LIM1215 (KRAS wildtype) and SW948 (KRAS mutant) xenograft mouse model. In vitro, cetuximab protected from hypoxia. In the LIM1215 model, a survival benefit with cetuximab and bevacizumab monotherapy was observed, but only the sequence CET->BEV showed an additional benefit. This effect was confirmed in the SW948 model. Our observations support the hypothesis that bevacizumab modulates the tumor microenvironment (e.g., by inducing hypoxia) where cetuximab could trigger protective effects when administered later on. The sequence CET->BEV therefore seems to be superior as possible mutual adverse effects are bypassed.

In many cancers, a high constitutive activation of transcription factor NF- κ B has been implicated in tumor progression and apoptosis resistance, making NF- κ B an attractive target for cancer therapy. Here, we describe the specific inhibition of NF- κ B by the intracellular delivery of I κ B α through VP22-mediated protein transduction. The Herpes virus protein VP22 has attracted great attention in gene therapy, because of its ability to migrate from an original expressing cell into surrounding recipient cells, resulting in high levels of protein transduction. To evaluate the use of VP22 as a vehicle for NF- κ B inhibition, we expressed several versions of VP22-I κ B α fusion proteins in baculovirus, bacteria, and mammalian cells. While we could not detect transcellular migration of different VP22-I κ B α constructs, interestingly, baculovirally expressed VP22-I κ B α was efficiently delivered into cells after exogenous administration. The purified and imported VP22-I κ B α retained its function and efficiently inhibited both constitutive and inducible NF- κ B activation. We further show that the 34 C-terminal amino acids of VP22 were sufficient for the import property, suggesting also that the ability of intercellular migration and cellular import are not linked to each other. Together, our results demonstrate that recombinant VP22 acts as an efficient vehicle for the exogenous delivery of I κ B α and, moreover, might find applications to block NF- κ B activation specifically.