Until recently, no truly effective treatment options have existed for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), a serious disease with poor prognosis. In ...November 2013, the targeted multikinase inhibitor, sorafenib, was approved for use in these patients based on substantially improved progression-free survival compared with placebo. A number of other targeted agents, including lenvatinib, are being investigated in phase II and phase III trials. With the advent of these new treatment options, practitioners are faced with making important decisions in determining which patients are candidates for systemic treatment and the optimal timing for treatment initiation. Since patients may remain asymptomatic for a protracted period of time, tumor size and growth rate are the primary considerations for making these choices. Proactive management of side effects is also critical in optimizing the effectiveness of treatment. Here we review targeted systemic agents that are either in use or are under investigation for RAI-refractory DTC and provide recommendations on the rationale for initiating systemic treatment and on managing adverse events. Four illustrative case studies are provided.
Background
Immune checkpoint inhibitors (ICIs) are increasingly used in various solid organ malignancies. However, there are limited data regarding their safety and efficacy in solid organ transplant ...(SOT) recipients. The aim of this study was to review our experience with ICIs in SOT recipients with advanced head and neck cutaneous squamous cell carcinoma (cSCC).
Methods
A retrospective review of ICIs used in SOT recipients from April 2011 to September 2019 was undertaken. Patient clinical and demographic features, ICI regimen, immunosuppression, treatment efficacy, and adverse events were reviewed.
Results
The seven SOT recipients (four kidney, two liver, one lung) were diagnosed with metastatic head and neck cSCC. All had undergone prior locoregional surgery and adjuvant radiation therapy. At a median of 10.8 years (range, 6.6–18.1) post‐transplant, six were treated with cemiplimab and one with pembrolizumab after minimizing calcineurin inhibitors (CNIs) or conversion of CNI to mammalian target of rapamycin (mTOR) inhibitors. During a median follow‐up of 7.1 months, overall tumor response rate was 57.1% with one complete responder and three partial responders. Four patients died at a median of 135 days after starting ICI with two dying from tumor progression and two dying from other causes. Regarding adverse events, one lung transplant recipient developed severe pneumonitis that resolved with high‐dose steroids, and one renal transplant patient developed progressive renal injury and died of unrelated causes. The three patients who received prophylactic prednisone all responded to cemiplimab with preserved allograft function and no adverse events.
Conclusion
Our data suggest that minimization of CNI and conversion of CNI to mTOR inhibitors along with judicious use of prophylactic steroids may allow for the safe use of ICIs in SOT recipients with advanced cSCC. Short‐term efficacy appears promising, but prospective studies with further follow‐up and a standardized protocol for prophylactic steroids are needed.
Implications for Practice
Solid organ transplant (SOT) recipients are at increased risk of developing malignancy because of long‐term post‐transplant immunosuppression. Although immune checkpoint inhibitors (ICIs) are increasingly shown to be successful in treating multiple types of cancer, SOT recipients have been excluded from clinical trials because of concerns regarding potential allograft rejection. This pilot study provides evidence that ICIs along with prophylactic steroids may be a safe and efficacious treatment option for selected SOT recipients with advanced cutaneous squamous cell carcinoma. However, further prospective studies using ICIs in this high‐risk patient population are needed.
This article focuses on the safety and efficacy of immune checkpoint inhibitors in solid organ transplant recipients with advanced head and neck cutaneous squamous cell carcinoma who have failed attempts at immunosuppression minimization, as well as prior surgical, radiation therapy, and other systemic therapies.
Purpose In the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with ...radioiodine-refractory differentiated thyroid cancer (RR-DTC). This prespecified subanalysis investigated the effect of age on the efficacy and safety of lenvatinib. Patients and Methods This randomized, double-blind, phase III study enrolled patients with histologically confirmed RR-DTC stratified by age (≤ 65 or > 65 years). Patients (N = 392) received lenvatinib 24 mg/day (n = 261) or placebo (n = 131). The primary end point was PFS; secondary end points included overall survival (OS), objective response rate, and safety. Results In both treatment arms, median ages were 56 (younger group) and 71 years (older group). PFS benefit was maintained with lenvatinib versus placebo in the younger and older age groups, with median PFS of 20.2 versus 3.2 months (hazard ratio HR, 0.19; 95% CI, 0.13 to 0.27; P < .001) and 16.7 versus 3.7 months (HR, 0.27; 95% CI, 0.17 to 0.43; P < .001), respectively. PFS did not differ with age in either treatment arm. OS was improved in older lenvatinib-treated patients versus placebo (HR, 0.53; 95% CI, 0.31 to 0.91; P = .020). Younger lenvatinib-treated patients showed significantly higher ORR (72% v 55%; P = .0038), longer time to first dose reduction (3.7 v 1.5 months), and lower proportion of grade ≥ 3 treatment-related adverse events (67% v 89%; P < .001) compared with older patients. Conclusion This subanalysis demonstrated improved PFS with lenvatinib treatment versus placebo in both age groups, although higher toxicity was observed in older patients. Despite the allowance of crossover after disease progression, the OS benefit was observed in older patients, suggesting that lenvatinib should be considered for treatment of patients of any age with RR-DTC.
