Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study.

BACKGROUND: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. METHODS: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. FINDINGS: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. FUNDING: Regeneron Pharmaceuticals and Sanofi.

A Phase I dose-escalation study of afatinib combined with nintedanib in patients with advanced solid tumors.

AIMS: To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. MATERIALS & METHODS: Patients received afatinib 10-20 mg daily plus nintedanib 150-200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. RESULTS: Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. CONCLUSION: The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.

Primary intestinal-type adenocarcinoma of the oral tongue: Case report and review of histologic origin and oncologic management.

BACKGROUND: Primary intestinal-type adenocarcinoma (ITAC) of the oral tongue is an extremely uncommon malignancy with only 3 cases reported in the literature. This high-grade malignancy originates from metaplasia of minor salivary glands. METHODS: A 40-year-old man presented with a gradually enlarging midline oral tongue mass, odynophagia, and dysphagia. Management included a median lingual glossectomy, bilateral neck dissections, and adjuvant chemoradiation with 5-fluorouracil (5-FU). Additional chemotherapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) was given to mimic therapy in colonic adenocarcinomas. RESULTS: Thirteen months after surgery and adjuvant chemoradiotherapy, there is no evidence of locoregional or distant disease. His diet and speech have normalized after reconstruction without free tissue transfer. CONCLUSION: We report the fourth case of oral tongue ITAC, and present the first histologic evidence of metaplasia of oral cavity salivary epithelium. We also discuss adjuvant therapy recommendations given the lack of clarity for treatment of this rare disease.

A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors.

PURPOSE: Based on our mouse xenograft model demonstrating that intermittent high-dose gefitinib sensitizes tumors to subsequent treatment with taxanes, we initiated this phase I trial to explore docetaxel in combination with escalating doses of intermittent gefitinib (Iressa) given prior to docetaxel. METHODS: This was a phase I study where patients with advanced cancer were treated with escalating doses of gefitinib (1,000, 1,500, 2,250, 3,000 mg) on days 1 and 2 followed by docetaxel (75 mg/m2) on day 3 of a 21 day cycle. Gefitinib pharmacokinetic data were obtained on days 1, 2, and 3 of cycles 1 and 2 at each dose level. RESULTS: 18 patients were enrolled in this study with the most frequent tumor types being non-small cell lung cancer and head and neck squamous cell cancer. The dose-limiting toxicity was neutropenia (n=1 at dose level 2, n=2 at dose level 4). Rash, diarrhea, and fatigue were the most common grade 1-2 toxicities. Pharmacokinetic data indicated no accumulation of gefitinib between cycles 1 and 2 and no clear correlation between gefitinib plasma levels and toxicity. Partial responses were observed in one patient with head and neck squamous cell carcinoma and one patient with anaplastic thyroid cancer. CONCLUSION: The recommended dose for phase II studies is gefitinib 2,250 mg on days 1 and 2, followed by docetaxel 75 mg/m2 on day 3.

Unusual Case of Papillary Thyroid Carcinoma with Choroidal Metastasis.

BACKGROUND: The choroid is a rare site of thyroid cancer metastases, and has been described in patients with evidence of advanced breast, lung, and prostate carcinomas. To the authors' knowledge, only seven reported cases exist with choroidal metastasis secondary to papillary thyroid carcinoma (PTC). This study describes an additional patient with metastatic PTC with simultaneous appearance of choroidal mass and cutaneous deposits while on systemic therapy with a tyrosine kinase inhibitor (TKI). These infrequent sites of metastasis are typically associated with a dismal prognosis following the diagnoses. However, this patient has not shown evidence of choroid or cutaneous recurrence one year following local targeted and systemic therapy. PATIENT FINDINGS: The case is presented of a 70-year-old male with widely metastatic PTC to the lymph nodes, lung, and mediastinum who was found to have choroidal metastasis six years after his initial diagnosis. SUMMARY: The patient was asymptomatic and was found to have an incidental right choroidal mass on routine ophthalmology exam. Magnetic resonance imaging of the orbit revealed an isolated right choroid lesion suspicious for melanoma or metastasis. Concurrent to this discovery, he was noted to have progression of the lung and mediastinal disease along with new dermal lesions on the chest wall suspicious for dermal metastasis. Both the choroid and dermal metastases occurred while being on a TKI. Given his previous history of male breast carcinoma, a biopsy of the choroid was performed, which confirmed PTC. The patient developed endophthalmitis and subsequently underwent enucleation of the right eye. The choroid mass was completely excised, measured 3.5 mm×9.5 mm with negative margins, and histopathology was consistent with metastatic PTC. Pulmonary, mediastinal, and cutaneous lesions regressed after external beam radiation therapy, following which systemic therapy was changed to a different multikinase inhibitor. CONCLUSION: A rare and unique case is reported of choroidal metastasis from PTC that presented with concurrent new dermal metastasis in addition to lung and mediastinal lymph node progression. Furthermore, the patient developed choroid and dermal lesions while on a TKI and remained stable without recurrence in these regions after switching to an alternate multikinase inhibitor.

