Summary
Background
Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen.
Methods
We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer.
Findings
Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells).
Interpretation
Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted.
Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m(2) and a maintenance weekly dose of 250 mg/m(2).
Bortezomib has modest single-agent activity in patients with relapsed or refractory advanced NSCLC using this schedule, with minor enhancement in combination with docetaxel. Additional investigation of bortezomib in NSCLC is warranted in combination with other drugs known to be active, or using different schedules.
Vorinostat (Zolinza ® ), a histone deacetylase inhibitor, was approved by the US Food and Drug Administration in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and hematologic malignancies and collated tolerability data from the vorinostat clinical trial program. Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4 drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination with other systemic therapies has been observed across a range of malignancies. Ongoing and planned studies will further evaluate the potential of vorinostat in combination therapy, including combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome.
Histone Deacetylase Inhibition with Vorinostat as a Target in OncologyAdvanced or refractory malignancy remains an area of high unmet medical need as patients often relapse and curative therapy is elusive. The mainstay of treatment is generally cytotoxic chemotherapy which can have limited efficacy and is often associated with significant toxicity; there is a need for novel agents that are not only effective
There was no statistically significant survival advantage for carboplatin-paclitaxel compared with cisplatin-etoposide. However, there was an overall benefit in quality of life with the carboplatin-paclitaxel regimen.
A B S T R A C T PurposeNon-small-cell lung cancer (NSCLC) commonly expresses the epidermal growth factor receptor (EGFR), which is associated with poor clinical outcome. Cetuximab is a chimerized monoclonal antibody that targets the EGFR and, in preclinical models, it demonstrates radiosensitization properties. We report a phase II trial testing the combination of cetuximab with chemoradiotherapy (CRT) in unresectable stage III NSCLC.
Patients and Methods
ResultsIn all, 93 patients were enrolled and 87 were evaluable. Median follow-up was 21.6 months. Response rate was 62% (n ϭ 54), median survival was 22.7 months, and 24-month overall survival was 49.3%. Adverse events related to treatment included 20% grade 4 hematologic toxicities, 8% grade 3 esophagitis, and 7% grade 3 to 4 pneumonitis. There were five grade 5 events.
ConclusionThe combination of cetuximab with CRT is feasible and shows promising activity. The median and overall survival achieved with this regimen were longer than any previously reported by the Radiation Therapy Oncology Group.
Endoglin is a homodimeric cell membrane glycoprotein receptor for transforming growth factor β and bone morphogenetic proteins. Endoglin is essential for angiogenesis, being densely expressed on proliferating endothelial cells and upregulated during hypoxia. Its expression is implicated in development of resistance to vascular endothelial growth factor (VEGF) inhibition. TRC105 is an antibody that binds endoglin and prevents endothelial cell activation. Targeting endoglin and the VEGF pathway concurrently improves treatment in vitro and appears to reverse resistance to bevacizumab in some refractory cancer patients. Randomized trials are under way to assess the clinical benefit of adding TRC105 therapy to bevacizumab therapy. Further trials are under way to assess the activity of TRC105 with small-molecule inhibitors of the VEGF pathway in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma. Stratification of soft tissue sarcomas based on endoglin expression levels is proposed to identify patients most likely to benefit from TRC105 treatment. The development of a TRC105 antibody-drug conjugate is also described.
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