This phase 2 study assesses the efficacy and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (anti-angiogenic agent) in women with pretreated recurrent or metastatic cervical cancer (ClinicalTrials.gov NCT03827837). Patients with histologically or cytologically confirmed cervical squamous cell carcinoma experiencing relapse or progression during or after 1-2 lines of systemic therapy for recurrent or metastatic disease are enrolled. Eligible patients receive camrelizumab 200 mg intravenously on day 1 of each 3-week cycle plus famitinib 20 mg orally once daily. The primary endpoint is the objective response rate. Secondary endpoints are duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety. The trial has met pre-specified endpoint. Thirty-three patients are enrolled; median follow-up lasts for 13.6 months (interquartile range: 10.0-23.6). Objective responses are observed in 13 (39.4%, 95% confidence interval [CI]: 22.9-57.9) patients; the 12-month duration of response rate is 74.1% (95% CI: 39.1-90.9). Median progression-free survival is 10.3 months (95% CI: 3.5-not reached) and the 12-month overall survival rate is 77.7% (95% CI: 58.9-88.7). All patients experience treatment-related adverse events; grade ≥3 events occur in 26 (78.8%) patients. Treatment-related serious adverse events and deaths are observed in 9 (27.3%) and 2 (6.1%) patients, respectively. Camrelizumab plus famitinib shows promising antitumor activity with a manageable and tolerable safety profile in patients with pretreated recurrent or metastatic cervical squamous cell carcinoma. This combination may represent a treatment option for this population.

Background: Multiple targeted therapeutics are available for radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), but it remains unclear which treatment is optimal to achieve long-term survival. Methods: A systematic search of the PubMed, Embase, and ClinicalTrials.gov databases was conducted to identify eligible randomized controlled trials (RCTs) comparing the efficacy and safety of targeted treatments for patients with RAIR-DTC from inception to April, 2022. Data were extracted by following the recommendations of the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. We calculated the odds ratio (OR) or hazard ratio (HR), its corresponding 95% credible intervals (CrI), and the surface under the cumulative ranking curve (SUCRA) to indicate ranking probability using Bayesian network meta-analyses. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade 3 or higher adverse events. Results: A total of 12 eligible RCTs involved 1,959 patients and 13 treatments: apatinib, cabozantinib, anlotinib, nintedanib, lenvatinib, lenvatinib with low dose (LD), sorafenib, sorafenib plus everolimus, donafenib (200 mg), donafenib (300 mg), pazopanib (continuous), pazopanib (intermittent), and vandetanib. Pooled analyses indicated that targeted therapeutics significantly prolonged PFS and OS in patients with RAIR-DTC (0.31, 0.21-0.41; 0.69, 0.53-0.85, respectively) compared with placebo. Network meta-analyses indicated that lenvatinib showed the most favorable PFS, with significant differences versus sorafenib (0.33, 0.23-0.48), vandetanib (0.31, 0.20-0.49), nintedanib (0.30, 0.15-0.60), and placebo (0.19, 0.15-0.25), while apatinib was most likely to be ranked first for prolonging OS with a SUCRA of 0.90. Lenvatinib showed the highest ORR (66%, 61%-70%), followed by anlotinib (59%, 48%-70%) and apatinib (54%, 40%-69%). Lenvatinib caused the most adverse events of grade 3 or higher, followed by lenvatinib (LD) and apatinib. Different toxicity profiles of individual treatment were also revealed. Conclusion: This network meta-analysis suggests that lenvatinib and apatinib were associated with the best progression-free survival and overall survival benefits, respectively, for patients with RAIR-DTC, compared with other targeted therapeutics. Patients who received lenvatinib or apatinib also had more grade 3 or higher adverse events. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=302249], identifier [CRD42022302249].

The current treatments for radioactive iodine (RAI) -refractory differentiated thyroid cancer (DTC) are evolving as cancer genomics are further understood. Multitargeted tyrosine kinase inhibitors are the first-line therapy for symptomatic or progressive disease; however, considerable adverse effects have spurred the development of targeted therapies for redifferentiation of iodine avidity and the treatment of RAI-refractory DTC. Next-generation sequencing allows for the use of tumor-targeted therapeutics, such as MEK1/2, BRAF, RET, and NTRK inhibitors. Immunotherapy is also under investigation as a therapeutic option for this disease.

The most frequent radioactive (RAI) refractory thyroid cancers are papillary thyroid carcinoma, followed by poorly differentiated thyroid carcinoma. They are rare and lethal. In recent years, significant therapeutic progress has been achieved.

This paper offers insights on refractoriness to RAI treatment and the optimization of treatment initiation and treatment choice. Clinical trials performed with anti-angiogenic kinase inhibitors and with targeted inhibitors in patients with BRAF, RAS mutation or RET, TRK or ALK fusion are discussed.