Randomized Multicenter Phase II Study of Modified Docetaxel, Cisplatin, and Fluorouracil (DCF) Versus DCF Plus Growth Factor Support in Patients With Metastatic Gastric Adenocarcinoma: A Study of the US Gastric Cancer Consortium.

PURPOSE: Docetaxel, cisplatin, and fluorouracil (DCF) is a standard first-line three-drug chemotherapy regimen for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and is associated with significant toxicity. We examined the safety and efficacy of a modified DCF (mDCF) regimen in a randomized multicenter phase II study. PATIENTS AND METHODS: Previously untreated patients with metastatic gastric or GEJ adenocarcinoma were randomly assigned to receive either mDCF (fluorouracil 2,000 mg/m2 intravenously [IV] over 48 hours, docetaxel 40 mg/m2 IV on day 1, cisplatin 40 mg/m2 IV on day 3, every 2 weeks) or parent DCF (docetaxel 75 mg/m2, cisplatin 75 mg/m2, and fluorouracil 750 mg/m2 IV over 5 days with granulocyte colony-stimulating factor, every 3 weeks). The study had 90% power to differentiate between 6-month progression-free survival of 26% and 43%, with type I and II error rates of 10% each. An early stopping rule for toxicity was included, defined as grade 3 to 4 adverse event rate > 70% in the first 3 months. RESULTS: From November 2006 to June 2010, 85 evaluable patients were enrolled (male, n = 61; female, n = 24; median age, 58 years; Karnofsky performance status, 90%; GEJ, n = 28; gastric, 57). mDCF (n = 54) toxicity rates included 54% grade 3 to 4 toxicity (22% hospitalized) within the first 3 months and 76% grade 3 to 4 toxicity over the course of treatment. The DCF arm (n = 31) closed early because of toxicity, with rates of 71% grade 3 to 4 toxicity (52% hospitalized) within 3 months and 90% grade 3 to 4 toxicity over the course of treatment. Six-month PFS was 63% (95% CI, 48% to 75%) for mDCF and 53% (95% CI, 34% to 69%) for DCF. Median overall survival was improved for mDCF (18.8 v 12.6 months; P = .007). CONCLUSION: mDCF is less toxic than parent DCF, even when supported with growth factors, and is associated with improved efficacy. mDCF should be considered a standard first-line option for patients with metastatic gastric or GEJ adenocarcinoma.

Immunoglobulin G4-related sclerosing disease of the paranasal sinus.

BACKGROUND: Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic disease characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. We present a case of a 69-year-old man with maxillary sinus IgG4 sclerosing disease, with orbital invasion treated with rituximab and dexamethasone pulse therapy. Surgery was used as well to debulk the disease and to obtain tissue for diagnosis. METHODS: A PubMed search using the key phrase "IgG4-related Sclerosing Disease" was performed. There were 304 different articles regarding the disease for a multitude of different organ sites. Of the 304 articles, there were 3 articles that reported this disease in the paranasal sinuses. CONCLUSIONS: IgG4-related sclerosing disease is a rare entity in the head and neck. There are documented reports of steroid therapy for this disease, but the patient presented here demonstrated clinical progression of disease with steroids alone. The use of combination therapy of surgery, dexamethasone, and rituximab provided clinical improvement and stable disease determined by radiographic means.

Evaluation of romidepsin for clinical activity and radioactive iodine reuptake in radioactive iodine-refractory thyroid carcinoma.

