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Background: Panitumumab has the potential to improve the therapeutic ratio of concurrent chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: This phase I dose-finding study investigated escalating doses of paclitaxel (Taxol) given concurrently with panitumumab, carboplatin and intensity-modulated radiotherapy (IMRT) for stage III–IVB SCCHN. Untreated patients with oral cavity, oropharynx, larynx, hypopharynx or unknown primaries were eligible. Additional eligibility criteria included measurable disease, good performance status and no contraindication to therapy. Patients received weekly fixed doses of panitumumab and carboplatin plus escalating doses of paclitaxel with IMRT. Results: Nineteen patients were enrolled on to two dose levels (DLs): weekly paclitaxel 15 mg/m2 (n = 3) and 30 mg/m2 (n = 16). One dose-limiting toxicity occurred in DL 2, which was declared the maximum tolerated dose. All patients experienced mucositis, primarily grade 3 or more. Oral pain, xerostomia, dysphagia, weight loss, dermatitis, nausea and acneiform rash were frequent. All patients had partial response according to RECIST, whereas the overall complete clinical response rate was 95%. At median follow-up of 21 months, 18 of 19 patients (95%) remained disease free. Conclusions: Panitumumab, carboplatin, paclitaxel and IMRT are well tolerated and appear highly active in the treatment of SCCHN. Further study of this regimen in SCCHN is warranted. [ABSTRACT FROM AUTHOR]

Since the pivotal KN-048 study, pembrolizumab, with or without chemotherapy, has become the first-line therapy for R/M HNSCC. Cetuximab is often used in a second or later-line treatment after ICI. While novel EGFR-targeted agents and various cetuximab combination regimens are being tested in R/M HNSCC, there is no established efficacy benchmark for cetuximab in the post-ICI setting. This study examines the efficacy of cetuximab as a subsequent treatment. We conducted a single-institution retrospective analysis of patients with R/M HNSCC who received cetuximab-based therapy after ICI, either with or without chemotherapy. Baseline demographic, clinicopathologic characteristics and treatment regimens were analyzed. The primary outcome measures were the duration of cetuximab therapy (DOT) and overall survival (OS) using multivariate Cox proportional hazard models. A total of 63 patients met the inclusion criteria. The median age was 77, 50 (79%) were male, and 27 (43%) had virus-mediated (25 HPV+ and 2 EBV+) SCC. The median interval from the last ICI therapy to cetuximab initiation was 5.7 weeks. Across all patients, median DOT was 7.9 weeks, and median OS was 6.2 months. DOT (12.1 vs. 5.1 weeks; HR 0.63, 95% CI 0.37-1.10) and OS (7.8 vs. 4.2 months; HR 0.49, 95% CI 0.28-0.84) were longer in patients with virus-negative HNSCC. Among all patients, 21% (N = 13) were treated with cetuximab for > 6 months. The proportion of patients on cetuximab for > 6 months was higher among patients with virus-negative (33%, N = 12) compared to patients with virus-positive HNSCC (3.7%, N = 1). In multivariate analyses, virus-negative disease was associated with increased DOT (HR 0.41, 95% CI 0.22-0.78), but the association with OS was not statistically significant (HR 0.63, 95% CI 0.31-1.25). Chemotherapy combinations, ICI-to-cetuximab interval, age at cetuximab start, sex, and smoking status were not associated with differences in DOT or OS. Our analysis indicates that cetuximab is active in a minority of patients with R/M HNSCC previously treated with ICIs. Using DOT as a surrogate for progression-free survival, these data recapitulate trials evaluating cetuximab in heavily pre-treated patients in the pre-ICI era. These findings reiterate the need for effective treatment in patients with R/M HNSCC who progress after ICI and suggest that cetuximab-based therapy may be a better option in virus-negative tumors. [ABSTRACT FROM AUTHOR]

Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with definitive chemoradiation therapy (CRT). However, locoregional recurrence rates of approximately 50% may occur in high-risk patients. As such, there is an unmet need for up-front treatment intensification in this patient population. Preclinical evidence suggests that both radiation therapy (RT) and cisplatin activate the PI3K/AKT pathway, leading to treatment resistance through multiple processes, including increased DNA repair, decreased apoptosis, and modulation of the tumor microenvironment by promoting angiogenesis, immune escape and hypoxia. Furthermore, AKT inhibitors have been shown to sensitize a subset of HNSCC models to RT and platinum chemotherapy in vitro and in vivo. However, radiosensitization using a specific AKT inhibitor has not yet been studied in humans. This phase I study will be the first to establish safety and preliminary efficacy of ipatasertib combined with standard of care definitive CRT for HNSCC. The primary objective of this study is to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of ipatasertib in combination with definitive CRT in locally advanced HNSCC based on dose-limiting toxicities (DLTs). Secondary objectives include assessment of acute and late toxicities, long term swallowing function, and a preliminary assessment of efficacy. Eligible subjects must have pathologically confirmed, previously untreated, non-metastatic HNSCC that is either human papilloma virus (HPV)-negative clinical stage III-IVB, or HPV-positive clinical stage III. The study schema includes dose escalation and expansion cohorts. All subjects will receive RT for a standard 70 Gy in 7-week course, with concurrent weekly cisplatin. Two 28-day cycles of orally administered ipatasertib will be given concurrently with CRT. The four dose levels of ipatasertib range from 100-400 mg daily. Dose escalation of ipatasertib will follow a Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design, with DLT window extending from the start of CRT, through 28 days after completion of RT. The expansion cohort will enroll an additional 10 subjects at the RP2D, and incorporate pharmacodynamic biopsies for each subject to evaluate whether the addition of ipatasertib to CRT will result in increased gamma-H2AX, consistent with radiosensitization, and also decreased pS6 and pPRAS40 to evaluate AKT pathway inhibition. Additional correlative studies include assessment of the pharmacokinetic profile of ipatasertib with CRT, as well as correlation of efficacy with tumor genotype (such as alterations in PIK3CA, PTEN, and/or AKT1), based on whole exome sequencing of pre-treatment biopsy specimens. Not applicable Enrollment is currently at dose level 2 in the escalation phase, and is expected to complete accrual in 2025. The clinicaltrials.gov registry number is NCT05172245. [ABSTRACT FROM AUTHOR]

Background Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET -altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and methods Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET -altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly. Results LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein −/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET- altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved. Conclusions These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET -altered tumors. [ABSTRACT FROM AUTHOR]

Background: Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up. Patients and methods: EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported. Results: Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P=0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P=0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P=0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis. Conclusion: The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib. [ABSTRACT FROM AUTHOR]

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are classified as actionable, but rare molecular markers in thyroid cancer (TC). Recently, two targeted therapies have been approved for pediatric and adult patients with advanced or metastatic solid tumors with NTRK gene fusions, marking the first small molecule inhibitor with a tissue agnostic indication. As a result of these advancements and the changing treatment landscape, staying current with emerging data and the impact on TC treatment paradigms can be challenging. The objective of this study was to determine if an online continuing medical education (CME) intervention could improve oncologists' and endocrinologists' understanding of NTRK gene fusions and available treatment options for patients with NTRK fusion-positive TC. The activity consisted of a 40-minute video discussion between two expert faculty. Educational effect was assessed with a repeated pairs pre-/post-assessment study including a 3-item, multiple choice, knowledge questionnaire and one confidence assessment question, with each participant serving as his/her own control. Pre- and post-assessment scores were compared to determine relative changes in the proportion of correct responses to knowledge questions. A paired samples t-test assessed overall number correct and confidence change and a McNemar's test assessed individual question statistical significance. The activity launched 5 May 2021; data were collected until 30 July 2021. The total number of learners was 650 (oncologists, N=192; endocrinologists, N=458). Overall, statistically significant improvements in knowledge were seen after education consumption for responding oncologists (N=60, P <.01) and endocrinologists (N=101, P <.001). Relative improvement in correct answers was 35% for oncologists and 54% for endocrinologists (total correct responses pre-/post-assessment were 46%/62% and 35%/54%, respectively). When evaluating outcomes by individual knowledge learning objective, statistically significant improvements were observed for both oncologists and endocrinologists (P <.05). Following the activity, 43% of oncologists and 50% of endocrinologists had a measurable increase in confidence regarding their ability to coordinate the care of patients with NTRK fusion-positive TC with other members of the healthcare team. Participation in an online, video discussion-based CME-certified activity resulted in statistically significant improvements in knowledge and measurable increases in confidence of oncologists and endocrinologists regarding NTRK gene fusions and available treatment options for patients with NTRK fusion-positive TC. The need for additional educational activities was also identified to address residual gaps and further increase clinicians' ability in this clinical setting. [ABSTRACT FROM AUTHOR]

Background: Locally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points. Patients and methods: These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy. Results: Among 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31–not reached] versus 24 months (95% CI: 13–42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41–0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12–59) versus 11 months (95% CI: 8–14) for PF (HR: 0.66; 95% CI: 0.45–0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37–0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030). Conclusions: In locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC. [ABSTRACT FROM AUTHOR]