Questioning Targeted Therapy in NSCLC

Not so Fast With That TKI

H. Jack West, MD


May 28, 2014

Epidermal Growth Factor Receptor Mutations: Effect on Volume Doubling Time of Non-Small-Cell Lung Cancer Patients

Nakamura R, Inage Y, Tobita R, et al
J Thorac Oncol. 2014 Jan 29. [Epub ahead of print]

Study Summary

Nakamura and colleagues report an interesting association of EGFR mutation status with the volume doubling time (VDT), an index of the growth rate and aggressiveness of a cancer, in resected non-small cell lung cancer (NSCLC). This report looks retrospectively at a series of 102 patients, most with stage I NSCLC, who were followed with serial CT scans, making it possible to calculate an estimated VDT for each lesion, who then underwent surgery and molecular marker testing. Findings were compared between those patients with an EGFR mutation vs wild type. The authors also evaluated correlations of VDT with other clinical or histologic features.

Although the VDT for the entire group was 188 days, the 35 patients with an EGFR mutation had a median VDT of 676 days, or nearly 2 years, which was significantly greater than the median VDT of 139 days in the 67 patients with EGFR wild type (P < .001). Also quite remarkable: The VDT in the entire population ranged from 24 to 9686 days, or from less than a month to over 25 years. The median VDT in patients with adenocarcinoma was significantly longer than those with squamous cell NSCLC (305 vs 81 days, P < .01), longer in nonsmokers than smokers (359 vs 147 days, P < .001), and longer in women than in men (272 vs 147 days, P < .004).


What should we glean from this report? Although it is a retrospective, single-center experience, the report highlights several points that are clinically relevant and suggests a potential value in individualizing our treatment approach. The authors note that doubling time may help to predict which patients have an EGFR mutation, but I would contend that the key issues are in highlighting that VDT of some cancers can be remarkably long (even extending into decades) and that this is particularly true of EGFR mutated cancers. We know that patients with an EGFR mutation who receive an EGFR tyrosine kinase inhibitor (TKI) have a median survival that is in the 2- to 3-year range in many recent trials,[1,2,3]but this is probably a product of their benefit from targeted therapy and an inherently more favorable, indolent tumor biology that translates to a longer survival even in the absence of an EGFR TKI, as has been reported previously.[4] As we consider the potential utility of administering adjuvant therapy, including targeted therapy such as an EGFR TKI, it is worth looking not only at the stage of a patient's tumor but at the biology of the cancer as illustrated by their VDT.

Molecular marker testing is becoming more widespread and is increasingly applied to early-stage NSCLC, ahead of any data demonstrating a survival benefit. Once a driver mutation is identified, it is quite tempting to administer EGFR TKI-based therapy as an adjuvant therapy on a presumption of benefit, including a favorable survival in these patients who receive an EGFR TKI. In fact, this is a strategy being actively studied[5] and sometimes pursued outside of a trial.

Despite the potential but unproven role of targeted therapy in this setting, it is very appropriate (and arguably optimal) to question the wisdom of administering a targeted therapy to a cohort of patients for whom the evidence demonstrates a particularly favorable survival regardless of subsequent interventions. In patients who have a significant probability of being cured or of having an indolent disease course even if recurrent, it would be irresponsible to administer a treatment costing over $60,000/year and with ongoing adverse effects, with no clear endpoint.

The authors also make the appropriate point that we should question the necessity of treating a lung cancer with a VDT measured in years as aggressively as a more rapidly progressing cancer. The authors note, "Further study will reveal whether these results indicate that NSCLCs with the EGFR mutation are indolent, and if so, whether we can select minimal surgical treatment for EGFR mutation-positive NSCLC patients who have severe comorbidity or are very old." This recognition that some cancers may be indolent enough to be at risk for overtreatment with a reflexive approach of a default standard of care for the vast majority of NSCLC tumors is one that the Asian lung cancer community has led the world in considering. Though more commonly seen in Asian populations than Western ones, there are cancers that are so indolent that they should beg the question of whether they truly require any intervention at all, especially in older patients and those with competing comorbidities.

Although "precision medicine" is generally interpreted as an application of molecular testing to medical care, this concept should also be extended to the question of which cancers require less aggressive treatment than is standard, or even no intervention at all. Along with our growing enthusiasm for the value of molecular studies, we would be wise to utilize insights from the observed clinical behavior of the cancer, as illustrated by measures such as the VDT, to optimize treatment recommendations for the individual patient rather than reflexively following a stage-specific guideline.



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