Change in non-small-cell lung cancer tumor size in patients treated with nintedanib plus docetaxel: analyses from the Phase III LUME-Lung 1 study

With the help of Staburo, a typeset manuscript has been published in its final form on the Dove Medical Press Ltd website. You can view and download it here: https://www.dovepress.com/articles.php?article_id=39709.

The study investigated the change in nsclc-tumor size in patients treated with nintedanib.

Background: Nintedanib in combination with docetaxel is approved in the European Union and other countries for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy, based on the overall survival findings of Phase III LUME-Lung 1 study. Change in target lesion size over time as a treatment effect was assessed in patients from this study.

Methods: Tumor size was evaluated using predefined tumor measurements. Mixed-effects models were used to quantify individual relationships between time from randomiza­tion and tumor burden, measured as the sum of longest diameter (SLD) of target lesions and assessed by an independent review (Response Evaluation Criteria In Solid Tumors [RECIST] v1.0). Exploratory analyses were conducted on the overall adenocarcinoma popula­tion, adenocarcinoma patients with time from start of first-line therapy ,9 months (TSFLT ,9), adenocarcinoma patients who had progressive disease as best response to first-line therapy (PD-FLT), and in squamous cell carcinoma patients.

Results: Estimated mean baseline SLD was 82.5 mm in the adenocarcinoma (n=658), 88.3 mm in the TSFLT ,9 (n=405), 98.1 mm in the PD-FLT (n=117), and 94.3 mm in the squamous cell carcinoma (n=555) populations. Treatment with nintedanib/docetaxel showed a significant reduction in tumor size over time (P,0.0001) in patients with adenocarcinoma compared with placebo/docetaxel, and in patients with squamous cell carcinoma (P=0.0049). Treatment difference at 6 months was 9.7 mm in the overall adenocarcinoma population, 16.8 mm in the TSFLT ,9 population, 19.7 mm in the PD-FLT population, and 6.8 mm in the squamous cell carcinoma population. SLD at 2 months post-randomization was identified as a surrogate endpoint for overall survival, in addition to progression-free survival, for all except the PD-FLT population.

Conclusion: Treatment with nintedanib/docetaxel significantly decreased tumor burden and decelerated tumor size over time compared with placebo/docetaxel in the overall adenocar­cinoma population, including in patients with the poorest prognosis due to aggressive tumor dynamics.

Staburo supported Scientific Advice at BfArM

Staburo’s Managing Director Josef Höfler prepared and took part in a Scientific Advice meeting at the agency BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte) in Bonn.

At the BfArM, roughly 1,000 employees (physicians, pharmacists, chemists, biologists, lawyers, engineers, technical assistants, administrative staff etc.) are involved in the tasks of licensing, improving the safety of medicinal products, detecting and evaluating the risks of medical devices, and monitoring the legal traffic in narcotic drugs and precursors. The most important aim of these activities is to increase the safety of medicinal products and thus that of the patients.

In this Scientific Advice, a client’s Biosimilar Clinical Development Program was discussed with the authorities, client representatives, consultants and Staburo’s Managing Director Josef Höfler. Main topics of the meeting were study design of the pivotal trial, including sample size considerations, primary endpoint and statistical analysis.

Staburo Wiesn Workshop

It is a very nice custom to have our Staburo statistics training session on the first Monday of the two-week Oktoberfest period. This year, the Staburo team had the chance to learn about the “Comparison of adaptive enrichment designs in clinical trials”. In the second talk, useful insights into cluster analysis were presented. “The cross-validated treatment effect for data-driven subgroup selection algorithms” was the third presentation and rounded up this very informative workshop. As always, this was a great opportunity to share knowledge with the whole Staburo team and we had a very good Q&A session afterwards. Contents of the workshop will be published here, soon.

The second important custom is to pay the Oktoberfest (or also called “Wiesn”) a visit after the workshop. Once again, we had a wonderful time with the team and long-time Staburo clients. We even topped the (by some nerdy team members with a complicated formula) estimated beer consumption – some say due to semi-transparent accounting on the waiters’ side, some think due to thirst. Everyone got home safely – with additional knowledge from the workshop and positive vibes from the Oktoberfest. We are already looking forward to the Staburo “Wiesn” Workshop 2019 and thank all participants for making this a great team event!

Biomarker analyses published in JAMA Oncology

Staburo supported biomarker analyses for a phase III lung-cancer trial. The paper, which was recently published in JAMA Oncology, is a retrospective analysis to assess the association of ErbB mutations with clinical efficacy. Statistical analyses include the identification of predictive and prognostic biomarkers, and the evaluation of their impact using standardized effect plots.

Highlights of the study:

DESIGN, SETTING, AND PARTICIPANTS:

Ad hoc secondary analysis of the LUX-Lung 8 trial, conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma, with progressive disease after 4 or more cycles of platinum-based chemotherapy.

MAIN OUTCOMES AND MEASURES:

Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression.

RESULTS:

Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation–positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome.

CONCLUSIONS AND RELEVANCE:

Next-generation sequencing may help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation.

You can find the full publication here:

Goss, Glenwood D., et al. “Association of ERBB mutations with clinical outcomes of afatinib-or erlotinib-treated patients with lung squamous cell carcinoma: secondary analysis of the LUX-Lung 8 randomized clinical trial.” JAMA oncology (2018).

https://jamanetwork.com/journals/jamaoncology/fullarticle/2684635

Staburo contributed to publication in the Journal of Cardiovascular Pharmacology and Therapeutics

Staburo could show, once again, its state-of-the-art biostatistics expertise, by supporting this scientific publication. Here, you find a short summary about the study.

Summary

Dabigatran etexilate is an oral direct thrombin inhibitor. Dabigatran excretion is 80% renal, so exposure increases
with severity of renal failure, which can lead to more adverse events (AE). The FDA approved dabigatran etexilate 75 mg twice daily (BID) for patients with nonvalvular atrial fibrillation (NVAF) having severely impaired renal function (creatinine clearance: 15-30 mL/min), based on post-hoc pharmacokinetic modeling and not based on results of a clinical trial for this population. In this trial, we assessed dabigatran exposure at trough and peak levels in patients with NVAF and severely impaired renal function and compared the result with predictions from PK model.

Methods

Patients received dabigatran etexilate (75 mg BID) for 7 days before blood sampling; Steady-state pre-dose concentration (trough) and steady-state peak concentration were taken. Pharmacodynamic parameters at baseline were assessed by established coagulation assays.

Results

Of 60 treated patient, 40% were male and 78.3% were white; median age was 84 years. Steady-state pre-dose concentration values were close to pharmacokinetic modeling predictions with a geometric mean (gMean) of 155 ng/mL, geometric coefficient of variation (gCV) of 76.9%, and range of 15.6 to 498 ng/mL. The Steady-state post-dose peak had a gMean of 202 ng/mL, gCV of 70.6%, and range of 42.0 to 680 ng/mL. Pharmacodynamic effects on coagulation paralleled dabigatran concentrations. Eleven (18.3%) patients had at least one AE; pharmacokinetic results for these patients versus those without AE showed higher trough and peak values. All bleeding events were considered minor by the investigators.

Conclusion

Dabigatran exposure levels largely confirmed earlier pharmacokinetic predictions, supporting the use of dabigatran etexilate 75 mg BID in patients with NVAF and severely impaired renal function. Pharmacodynamic results were also in agreement with earlier studies.

Click here for the abstract on the publication website.