Gregory Otterson, MD, Professor of Internal Medicine; Interim Division Director of Medical Oncology; Co-Director, Thoracic Oncology Program; Program Director, Hematology & Medical Oncology Fellowship Program; The Ohio State University Wexner Medical Center.
Q: How has the introduction of molecular testing of non small cell lung cancer (NSCLC) altered therapy and outcomes?
A: The understanding of lung cancer as a genetic disease has been developing over at least 30 years. The technology (and cost of this technology) to utilize this understanding has only been developed over the last 10 years, and importantly, along with the technical ability to test for molecular/genetic abnormalities has been the development of a new generation of targeted agents that can specifically target these abnormalities.
In 2004, several groups described mutations with the epidermal growth factor receptor (EGFR) in patients who had sustained substantial responses to EGFR targeted tyrosine kinase inhibitors (TKIs). At this time, a number of TKIs had been approved for treatment of non-small cell lung cancer without respect to mutations. Over the next months and years, clinicians started to understand the frequency and clinical characteristics of these mutations – seen in adenocarcinomas from patients with a light or never smoking history, and especially those from East Asia. The concept of “clinical selection” of patients most likely to benefit from these agents developed between 2004 and 2009. This strategy changed forever however in 2009 with the publication of the IPASS (Iressa Pan Asia Study) which compared gefitinib (Iressa®) to standard platinum based chemotherapy in patients with a light or never smoking lung adenocarcinoma. This study demonstrated conclusively that clinical selection was inadequate – patients with the sensitizing EGFR mutations had profound benefit from the TKI, while those with the same clinical features, but lacking the mutation, had essentially no benefit from the TKI. Multiple subsequent studies have confirmed the benefit from EGFR TKI treatment in patients with molecular selection.
More recently, the development of additional TKIs against the anaplastic lymphoma kinase (ALK) and ROS1 genes have been developed SOLELY in patients who express the molecular abnormality – i.e. the drug and the molecular test have been developed concurrently. The co-development of drug and diagnostic test has revolutionized the diagnostic evaluation of patients with lung cancer because the benefit seen in patients with the abnormality (compared with those without the abnormality) is profoundly different. We expect a response rate exceeding 60% in patients treated with the matched TKI, while those without the molecular abnormality can expect little more than placebo effect benefit, and the standard treatment ought to be cytotoxic chemotherapy. More important than the response rate, the DURATION of response and the overall survival is substantially improved (at least double) in patients matched with the appropriate drug for the defined molecular abnormality (compared with patients not bearing the mutation or treated with the targeted agent).
In the last 2-3 years, several major developments have “moved the goalpost;” the development of second (and third) generation TKIs that are targeted to specific resistance mutations, and the ability to perform sequencing from cell free DNA in blood and other biological samples. Interestingly, while the responsiveness of tumors with specific molecular abnormalities to agents targeted to these abnormalities is profound, the duration of these responses is, on average, less than a year. Essentially all tumors will eventually develop resistance. The mechanism(s) of resistance are profoundly different depending upon the specific targeted gene – for example resistance to EGFR TKIs is most commonly (approximately 60% of the time) via a secondary EGFR mutation (T790M) which acts as a “gatekeeper” mutation preventing binding of the 1st/2nd generation TKI from accessing their binding pocket. Osimertinib (Tagrisso®) is an interesting EGFR TKI with the interesting property of being specific for mutant EGFR proteins (including T790M) and was recently approved by virtue of its ability to “rescue” patients who have progressed after initial responsiveness to the first generation TKI. Importantly, the approval (and insurance coverage) for this agent is dependent upon the demonstration of the presence of this mutation – meaning that, unlike the situation 10+ years ago, it is now considered the STANDARD OF CARE to biopsy patients at multiple time points during the course of their disease.
The second important recent development has been the ability to detect miniscule amounts of tumor DNA (and the corresponding mutation spectrum) from non-tumor tissue (most commonly blood, but also urine and other more accessible bio-specimens). The ability to detect mutations in cell free DNA samples provides an easier and safer mechanism to monitor patients and to detect resistance mutations.
The future of molecular analysis of tumors, and the integration of this technology with the other major treatment revolution in the last 10 years (immunotherapy/checkpoint inhibitors) is a story that remains to be told. Molecular analysis of NSCLC is undoubtedly only going to grow in importance.
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