BACKGROUND: Historically, systemic therapy for radioactive iodine (RAI)-refractory thyroid cancer has been understudied. Available drugs have modest efficacy. Romidepsin is a histone deacetylase inhibitor with potent antitumor effects both in vitro and in vivo. In thyroid cancer cell lines, romidepsin increases expression of both thyroglobulin and the sodium iodide symporter messenger RNAs, suggesting the possibility of improved iodine concentrating ability of RAI-resistant tumors. METHODS: This was a single-institution Simon 2-stage phase II clinical study. Eligible patients had progressive, RAI-refractory, recurrent/metastatic, nonmedullary, nonanaplastic thyroid cancer. Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 measurable disease and adequate organ/marrow function were required. Romidepsin 13 mg/m² was administered intravenously on days 1, 8, and 15, in cycles of 28 days. The primary endpoint was the response rate by RECIST; change in RAI avidity was a secondary endpoint. The study closed after the first stage due to the lack of response. RESULTS: Twenty patients were enrolled: female, 50%; median age, 64 years; histology, 8 papillary/1 follicular/11 Hürthle. Grade 4-5 adverse events (AEs) possibly related to the drug: grade 5, 1 sudden death; grade 4, 1 pulmonary embolus. Twelve of 20 subjects had a reported adverse event. No RECIST major responses have been seen. Response per protocol: stable disease, 13; disease progression, 7. Restoration of RAI avidity was documented in two patients. Median overall survival and time on study was 33.2 (1-71+) and 1.7 (0.46-12) months, respectively. CONCLUSIONS: We observed preliminary signs of in vivo reversal of RAI resistance after treatment with romidepsin. However, no major responses were observed and accrual was poor after the grade 5 AE.

Double-blind, placebo-controlled, randomized trial of granulocyte-colony stimulating factor during postoperative radiotherapy for squamous head and neck cancer.

UNLABELLED: To evaluate the ability of granulocyte-stimulating factor to decrease mucositis during postoperative radiotherapy for stage II-IV squamous head and neck cancer in a randomized, double-blind, placebo-controlled trial. METHODS: After undergoing complete resection, patients were randomized to receive granulocyte-colony stimulating factor or placebo by daily subcutaneous injection during radiotherapy (63 Gy, 1.8 Gy/day). Patients undergoing prior radiotherapy or chemotherapy were excluded from the study. The primary outcome was the need for percutaneous endoscopic gastrostomy placement. Severity of mucositis was a secondary outcome. RESULTS: Forty-one patients were enrolled (132 planned). The study closed after slow accrual. Patient characteristics were as follows (granulocyte-colony stimulating factor vs placebo): median age, 59 versus 54 years; pT4, 16% versus 23%; pN2/3, 68% versus 59%; stage IV, 79% versus 68%. Forty patients were evaluable for planned outcomes. Patients in the granulocyte-colony stimulating factor arm showed trends toward lower rates of percutaneous endoscopic gastrostomy placement (0% vs 14%, P = 0.2) and severity of mucositis (P = 0.13), and had shorter mean radiotherapy duration (48.4 +/- 4.32 days vs 51.6 +/- 1.84 days, P = 0.005). Overall survival was significantly greater in the granulocyte-colony stimulating factor arm (hazard ratio, 0.37; P = 0.037). DISCUSSION: Granulocyte-colony stimulating factor during radiotherapy was feasible and led to significantly shorter radiotherapy duration and trends toward less percutaneous endoscopic gastrostomy placement and mucositis. The unanticipated improvement in survival outcomes warrants further hypothesis-driven investigation and validation.

Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm.

PURPOSE: Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. Cetuximab has activity in squamous cell carcinoma and enhances both chemotherapy and radiotherapy. We conducted a pilot phase II study of a new combined-modality paradigm of targeted therapy (cetuximab) with chemoradiotherapy. PATIENTS AND METHODS: Eligible patients had stage III or IV, M0, squamous cell head and neck cancer. Treatment included concomitant boost radiotherapy (1.8 Gy/d weeks 1 to 6; boost: 1.6 Gy 4 to 6 hours later weeks 5 to 6; 70 Gy total to gross disease), cisplatin (100 mg/m2 intravenously weeks 1 and 4), and cetuximab (400 mg/m2 intravenously week 1, followed by 250 mg/m2 weeks 2 to 10). RESULTS: Twenty-two patients were enrolled (median age, 57 years; range, 41 to 72 years; median Karnofsky status, 90%; range, 70% to 90%; oropharynx primary tumor, 59% of patients; T4, 36%; N2/3, 77%; stage IV disease, 86%). One patient did not receive study treatment because of an ineligible diagnosis. The severity of expected, acute toxicities was typical of concurrent cisplatin and radiotherapy alone. Grade 3 or 4 cetuximab-related toxicities included acne-like rash (10%) and hypersensitivity (5%). However, the study was closed for significant adverse events, including two deaths (one pneumonia and one unknown cause), one myocardial infarction, one bacteremia, and one atrial fibrillation. With a median follow-up of 52 months, the 3-year overall survival rate is 76%, the 3-year progression-free survival rate is 56%, and the 3-year locoregional control rate is 71%. CONCLUSION: This regimen is not currently recommended outside of the clinical trial setting. Further investigation of its safety profile is needed. However, preliminary efficacy is encouraging, and further development of this targeted combined-modality paradigm is warranted.