Targeted therapy proves to be the better bet against the big C
LUNG cancer is generally divided into non-small cell lung cancer (NSCLC) comprising 85 per cent of cases and neuroendocrine lung cancer including small cell which comprises approximately 10 to 15 per cent of cases. The prognosis for advanced stage NSCLC has historically been very poor with hardly any survivors at five years.
The traditional way of treating such patients was with chemotherapy, which can produce significant side effects and impacts unfavourably upon quality of life. Furthermore, the benefit of chemotherapy tends to be short-lived with these cancers usually progressing after six months.
All this changed about a decade ago when it was discovered that a subset of lung cancer patients, more typically females who have never smoked responded very well to oral tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR).
Not only did their progression free survival double compared to chemotherapy, they experienced less side effects as a result of treatment. This led to a whole new field of using targeted therapy in lung cancer.
Current trend in lung cancer
Fast forward to today, we now know that just over 40 per cent of lung cancer suffers in Malaysia harbour a mutation in EGFR gene, usually an exon 19 deletion mutation or an L858R substitution mutation, which renders these tumours therapeutically amenable to oral EGFR TKIs.
A mutated EGFR gene produces an overactive oncogenic cell receptor protein that signals cell growth and multiplication. Using an oral TKI, the drug binds to the intracellular kinase domain which inactivates the receptor.
Better outcome with osimertinib
Presently, there are three generations of EGFR TKI available in Malaysia; First generation (gefitinib, erlotinib), second generation (afatinib) and third generation (osimertinib).Each has been compared to chemotherapy in randomized controlled trials and have proven superior.
The third generation TKI has been compared to the first generation in a randomised control trial (FLAURA study) and the results show third generation TKI to be superior in terms of progression free and overall survival.
Side effects of treatment
Common side effects vary from drug to drug, but in general, it may cause a skin rash ranging from mild dermatitis to an acneiform rash. Patients are advised to stay out of direct sunlight and use emollients, hydrating skin lotions and in more severe cases anti-histamines and antibiotics.
These medications can also cause pimple like changes in the nails termed paronychia which can be painful. Rarely they may affect liver function or result in lung inflammation and low platelets counts.
TKI over chemotherapy
Even in patients with a heavy disease burden which may even impair organ function, treatment with TKI is preferred over chemotherapy as it has a higher response rate (60 to 80 per cent) compared to chemotherapy (40 per cent) and has a quicker onset of action (within 2-3 weeks).
This phenomenon has been sometimes termed the “Lazarus” effect, whereby patients with severe life-threatening
disease in ICU manage to recover back to normality.
As recent as two decades ago such patients would not have any effective therapies
available. Chemotherapy has very poor
blood brain barrier penetration and we would be concerned about subjecting someone in such poor general health to cytotoxic treatment.
Whole brain radiotherapy alone has also been proven to be no better than best supportive care in a phase three randomised trial. However, with a combination of radiotherapy and oral TKI treatment, this patient made a full neurological recover and managed to receive a sustained benefit for a year.
Her MRI brain showed near complete resolution of the disease. Brain metastases which occurs in about 30 to 40 per cent NSCLC patients is the most debilitating site of metastases and is the most difficult to manage. TKI have afforded us an effective treatment for this condition.
In addition to EGFR mutation, other genomic aberrations are now recognised within NSCLC for which there are effective TKI treatments.
The College of Pathologists, Academy of Medicine Malaysia, the Malaysian Thoracic Society, and the Malaysian Oncological Society have recently published a consensus statement recommending that mutations in EGFR, ALK (anaplastic lymphoma kinase) and ROS-1 genes be routinely tested for in advanced NSCLC to enable consideration of TKI therapy.
These therapies include for ALK – crizotinib, ceritinib, alectinib, lorlatinib, brigatinib and for ROS-1 – crizotinib, ceritinib, lorlatinib. Provision of such testing is however, not universal in Malaysia and is limited to certain laboratories with advanced technologies.
Patient samples will then need to be transported to these laboratories in a timely fashion to enable testing.
What the future holds
Looking to the future, many more genetic mutations are being recognised in NSCLC for which drugs are being or have been developed. Among these are RET, MET, NTRK, BRAF, HER2, KRAS.
Therefore, the field will have to move away from sequential single gene testing to a concurrent multi-gene testing platform. Fortunately in Malaysia, such efforts are already underway and will be available soon.
We will need to work closely with our respiratory and interventional radiology colleagues to ensure adequate tissue is taken at the time of biopsy to ensure sufficient DNA is available for testing.
To this extent the Lung Cancer Network of Malaysia (LCNM) will be working in a multi-disciplinary fashion to encourage closer working relationships between different specialties for the benefit of lung cancer sufferers nationwide.— The Health
Dr Tho Lye Mun is the Vice President of the Lung Cancer Network of Malaysia (LCNM) and a senior consultant clinical oncologist