HPV-related oropharyngeal cancer: a review on burden of the disease and opportunities for prevention and early detection

The incidence of oropharyngeal cancer (OPC) related to infection with human papillomavirus (HPV) is rising, making it now the most common HPV-related malignancy in the United States. These tumors present differently than traditional mucosal head and neck cancers, and those affected often lack classic risk factors such as tobacco and alcohol use. Currently, there are no approved approaches for prevention and early detection of disease, thus leading many patients to present with advanced cancers requiring intense surgical or nonsurgical therapies resulting in significant side effects and cost to the health-care system. In this review, we outline the evolving epidemiology of HPV-related OPC. We also summarize the available evidence corresponding to HPV-related OPC prevention, including efficacy and safety of the HPV vaccine in preventing oral HPV infections. Finally, we describe emerging techniques for identifying and screening those who may be at high risk for developing these tumors

Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibit ROS1/TRK/ALK solvent-front mutations

The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA-C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROSI, or NTRK1-3 rearrangements: however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALK(G1202R), ROS1(G2032R) or ROS1(D2033N), TRKA(G595R), and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA-C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solventfront substitutions in vitro and in vivo. As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusionpositive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance. SIGNIFICANCE: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1-3, and ALK. Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRKI-3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. (C) 2018 AACR.