A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Safety and clinical activity of atezolizumab plus erlotinib in patients with non-small-cell lung cancer.

BACKGROUND: Acquired resistance limits long-term epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) in whom anti-programmed death-ligand 1 (PD-L1) efficacy is also limited. We hypothesized that combining atezolizumab with erlotinib could enhance antitumor immunity and extend efficacy in these patients. PATIENTS AND METHODS: This open-label phase Ib trial was conducted in adults aged ≥18 years who had advanced, unresectable NSCLC. Stage 1 (safety evaluation) enrolled EGFR TKI-naive patients regardless of EGFR status. Stage 2 (expansion) enrolled patients with EGFR-mutant NSCLC treated with ≤1 prior non-EGFR TKI therapy. Patients received 150 mg erlotinib orally once daily. After a 7-day erlotinib run-in, atezolizumab 1200 mg was administered intravenously every 3 weeks. The primary endpoint was the safety and tolerability of the combination in all patients; secondary endpoints included antitumor activity per RECIST 1.1 in stage 2 patients. RESULTS: At the data cut-off on 7 May 2020, 28 patients (8 in stage 1, 20 in stage 2) were assessable for safety. No dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred. Grade 3 treatment-related adverse events occurred in 46% of patients; the most common were increased alanine aminotransferase, diarrhea, pyrexia, and rash (each in 7% of patients). Serious adverse events occurred in 50% of patients. Pneumonitis (grade 1) was reported in a single patient (4%). The objective response rate was 75% [95% confidence interval (CI) 50.9% to 91.3%]), median response duration was 18.9 months (95% CI 9.5-40.5 months), median progression-free survival was 15.4 months (95% CI 8.4-39.0 months), and median overall survival was not estimable (NE) (95% CI 34.6-NE). CONCLUSIONS: Atezolizumab combined with erlotinib demonstrated a tolerable safety profile and encouraging, durable clinical activity in patients with advanced EGFR mutation-positive NSCLC.

OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer.

BACKGROUND: Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. PATIENTS AND METHODS: Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%-50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity. RESULTS: Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P < 0.0001). CONCLUSIONS: Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. CLINICAL TRIAL REGISTRATION: Clinical trials.gov identifier: NCT02258659.

Response-adapted volume de-escalation (RAVD) in locally advanced head and neck cancer.

BACKGROUND: Efforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiotherapy (RT) dose de-escalation. In this phase I/II protocol investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction. PATIENTS AND METHODS: Patients with measurable LA-HNSCC received two cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus). Patients with ≥50% reduction in the sum of tumor diameters [good response (GR)] received TFHX (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to a dose of 75 Gy with the single planning target volume (PTV1) encompassing exclusively gross disease. Patients with <50% response [non-response (NR)] were treated with TFHX encompassing PTV1 and the next nodal station at risk (PTV2) to a dose of 45 Gy followed by a sequential boost to PTV1 to a dose of 75 Gy. RESULTS: Ninety-four patients were enrolled. Randomization to everolimus was discontinued on interim analysis after 50 patients due to futility. IC response was evaluable in 89 patients. Thirty-seven patients (41.6%) had GR and 52 (58.4%) had NR. There was a trend for improved progression-free (P = 0.086) but not overall survival (P = 0.94) for GR versus NR. The 2-year PFS and OS were 86.0% and 83.5% for GR and 68.7% and 85.4% for NR, respectively. NR were significantly more likely to undergo G-tube placement during treatment (50.0% GR versus 73.5% NR, P = 0.040) and be G-tube dependent at 6-month follow-up (5.7% GR versus 32.6% NR, P = 0.005). CONCLUSIONS: The addition of everolimus to IC was not beneficial. The elimination of elective nodal coverage in patients with GR to IC did not appear to compromise outcomes and resulted in significantly decreased late toxicity. Further investigation of RAVD is warranted. CLINICALTRIALSGOV: NCT01133678.

Leptomeningeal carcinomatosis in esophageal cancer: a case series and systematic review of the literature.

The aim of this study was to more clearly define the clinical course of leptomeningeal carcinomatosis due to esophageal cancer. A single institution retrospective case series was conducted. Additionally, a systematic review of the literature was performed. We present a large case series (n = 7) of leptomeningeal carcinomatosis due to esophageal cancer. Our case series and systematic review of the literature report similar findings. In our series, we report a predominance of male patients (86%) with adenocarcinoma histology (77%). Variable onset of leptomeningeal involvement of esophageal cancer in relation to the original diagnosis of the primary disease (5 months to 3 years and 11 weeks) was noted. Disease progresses quickly and overall survival is poor, measured in weeks (2.5-16 weeks) from the diagnosis of leptomeningeal involvement. Four of our patients initiated whole-brain radiation therapy with only two completing the course prior to clinical deterioration. Our patient with the longest survival (16 weeks) received intrathecal topotecan and oral temozolomide. Leptomeningeal carcinomatosis secondary to esophageal cancer has a poor prognosis. A clearly beneficial treatment modality is lacking.

Phase II trial of pemetrexed-based induction chemotherapy followed by concomitant chemoradiotherapy in previously irradiated patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Concurrent chemoreirradiation therapy (CRRT) offers a therapeutic option for patients with locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that response to induction chemotherapy (IC) would improve outcome and predict increased survival. PATIENTS AND METHODS: Subjects with recurrent SCCHN not amenable to standard therapy were eligible. IC consisted of two 28-day cycles of gemcitabine and pemetrexed on days 1 and 14, followed by surgical resection, if appropriate, and/or CRRT consisting of carboplatin, pemetrexed, and single daily fractionated radiotherapy. RESULTS: Thirty-five subjects were enrolled, 31 were assessable for response, with 11 responders [response rate = 35%; 95% confidence interval (CI) 19.2-54.6]. Among 24 subjects who started CRRT, 11 were assessable for radiographic response, 4 complete response, 2 partial response, and 5 progressive disease. Median progression-free survival and overall survival (OS) were 5.5 months (95% CI 3.6-8.3) and 9.5 months (95% CI 7.2-15.4), respectively. One-year OS was 43% (95% CI 26% to 58%). Subjects who responded to IC had improved survival (P = 0.02). Toxic effects included mucositis, dermatitis, neutropenia, infection, hemorrhage, dehydration, and pain. CONCLUSIONS: The combination of pemetrexed plus gemcitabine was active and well tolerated in recurrent SCCHN. Response to IC may help stratify prognosis and offer an objective and dynamic metric in recurrent SCCHN patients being considered for CRRT.