A Phase II Trial of Pevonedistat and Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: Postimmunotherapy (IO) treatment options for stage IV non-small-cell lung cancer (NSCLC) remain limited. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRL) catalyze degradation of tumor suppressor proteins and are overactivated in NSCLC. Neddylation, which is catalyzed by the NEDD8 activating enzyme (NAE), is required for the activation of CRLs. Pevonedistat, a first-in-class small molecule NAE inhibitor, exerted antitumor activity when combined with docetaxel in preclinical studies. METHODS: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with relapsed/refractory stage IV NSCLC. Patients received docetaxel 75 mg/m2 on day 1 and pevonedistat 25 mg/m2 on days 1, 3 and 5 of a 21-day cycle. The primary endpoint was objective response rate (ORR). RESULTS: From March 5, 2018 to January 26, 2021, we enrolled 31 patients. The ORR was 22% (1 CR, 5 PR), median PFS was 4.1 months, and median OS was 13.2 months. The incidence of Grade ≥3 adverse events (AE) was 53% in patients (n = 30) who received at least 1 dose of both drugs, with the most frequent being neutropenia and AST/ALT elevation. One patient was taken off study for a Grade 4 transaminase elevation. There were no Grade 5 toxicities. CONCLUSION: Our data suggest that the combination of docetaxel and pevonedistat is safe and exerts activity in patients with relapsed NSCLC. These encouraging results suggest that the neddylation pathway is an antitumor pathway that should be further studied.

Phase II trial of biweekly gemcitabine and paclitaxel with recurrent or metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group study S0329.

BACKGROUND: A phase I study and an institutional pilot study in patients with metastatic/recurrent squamous cell carcinoma of the head and neck (SCCHN) utilizing biweekly gemcitabine and paclitaxel (GEMTAX), showed an overall response rate of 53%. 1 This phase II trial was conducted to determine the feasibility, tolerability, and efficacy of this combination. METHODS: Patients with metastatic/recurrent SCCHN were treated with gemcitabine (3000 mg/m2) and paclitaxel (150 mg/m2) on days 1 and 15 of every 28-day cycle. RESULTS: In 57 patients with measurable disease, median progression-free survival (PFS) was 4 months and median overall survival (OS) was 8 months. Overall response rate of 28% and disease stabilization in 19% were seen. There were no treatment-related deaths with grade 3/4 hematologic toxicity seen in 20% of the patients. CONCLUSION: Biweekly GEMTAX is feasible, well tolerated, and demonstrated reasonable efficacy. This may be an alternative for patients who are not candidates for platinum-based chemotherapy.

Carboplatin-pemetrexed in treatment of patients with recurrent/metastatic cancers of the head and neck; superior outcomes in oropharyngeal primaries.

BACKGROUND: Platinum-based therapy in combination with 5-fluorouracil with cetuximab has shown the best survival in pts with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The purpose of this study is to evaluate the efficacy and tolerability of carboplatin, pemetrexed and to assess differential outcomes in patients with oropharyngeal primary and HPV related disease. PATIENTS AND METHODS: The charts of consecutive patients with R/M SCCHN were reviewed. All patients receiving at least one cycle of the two-drug regimen (pemetrexed 500 mg/m(2), carboplatin area under the curve of five intravenously), were included for assessment of response, safety, toxicity, and survival. RESULTS: A total of 86 patients received this regimen between January 2008 and December 2012, of which, 63 were included in this analysis. Forty-one percent (26) of the patients had cancers of the oropharynx, and of those, 50% had HPV-positive disease, 32% (20) had cancers of the larynx, and 24% (15) of the oral cavity. Median number of cycles administered was 4 (range 1-14 cycles) with 50% of the patients receiving four or more cycles. Half the patients achieved stable disease as their best response, 8% (5) attained a partial response, 24% progressed on therapy, and the remaining patients (12) could not have their response assessed. On the basis of Kaplan-Meier analysis, median progression-free survival (PFS) was 5.1 months (95% CI 3.2, 6.2) and median overall survival (OS) was 9.4 months (95% CI 4.3, 13.1). Among pts with oropharyngeal primary (n = 26), median PFS was 6.4 months (95% CI 2.8, 7.9) and median OS was 16.6 months (95% CI 9.6, 19.5). Among HPV+ pts (n = 13), median PFS was 7.0 months (95% CI 4.8, ne) and median OS was 17.1 months (95% CI 11.2, 21.7). CONCLUSION: Combination carboplatin-pemetrexed is an effective and well-tolerated treatment, associated with a median PFS of 5.1 months and a clinical benefit in at least 57% of the patients treated.

