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The RET receptor tyrosine kinase is oncogenically activated by I RET i gene fusions in 1% to 2% of non-small-cell lung cancers (NSCLC) and by I RET i gene mutations in most medullary thyroid cancers (MTC).[1] Although multikinase inhibitors (MKIs) with nonspecific anti-RET activity are approved for the treatment of MTC irrespective of I RET i mutation status, their investigational use for patients with I RET i fusion-positive NSCLC has been limited by substantial off-target adverse effects that lead to dose reductions and inadequate RET-specific inhibition.[2]-[7] As a result, tumor responses to MKIs have been infrequent and short lived, and a comprehensive molecular understanding of MKI response and resistance is lacking. It is highly potent against and selective for diverse founder activating RET alterations in human cancers, and in preclinical experiments, it overcomes RET V804 gatekeeper mutations, which have been identified in rare patients with acquired resistance to anti-RET MKIs. To our knowledge, case 1 is the second patient with NSCLC to be described as having an acquired RET gatekeeper mutation after prior anti-RET MKI treatment and the first to be treated successfully with RET-targeted therapy.[14] To our knowledge, this is also the first published report of a patient with hereditary RET V804M-mutant MTC treated successfully with RET-targeted therapy. [Extracted from the article]

The article focuses on the importance of adjuvant chemotherapy for the locoregionally advanced nasopharyngeal carcinoma (LA-NPC). It discusses controversy surrounding adjuvant chemotherapy and induction chemotherapy as per the guidelines by Current National Comprehensive Cancer Network. It also talks about improving the quality of life for NPC suffering patients.

HPV-positive (HPV+) oropharyngeal carcinoma (OPC) continues to increase in incidence across the globe. Multimodality treatment offers a high likelihood of cure in HPV+ OPC but comes at a high cost of treatment-related morbidity. As a result, de-escalation of treatment to limit toxicity without compromising high cure rates has emerged as a major trend in head and neck cancer clinical research. Primary surgery with minimally invasive resection of the primary disease may allow for the elimination of chemotherapy and decrease radiation dose intensity. Primary dose-reduced radiation, with or without systemic therapy, is also under study, as is replacing concurrent cisplatin with newer systemic agents. Numerous institutional series and phase II trials have been presented, and the first generation of de-escalation randomized phase III trials have now been published. The various combinatorial multimodality strategies to achieve less intensive and toxic therapy are many. Has the time come for de-escalation as a standard approach to HPV+ OPC? The pros and cons, as well as the best approaches for de-escalated treatment of HPV+ OPC, are debated here.

Purpose: This phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC)., Patients and Methods: Patients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib 125 mg/d orally for up to 48 weeks or until unacceptable toxicity or disease progression. The primary end point was objective response by independent review. Other end points included duration of response, progression-free survival, safety, pharmacokinetics, and changes in tumor markers., Results: Of 91 enrolled patients who received motesanib, two (2%) achieved objective response (95% CI, 0.3% to 7.7%); their duration of response was 32 weeks (censored) and 21 weeks (disease progressed). Eighty-one percent of patients had stable disease (48% had durable stable disease > or = 24 weeks), 8% had disease progression as best response, and 9% were not evaluated; 76% experienced a decrease from baseline in target lesion measurement. Median progression-free survival was 48 weeks (95% CI, 43 to 56 weeks). Among patients with tumor marker analysis, 69 (83%) of 83 and 63 (75%) of 84 had decreased serum calcitonin and carcinoembryonic antigen during treatment, respectively, compared with baseline. The most common treatment-related adverse events were diarrhea (41%), fatigue (41%), hypothyroidism (29%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study., Conclusion: Although the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable disease while receiving motesanib.

Purpose: Effective and tolerable palliative treatments are needed for patients with incurable squamous cell carcinoma of the head and neck (SCCHN). Single-agent targeted therapies have limited activity in this setting. The feasibility of adding celecoxib to gefitinib for the treatment of incurable SCCHN is unknown., Patients and Methods: Nineteen patients with unresectable recurrent locoregional and/or distant metastatic SCCHN with progressive disease after at least one prior chemotherapy or chemoradiotherapy regimen were enrolled onto this single-institution phase I study. Three dose levels were explored: (1) celecoxib 200 mg twice daily plus gefitinib 250 mg daily; (2) celecoxib 400 mg twice daily plus gefitinib 250 mg daily; and (3) celecoxib 400 mg twice daily plus gefitinib 500 mg daily., Results: No dose-limiting toxicities were encountered at any dose level. The most common toxicities were acneiform rash, diarrhea, hand reaction, dyspepsia, and anemia. Four of 18 patients assessable for response (22%; 95% CI, 2% to 42%) achieved a confirmed partial response., Conclusion: The combination of gefitinib 500 mg daily plus celecoxib 400 mg twice daily is well-tolerated. The encouraging responses seen in this early study suggest further evaluation of epidermal growth factor receptor and cyclooxygenase-2 inhibitors in SCCHN is warranted.