Dermatological toxicity associated with Afatinib for the treatment of Non-Small Cell Lung Carcinoma (NSCLC)
Epidermal Growth Factor Receptor (EGFR) is a major factor in determining the prognosis of Non-Small Cell Lung Cancer (NSCLC). Dermatological toxicity has been associated with afatinib (a pan-ErbB EGFR inhibitor), but little work has been done to assess how this relates to treatment response.1,2,3
Dispensing and clinical data from the Queen Elizabeth Hospital Birmingham (QEHB) was reviewed for 39 patients with EGFR mutation-positive (M+) NSCLC in a retrospective, longitudinal study between May 2014 – September 2019 to assess this relationship.
It was seen that 82.1% (n = 32/39) of patients developed a rash whilst taking afatinib in this study, which is in concordance with the literature value (80%).3,4 Rash patients were seen to have a greater median Progression-Free Survival (PFS) period compared to non-rash patients (25.11 vs 3.29 months; log-rank test p = 0.0074, Χ2 = 7.17). Demographic/genetic factors were also briefly assessed during this study to determine any potential factors which may influence the development of dermatological toxicity. However, further work needs to be done to investigate this, as none of these demographic/genetic factors were significantly associated with the development of a rash. The T790M mutation was also briefly assessed to determine eligibility for osimertinib and how this related to the different demographic factors.
Developing dermatological toxicity may improve survival outcomes whilst on afatinib. Using a larger sample size in future may give a better indication of the significance of these findings, as well as any demographic/genetic factors which may also impact on the development of a rash.
- Kudo K,et al.Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience. Cancer chemotherapy and pharmacology. 2016 May 1;77(5):1005-9.
- Nasu S,et al. Skin rash can be a useful marker for afatinib efficacy. Anticancer research. 2018 Mar 1;38(3):1783-8.
- Arrieta O,et al. Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients. Lung Cancer. 2015 Jun 1;88(3):282-8.
- Miller VA,et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. The lancet oncology. 2012 May 1;13(5):528-38.
Monoclonal antibodies (mAbs) are a class of biological therapeutic agents used in oncology or autoimmune diseases like Rheumatoid arthritis (RA). Its sensitivity in ambient conditions causes instability during manufacturing, storage and administration. Employing certain conditions and excipients may improve the mAbs’ pharmaceutical stability.
Materials and Methods:
Samples (1mg/ml and 6mg/ml of Immunoglobulin, IgG, from human serum, in citrate buffer) were tested in the absence and presence of β-cyclodextrin (CD), 1:1 weight ratio. Solutions were tested using Solution Differential Scanning Calorimetry (SDSC) from 20-90oC at 60oC/hr.
Results and Discussion:
From literature, the effectiveness and suitability of common (amino acids, silicone oil) and novel (dipicolinic acid, quinolinic acid, arginine-glutamate) excipients in countering challenges such as viscosity, opalescence and aggregation have been established. The findings (Singh, 2011) were used to discuss and account for the safety and efficacy of Tocilizumab, used in RA. Findings demonstrated that amino acids have concentration dependent stabilising and destabilising effects whereas silicone oil induces aggregation and protein instability. Stress induced the most aggregation, leading to colloidal instability, as demonstrated also by our experiment, where the SDSC thermograms showed that CD increased Transition temperature (Tm) by 2oC for the 1mg/ml solution, indicating some stabilising effect. At high IgG concentrations, Tm was reduced by 8oC and solutions after SDSC runs showed aggregation. Based on our in-vitro experiments, CD showed promise as an effective stabiliser, similar to amino acids, however more research is needed to strengthen its use.
In conclusion, the literature creates more potential for research to be conducted in terms of evaluating mAb therapeutics in different patient types (Maggio, 2017). According to our research, using different CD concentrations on IgG solutions should be considered for a more comprehensive evidence base.
- Edward Maggio (2017) Polysorbates, Biotherapeutics, and Anaphylaxis: A Review, Available at: https://bioprocessintl.com/manufacturing/formulation/polysorbates-biotherapeutics-and-anaphylaxis-a-review/ (Accessed: 22/12/2018).
- Satish Kumar Singh (2011) 'Impact of product‐related factors on immunogenicity of biotherapeutics', Journal of Pharmaceutical sciences, 2011,[Online]. Available at: https://onlinelibrary.wiley.com/doi/10.1002/jps.22276 (Accessed: 3/3/2019).
Pfizer is leading the way to unlock the promise of gene-therapy
Gene therapy is the next generation of medicine targeting the underlying cause of genetic disease. It has the potential to offer transformational clinical benefit and dramatically improve the quality of life of patients.
Our recombinant Adeno Associated Virus (rAAV) vector delivers genes directly to targeted cells. When the vector is integrated in the cell, the functioning gene is transferred and used as a blueprint to produce the missing or non-functioning protein. This is different from other gene therapy techniques like CRISPR, in which the functioning gene is integrated into a patient’s chromosome. Pfizer is currently focusing on diseases caused by single-gene alterations such as hemophilia A/B and Duchenne’s. Moreover, our robust pipeline includes potential gene therapy solutions for a.o. Wilson’s disease, Friedreich’s ataxia and ALS.
Pfizer’s gene therapy platform, comprised of internal capabilities and strategic partnerships, enables us to provide end-to-end solutions for all challenges of gene therapy; from drug design to global commercialization. Together with all stakeholders involved we need to lay the groundwork now; by 2023 there could be 40 gene therapies available for patients.
In this presentation a selection of the many challenges related to gene therapy are highlighted. Size matters when it comes to offering gene therapy to patients, in terms of size of transferred genes as well as size of manufacturing capabilities!