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Lung cancer -7- Treatment of stage 4 part 2


(All the articles published in past are available at

Question: Thank you Chiragbhai for explaining treatment of stage 4, and how overall survival has more than doubled in last decade or so. Importance of histology and identifying targets for therapy were emphasized well. Proper histology, including tests for molecular targets help in deciding best form of chemotherapy and/or non chemotherapy medicines. We learned about EGFR inhibitors as the first successful targeted therapy in lung cancer, and how it is widely available now and is very affording at about Rs 5,000 only per month.
What other targeted therapies do we have? I am sure there are other targets as well in lung cancer.
Ans: Definitely. In fact, every year we learn about new targets due to improvement in molecular analysis methods. From simple immunohistochemistry to various levels of advancements in PCR, FISH etc and recently even complete sequencing of genes of interest (by NGS – next generation sequencing), the testing methods are fast improving. Hence more and more new mutations are being discovered. Also we are able to detect known mutations with more frequency due to higher sensitivity of these methods. Of course, new tests do not always mean easy answers. Sometimes, they also come up with mutations whose significance is unknown. Or some of these mutations have prognostic significance to some extent, but do not predict response to any therapy.
Anyway, Second breakthrough in targeted therapy came with identification of ALK mutation. About 5% of adenocarcinoma patients harbor this mutation. And a drug, Crizotinib, works very well in these patients. This is again an oral tablet, is well tolerated, and is very convenient. Side effects include nausea, vomiting, diarrhea, liver function test abnormalities, sinus bradycardia, some transient visual disturbances, and rarely severe pneumonitis. Generally these are manageable and do not require drug discontinuation. Ceritinib is a second generation ALK inhibitor, which is more potent, approved for patients who have progressed on crizotinib or cannot tolerate crizotinib. Alectinib is another drug in this category for those who have progressed on crizotinib, which also has somewhat better efficacy against brain metastases.
It is important to remember that even among patients who do not have adenocarcinoma, EGFR and ALK testing may sometime be indicated. This includes patients who are never smokers, or biopsy is small (chance of missing adenocarcinoma component) or mixed histology (adenosquamous carcinoma).
Apart from the very established mutations as noted above, there are others which are very likely to become standard soon, with active ongoing clinical trials. If available, it is recommended to test for these as part of panel (screening for major known mutations by various methods – considered near standard of care in some countries), including MET, RET, ROS1, BRAF, Her2, and others. Medicines are available as of now which act against these mutations.
Que: We have recently read a lot about immunotherapy options in various cancers. Does it have a role in lung cancers too?
Ans: Fortunately yes. Immunotherapy refers to various medicines whose main method is to allow our own immune system to work against cancer. It is well known that we all have various mechanisms in immune system to prevent formation of cancer, control growth or spread of cancer. Some cancers evade these mechanisms in various ways, and sort of ‘hide from our immune system’. One of the mechanisms how cancer cells do this hiding is by blocking a receptor on T cells PD-1. They block this receptor by producing a ligand, PD-L1. Two drugs approved now are antibodies against PD-1 receptor. Nivolumab and Pembrolizumab. Both have shown good results in randomized trials, including significant improvement in overall survival, not just response rates, in both squamous cell cancer and non squamous cell cancers (such as adenocarcinoma). They are approved for use after failure of first line chemotherapy, however trials are ongoing for their use in first line treatment. Early results from pembrolizumab are positive for first line as well, however international guidelines are yet to put this in formal recommendation awaiting detailed publication of the results. Interestingly, both medicines are tolerated well, much better compared to chemotherapy. As of now, the cost difference however is very high compared to currently approved other medicines, but hopefully will come down soon. Few medicines which act against ligand PD-L1, instead of the receptor, are also in active phases of clinical trials, and likely to be approved soon.
Immunotherapy agents are a completely new way to treat cancers in general, hence they are being evaluated in combination with chemotherapy or other targeted therapies as well. Number of options available to treat lung cancer has grown remarkably in last decade.
September 14th 2016.

Dr. Chirag A. Shah; M.D. Oncology/Hematology (USA), 079 26754001. Diplomate American Board of Oncology and Hematology. Ahmedabad. Shyam Hem-Onc Clinic. 402 Galaxy, Near Shivranjani, Opp Jhansi ki Rani BRTS, Ahmedabad.