Purpose: Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic MET exon 14-mutant NSCLC.Experimental Design: Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS).Results: A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal MET kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the MET exon 14mutant allele, were observed in 7 patients (35%). A number of offtarget mechanisms of resistance were detected in 9 patients (45%), including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF; one case displayed both on-and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses.Conclusions: On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.

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Objectives Checkpoint inhibitor (CPI)–associated colitis can limit therapy and has resemblance to inflammatory bowel disease (IBD). Studies exploring mechanistic similarities between these colitides are limited, yet therapeutic targets for either disorder could emerge from shared pathophysiology. Methods The morphology and inflammatory content of colonic biopsy specimens from anti–CTLA-4 and anti–PD-1/PD-L1 antibody-treated patients with CPI colitis were compared with initial biopsy specimens from patients with IBD. Predictors of the need for infliximab were sought in CPI patients. Results Biopsy specimens from CPI patients showed significantly lower chronicity scores and similar activity scores compared with patients with IBD. Anti–CTLA-4 and IBD groups showed equivalent CD8, CD4, PD-1, and PD-L1 expression, while FoxP3 scores were lower and CD68 scores were higher in anti–CTLA-4 compared with IBD biopsy specimens. Anti–PD-1/PD-L1 group had lower scores for CD8, CD4, and PD-1 and equivalent scores for FoxP3, PD-L1, and CD68 compared with IBD. Anti–CTLA-4 biopsy specimens had higher scores for CD8, PD-1, PD-L1, and CD68 than anti–PD-1/PD-L1 biopsy specimens. CD8/FoxP3 ratios and CD68 scores were higher among CPI patients requiring infliximab therapy for colitis compared with those responding to steroids. Conclusions The proinflammatory immune phenotype of anti–CTLA-4–associated colitis has significant overlap with IBD. CD8/FoxP3 ratios may predict therapeutic response in CPI-associated colitis.

PARP inhibitors target BRCA mutations and defective homologous recombination repair (HRR) for the treatment of epithelial ovarian cancer (EOC). However, the treatment of HRR-proficient EOC with PARP inhibitors remains challenging. The objective of this study was to determine whether the combination of triapine (ribonucleotide reductase inhibitor), cediranib (vascular endothelial growth factor receptor tyrosine kinase inhibitor), and the PARP inhibitor olaparib synergized against BRCA wild-type and HRR-proficient EOC in xenograft mouse models. In addition, the mechanisms by which cediranib augmented the efficacy of triapine and olaparib were investigated. BRCA-wild type and PARP inhibitor-resistant EOC cell lines were implanted subcutaneously (s.c.) into nude mice or injected intraperitoneally (i.p.) into SCID-Beige mice. Mice were then treated i.p. with olaparib, cediranib, triapine, various double and triple combinations. The volume of s.c tumor in nude mice and the abdominal circumference of SCID-Beige mice were measured to evaluate the effectiveness of the treatment to delay tumor growth and prolong the survival time of mice. In both xenograft mouse models, the combination of triapine, olaparib and cediranib resulted in marked suppression of BRCA-wild type EOC growth and significant prolongation of the survival time of mice, with efficacy greater than any double combinations and single drugs. Furthermore, we identified that cediranib abrogated pro-survival and anti-apoptotic AKT signaling, thereby enhancing the efficacy of triapine and olaparib against BRCA-wild type EOC cells. Taken together, our results demonstrate a proof-of-principle approach and the combination regiment holds promise in treating BRCA-wild type and PARP inhibitor-resistant EOC.

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Alterations in c‐MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non‐small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14‐mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET‐selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41‐year‐old woman with advanced NSCLC harboring an HLA‐DRB1‐MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. Key Points To our knowledge, this is the first report of a patient with non‐small cell lung cancer harboring an HLA‐DRB1‐MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.

Treatment modalities of head and neck squamous cell cancer include surgery, radiation, chemotherapy, targeted agents and immune checkpoint inhibition. Treatment is often toxic and can affect long-term function and quality of life. In this context, identification of biomarker data that can help tailor therapy on an individualized basis and reduce treatment-related toxicity would be highly beneficial. A variety of predictive biomarkers have been discovered and are already utilized in clinical practice, while many more are being explored. We will review p16 overexpression as a surrogate biomarker in HPV-associated head and neck cancer and plasma EBV DNA as a biomarker in nasopharyngeal carcinoma, the two established biomarkers currently utilized in clinical practice. We will also examine novel predictive biomarkers that are in clinical development and may shape the future landscape of targeted head and neck cancer therapy. These emerging biomarkers include the tyrosine kinases and their signaling pathway, immune checkpoint biomarkers, tumor suppressor abnormalities, and molecular predictors of hypoxia-targeted therapy. We will also look at futuristic biomarkers including detection of circulating DNA from clinical specimens and rapid tumor profiling. We will highlight the ongoing effort that will see a shift from prognostic to predictive biomarker development in head and neck cancer with the goal of delivering individualized cancer therapy. Trial registration: N/A.

Context: Studies of lungs in patients with COVID-19 have focused on early findings. Objective: To systematically study histopathologic, imaging features and presence of SARSCoV-2 RNA in lung tissue from patients in later stages of COVID-19. Design: Autopsies, explants, surgical lung biopsies; and transbronchial, cryo, and needle biopsies were studied from patients with COVID-19, whose onset of symptoms/confirmed diagnosis was more than 28 days before the procedure. Available images were reviewed. Reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) for SARS-CoV-2 RNA was performed on lung tissue. Results: Forty-four specimens (43 patients, median age 59.3 years, 26 [60.5%] male) showed features of acute lung injury (ALI) in 39 (88.6%), predominantly organizing pneumonia (OP) and diffuse alveolar damage (DAD), up to 298 days after onset of COVID-19. Fibrotic changes were found in 33 specimens (75%), most commonly fibrotic DAD (N=22) and cicatricial OP (N=12). Time between acquiring COVID-19 and specimen was shorter in patients with diffuse ALI (median 61.5 days) compared to patients with focal (140 days) or no ALI (130 days) (P=.009). Sixteen (of 20, 80%) SARS-CoV-2 RT-ddPCR tests were positive, up to 174 days after COVID-19 onset. Time between COVID-19 onset and most recent CT in patients with consolidation on imaging was shorter (median 43.0 days) versus patients without consolidation (87.5 days; P=.02). Reticulations were associated with longer time after COVID-19 onset to CT (median 82 days vs 23.5 days, P=.006). Conclusions: ALI and SARS-CoV-2 RNA can be detected in patients with COVID-19 for many months. ALI may evolve into fibrotic interstitial lung disease.