Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

Near-Complete Whole-Genome Sequencing of Two Burkholderia pseudomallei Strains Harbouring Novel Molecular Class D Beta-Lactamase Genes, Isolated from Malaysia.

Here, we present two 7.1- and 7.3-bp near-complete genome sequences of Burkholderia pseudomallei strains of HTAA077 and HRPB058, isolated from a pus culture from a confirmed melioidosis patient at Hospital Tengku Ampuan Afzan, Kuantan, Malaysia, and from blood culture from a patient at Hospital Raja Permaisuri Bainun, Ipoh, Malaysia, using a Nanopore MinION instrument.

Whole genome sequence analysis showing unique SARS-CoV-2 lineages of B.1.524 and AU.2 in Malaysia.

SARS-CoV-2 has spread throughout the world since its discovery in China, and Malaysia is no exception. WGS has been a crucial approach in studying the evolution and genetic diversity of SARS-CoV-2 in the ongoing pandemic. Despite considerable number of SARS-CoV-2 genome sequences have been submitted to GISAID and NCBI databases, there is still scarcity of data from Malaysia. This study aims to report new Malaysian lineages of the virus, responsible for the sustained spikes in COVID-19 cases during the third wave of the pandemic. Patients with nasopharyngeal and/or oropharyngeal swabs confirmed COVID-19 positive by real-time RT-PCR with CT value < 25 were chosen for WGS. The selected SARS-CoV-2 isolates were then sequenced, characterized and analyzed along with 986 sequences of the dominant lineages of D614G variants currently circulating throughout Malaysia. The prevalence of clade GH and G formed strong ground for the presence of two Malaysian lineages of AU.2 and B.1.524 that has caused sustained spikes of cases in the country. Statistical analysis on the association of gender and age group with Malaysian lineages revealed a significant association (p <0.05). Phylogenetic analysis revealed dispersion of 41 lineages, of these, 22 lineages are still active. Mutational analysis showed presence of unique G1223C missense mutation in transmembrane domain of the spike protein. For better understanding of the SARS-CoV-2 evolution in Malaysia especially with reference to the reported lineages, large scale studies based on WGS are warranted.

Cancer-Associated Thrombosis: A Clinical Scoping Review of the Risk Assessment Models Across Solid Tumours and Haematological Malignancies.

Cancer-associated thrombosis (CAT) is a leading cause of death in cancer patients receiving outpatient chemotherapy. The latest guidelines emphasize stratifying the patients in terms of CAT risks periodically. Multiple risk assessment models (RAMs) were developed to classify patients and guide thromboprophylaxis to high-risk patients. This study aimed to discuss and highlight different RAMs across various malignancy types with their related advantages and disadvantages. A scoping review was conducted using predefined search terms in three scientific databases, including Google Scholar, Science Direct, and PubMed. The search for studies was restricted to original research articles that reported risk assessment models published in the last thirteen years (between 2008 and 2021) to cover the most recently published evidence following the development of the principal risk assessment score in 2008. Data charting of the relevant trials, scores, advantages, and disadvantages were done iteratively considering the malignancy type. Of the initially identified 1115 studies, 39 studies with over 67,680 patients were included in the review. In solid organ malignancy, nine risk assessment scores were generated. The first and most known Khorana risk score still offers the best available risk assessment model when used for high-risk populations with a threshold of 2 and above. However, KRS has a limitation of failure to stratify low-risk patients. The COMPASS-CAT score showed the best performance in the lung carcinoma patients who have a higher prevalence of thrombosis than other malignancy subtypes. In testicular germ cell tumours, Bezan et al RAM is a validated good discriminatory RAM for this malignancy subtype. CAT in haematological malignancy seems to be under-investigated and has multiple disease-related, and treatment-related confounding factors. AL-Ani et al score performed efficiently in acute leukemia. In multiple myeloma, both SAVED and IMPEDED VTE scores showed good performance. Despite the availability of different disease-specific scores in lymphoma-related thrombosis, the standard of care needs to be redefined.

Fatal co-infection--melioidosis and leptospirosis.

Co-infection of melioidosis and leptospirosis is uncommon. We report here four such cases, confirmed by blood culture for melioidosis and blood polymerase-chain reaction for leptospirosis, which occurred among rescuers involved in a search and rescue operation for a young man who was suspected to have drowned in Lubuk Yu, a recreational forest in Pahang, Malaysia. Despite treatment, three of the patients died from the co-infection.

Embolisation of a bronchial artery of anomalous origin in massive haemoptysis.

Massive haemoptysis is the most dreaded of all respiratory emergencies. Bronchial artery embolisation is known to be a safe and effective procedure in massive haemoptysis. Bronchial artery of anomalous origin presents a diagnostic challenge to interventional radiologists searching for the source of haemorrhage. Here, we report a case of massive haemoptysis secondary to a lung carcinoma with the bronchial artery originating directly from the right subclavian artery. This artery was not evident during the initial flush thoracic aortogram. The anomalous-origin bronchial artery was then embolised using 15% diluted glue with good results. An anomalous-origin bronchial artery should be suspected if the source of haemorrhage is not visualised in the normally expected bronchial artery location.