These treatments provide high response rates. Anti-angiogenic kinase inhibitors improve median progression-free-survival; however, their benefit in terms of overall survival has been shown in only few subsets of patients. Treatment sequencing is challenging; in the absence of targetable abnormality, lenvatinib should be used as first line treatment. Options for second line treatment include lenvatinib (if not given at first line), cabozantinib or the addition of an anti-checkpoint antibody. In patients with a targetable abnormality, specific inhibitors, might be used as first line treatment and lenvatinib as second line or vice-versa. Further studies are needed, based on documented genomic and immunologic characteristics of the tumor to assess the potential role of combination and redifferentiation therapy.

Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear.

In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician's choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly [with a cycle of 3 weeks on and 1 week off]). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair-proficient (pMMR) disease and in all patients. Safety was also assessed.

A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy.

Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme [a subsidiary of Merck]; Study 309-KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.).

The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient's features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.

Recent advances in the development of multitarget tyrosine kinase inhibitors (MTKIs), which mainly target the vascular endothelial growth factor receptor (VEGFR), have improved prognoses and dramatically changed the treatment strategy for advanced thyroid cancer. However, adverse events related to this inhibition can interrupt treatment and sometimes lead to discontinuation. In addition, they can be annoying and potentially jeopardize the subjects' quality of life, even allowing that the clinical outcome of patients with advanced thyroid cancer remains limited. In this review, we summarize the potential mechanisms underlying these adverse events (hypertension, proteinuria and renal impairment, hemorrhage, fistula formation/gastrointestinal perforation, wound healing, cardiovascular toxicities, hematological toxicity, diarrhea, fatigue, and acute cholecystitis), their characteristics, and actual management. Furthermore, we also discuss the importance of related factors, including alternative treatments that target other pathways, the necessity of subject selection for safer administration, and patient education.

The combination of lenvatinib plus pembrolizumab has shown efficacy in treatment of advanced endometrial carcinoma (that is not microsatellite instability-high or mismatch repair deficient) following prior systemic therapy in any setting in the open-label, single-arm, phase Ib/II Study 111/KEYNOTE-146. With the exception of hypothyroidism, the safety profile of the combination was comparable to that of each monotherapy. Given the medical complexity and fragility of patients with endometrial carcinoma, further characterization of adverse reactions (ARs) associated with treatment will help health care professionals to optimize treatment with lenvatinib plus pembrolizumab combination therapy.

In Study 111/KEYNOTE-146, patients received lenvatinib at a starting dose of 20 mg orally once daily and pembrolizumab 200 mg intravenously every 3 weeks. Selected ARs (hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria) were chosen for detailed post hoc analyses.

Median times to first onset of the selected ARs in this analysis all occurred within the first 10 weeks of treatment. Of the selected ARs, grade ≥3 severity of fatigue, hypertension, and nausea occurred in ≥5% of patients. Overall incidence of hypothyroidism was 51%, primarily of grade 2 severity (46%). Most of the ARs assessed were managed with a combination of study drug dose modifications and concomitant medications.

No new safety signals were identified and the toxicity profile in this study was manageable with supportive medications, dose interruptions, and/or lenvatinib dose reductions. This analysis provides AR management guidance for patients with endometrial cancer receiving lenvatinib plus pembrolizumab combination therapy.

Lenvatinib plus pembrolizumab has shown efficacy in the treatment of patients with advanced endometrial carcinoma (that is, not microsatellite instability-high or mismatch repair deficient) following at least one prior systemic therapy in any setting. Patients may experience toxicity associated with this combination, including adverse reactions of hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria. These adverse reactions may be managed with a combination of concomitant supportive care medications and judicious lenvatinib dose modifications. This article provides context and guidance for the recognition and management of adverse reactions in patients receiving lenvatinib plus pembrolizumab.

Lenvatinib is a standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, because of the high incidence of adverse events resulting from this treatment, it is not easy to maintain the dose intensity of lenvatinib, especially in Japanese patients. Although the prognostic impact of lenvatinib dose interruption has been reported, the target dose intensity of lenvatinib to optimize survival benefits remains unknown. We therefore propose a target dose intensity of lenvatinib during the first 8 weeks of treatment. We retrospectively analyzed 42 RR-DTC patients who were treated with lenvatinib for more than 8 weeks. We performed receiver operating characteristic curve analysis to determine the cut-off value of 8 weeks' relative dose intensity (8w-RDI) to predict treatment response, and identified that the optimal cut-off value of 8w-RDI was 60% (sensitivity: 81.8%; specificity: 80.6%). Median progression-free survival (PFS) (not reached [NR] vs. 11.0 months; hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.11-0.72; p < 0.01) and overall survival (NR vs. 27.6 months; HR 0.44; 95% CI 0.11-0.91; p = 0.03) were longer in the higher 8w-RDI (≥60%) patients than in the lower 8w-RDI (<60%) patients. Multivariate analysis revealed that 8w-RDI at ≥60% was an independent prognostic factor for PFS (HR 0.29; 95% CI 0.09-0.96; p = 0.04). Targeting for ≥60% of the relative dose intensity during the first 8 weeks of lenvatinib treatment can be sufficient to achieve significant tumor shrinkage and prolong PFS in RR-DTC patients.