SummaryBackgroundMost head and neck squamous-cell carcinomas (HNSCCs) are driven by p16 INK4A inactivation and cyclin D1 overexpression that results in hyperactivation of cyclin-dependent kinase 4 ...and 6 (CDK4/6), rather than by the human papillomavirus (HPV). Deregulated cyclin D1 expression also causes resistance to EGFR inhibitors. We previously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibitor) was safe. The aim of this study was to establish the proportion of patients achieving an objective response with palbociclib and cetuximab in recurrent or metastatic HNSCC. MethodsWe did a multicentre, multigroup, phase 2 trial to evaluate the activity of palbociclib and cetuximab in platinum-resistant (group 1) and cetuximab-resistant (group 2) HPV-unrelated HNSCC. The study was done across eight university sites in the USA. Eligibility required measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1·1 RECIST 1·1), Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, age of 18 years or older, and disease progression on platinum but cetuximab-naive (group 1) or disease progression on cetuximab (group 2). All patients received palbociclib orally (125 mg/day, on days 1–21) and intravenous cetuximab (400 mg/m 2 on cycle one, day 1, then 250 mg/m 2 once per week) in 28-day cycles. The primary endpoint was objective response (complete responses and partial responses per RECIST 1·1). Analyses were done per protocol. This trial was registered with ClinicalTrials.gov, NCT02101034, and is ongoing, but both groups are closed to accrual. FindingsBetween Oct 19, 2015, and Nov 7, 2018, 62 patients were enrolled onto the trial: 30 patients were enrolled in group 1 and 32 in group 2. Median follow-up was 5·4 months (IQR 4·4–12·1) for group 1 and 5·5 months (4·3–8·3) for group 2. In group 1, of 28 evaluable patients, an objective response was achieved by 11 (39%; 95% CI 22–59). In group 2, of 27 evaluable patients, an objective response was achieved by five (19%; 6–38) in group 2. The most common grade 3–4 palbociclib-related adverse event was neutropenia (in 21 34% of 62 patients). No treatment-related deaths occurred. InterpretationIn patients with platinum-resistant or cetuximab-resistant HPV-unrelated HNSCC, palbociclib and cetuximab results in promising activity outcomes. Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC. FundingPfizer.
Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell ...carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC.
This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0–1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants.
Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9–10·9). By 6 months, the overall response rate was 45% (95% CI 28–62), with 15 of 33 participants achieving a partial response. The most common grade 3–4 treatment-related adverse event was oral mucositis (three 9% of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred.
Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation.
Merck Sharp & Dohme.
Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we ...evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.
The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with locally advanced disease, which requires site-specific combinations of surgery, radiation, and chemotherapy. ...Despite aggressive therapy, survival outcomes remain poor, and treatment-related morbidity is not negligible. For patients with recurrent or metastatic disease, therapeutic options are further limited and prognosis is dismal. With this in mind, molecularly targeted therapy provides a promising approach to optimizing treatment efficacy while minimizing associated toxicity. The ErbB family of receptors (ie, epidermal growth factor receptor EGFR, ErbB2/human epidermal growth factor receptor HER-2, ErbB3/HER3, and ErbB4/HER4) is known to contribute to oncogenic processes, such as cellular proliferation and survival. EGFR, specifically, is upregulated in more than 90% of HNSCC, has been implicated in radiation resistance, and correlates with poorer clinical outcomes. The central role of EGFR in the pathogenesis of HNSCC suggests that inhibition of this pathway represents an attractive treatment strategy. As a result, EGFR inhibition has been extensively studied, with the emergence of two classes of drug therapy: monoclonal antibodies and tyrosine kinase inhibitors. While the monoclonal antibody cetuximab is currently the only US Food and Drug Administration-approved EGFR inhibitor for the treatment of HNSCC, numerous investigational drugs are being evaluated in clinical trials. This paper will review the role of the ErbB family in the pathogenesis of HNSCC, as well as the evidence-based data for the use of ErbB family inhibition in clinical practice.
Patterns and prognostic implications of recurrent adrenocortical carcinoma are poorly understood. In this study, we aim to describe temporal and spatial patterns of adrenocortical carcinoma ...recurrence.
This is a retrospective review of 576 patients with adrenocortical carcinoma evaluated at a single institution. Clinicopathologic and follow-up data were collected longitudinally.
A total of 354 patients underwent resection of stage I-III adrenocortical carcinoma. We found that 249 (70%) patients developed disease recurrence. The median recurrence-free interval after primary resection was 11 months. The most common sites of initial recurrence were lung and tumor bed. The shortest time to recurrence was associated with lung or multiple site metastases. We found that 142 of 249 patients developed one or more additional sites of recurrence (median 5 months), most commonly involving the lungs. A total of 20 patients developed a third site of recurrence. We found that 100 patients underwent one or more reoperations or metastasectomies and 79 recurred again after reoperation. Same organ or site recurrence was common after reoperation (67%). Although lung metastases occurred early, recurrences to the peritoneal cavity or to multiple sites were associated with worse survival. Metastasectomy beyond three total operations did not improve overall survival.
Survival varies according to site of recurrence and other clinicopathologic factors. Knowledge of patterns of recurrence may assist in anticipating disease course and lead to better informed selection of treatment.
mutations occur in 70% of medullary thyroid cancers, and
fusions occur rarely in other thyroid cancers. In patients with
-altered thyroid cancers, the efficacy and safety of selective RET inhibition ...are unknown.
We enrolled patients with
-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated
fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.
In the first 55 consecutively enrolled patients with
-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval CI, 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with
-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated
fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.
In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
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