Dermatofibrosarcoma protruberans treatment with platelet-derived growth factor receptor inhibitor: a review of clinical trial results.

PURPOSE OF REVIEW: Dermatofibrosarcoma protuberans (DFSP) is a rare mesenchymal neoplasm arising in the dermis, accounting for less than 0.1% of all cancers. Given its rarity, and paucity of randomized trials, the nuances of treatment are not widely understood. In this review we attempt to summarize the available data to guide treatment choices for physicians managing this disease. RECENT FINDINGS: DFSP carries a translocation of chromosomes 17 and 22 leading to juxtaposition of the collagen type-1α1 promoter to the platelet-derived growth factor (PDGF) gene. This results in unregulated expression of PDGF leading to autocrine or paracrine activation of its receptor (PDGFRß). This molecular pathway is the target of our current drug therapy for DFSP, imatinib, a tyrosine kinase inhibitor that interferes with the phosphorylation and activation of PDGFRß. In case reports and prospective studies, imatinib was noted to be an effective treatment for patients with unresectable or metastatic DFSP, associated with response rates approaching 50%. It has also been used preoperatively to improve the resectability of tumors. Since metastasis is rarely seen and local recurrences are uncommon following wide excision with pathologically negative margins, surgery remains the backbone of treatment. SUMMARY: Imatinib, a tyrosine kinase inhibitor, is the current preferred agent for treatment of unresectable or metastatic DFSP. Clinical trials evaluating broader-spectrum kinase inhibitors such as pazopanib are in development.

Carboplatin/pemetrexed/bevacizumab in the treatment of patients with advanced non-small-cell lung cancer: a single-institution experience.

PURPOSE: The purpose of this study was to determine the efficacy and tolerability of carboplatin, pemetrexed, and bevacizumab in patients with advanced, nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The charts of consecutive patients with stage IIIB/IV nonsquamous NSCLC were reviewed. All patients receiving at least 1 cycle of the 3-drug regimen (pemetrexed 500 mg/m2, carboplatin area under the curve of 5-6, bevacizumab 15 mg/kg intravenously), were included for assessment of response, safety, and toxicity. RESULTS: A total of 27 patients received this regimen between February 2008 and July 2009; 63% were women. Median follow-up was 6.3 months (range, 1.6-21.1 months). Median number of cycles was 6 (range, 1-6 cycles); 67% completed 6 cycles; 83% went on to receive maintenance bevacizumab/pemetrexed. Among those who received maintenance, the median number of cycles administered was 4.5 (range, 1-18 cycles). Response rate was 52%; stable disease was observed in another 40%. On the basis of Kaplan-Meier analysis, actuarial overall survival was 83% at 12 months; actuarial progression-free survival was 83% and 63% at 6 and 12 months, respectively. Clinical improvement was noted in 41% of the patients, with clinical stability in another 48%. Grade 2 and 3 toxicities from the regimen included anemia (11% and 15%), fatigue (37% and 7.4%), febrile neutropenia (7.4%; grade 3 only), thrombocytopenia (7.4% and 0), and thromboembolic disorders (3.7% and 3.7%). Bevacizumab-induced side effects (any grade) included headaches (22.2%), epistaxis (30%), hemoptysis (3.7%), and hypertension (11%). No grade 4 or 5 toxicities were seen. CONCLUSION: Combination carboplatin/pemetrexed and bevacizumab followed by maintenance therapy with pemetrexed/bevacizumab is effective, with response rates > 50%, acceptable toxicity, and promising early survival in patients with advanced nonsquamous NSCLC.

T(p-e)/QT ratio as an index of arrhythmogenesis.

An increasing number of basic and clinical studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (T(p-e)) may correspond to the transmural dispersion of repolarization and that amplification of the T(p-e) interval is associated with malignant ventricular arrhythmias. In this review, we outline the utility of the T(p-e) interval and the T(p-e)/QT ratio as an electrocardiographic index of arrhythmogenesis for both congenital and acquired ion channel disease leading to ventricular arrhythmias. In healthy individuals, the T(p-e)/QT ratio has a mean value of approximately 0.21 in the precordial leads and it remains relatively constant between the heart rates from 60 to 100 beats per minute. Interestingly, the T(p-e)/QT ratio is significantly greater in the patients at risk for arrhythmic event such as those with long QT syndrome, Brugada syndrome, short QT syndrome, and also in patients with organic heart disease such as acute myocardial infarction. Functional reentry is the underlying mechanism for arrhythmogenesis associated with an increased T(p-e)/QT ratio.