Acquired Resistance in EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer: The Role of a Repeat Biopsy

H. Jack West, MD


January 11, 2016

For more than a decade, a subset of patients with advanced non-small cell lung cancer (NSCLC) have experienced a dramatic and prolonged benefit from first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, or second-generation EGFR TKIs, such as afatinib; these responses are now known to be far more likely in patients with an activating mutation in the EGFR gene, an exon 19 deletion or L858R substitution.

These responses, however, last for a median of 9-13 months before patients demonstrate progression through acquired resistance, which is mediated by a variety of mechanisms.[1] The most common of these is the development of a secondary T790M mutation on exon 20, present in about 50%-60% of patients who develop acquired resistance to an EGFR mutation.[1]

Until very recently, the value of repeating a biopsy from a site of progressing cancer in this setting was a debatable point. Although a small proportion (5%-14%) of patients have been demonstrated to show transition to small cell histology with acquired resistance,[2] this finding was seen infrequently enough that it failed to lead to broad adoption of a repeat biopsy. Early research efforts with the third-generation EGFR TKIs osimertinib[3] and rociletinib[4] reported promising efficacy in patients with T790M-positive acquired resistance and the utility of these agents in clinical trial settings provided a potential clear value to repeat biopsies upon progression; however, this strategy has yet to be widely practiced because of the limited availability of clinical trials with these agents.

The recent US Food and Drug Administration (FDA) approval of osimertinib therefore not only offers a new treatment option for the majority of patients with acquired resistance to a prior EGFR TKI, but also should lead to a key change in clinical practice by providing a very compelling rationale for repeat biopsies in order to look for evidence of a T790M mutation as detected by the cobas® EGFR Mutation Test (Roche; Basel, Switzerland) approved as a companion diagnostic.

For those patients with this marker, osimertinib has been shown to have an objective response rate (ORR) of 57% and 61% in two phase 2 trials including a combined 411 patients.[5] Of note, osimertinib at the approved dose of 80 mg by mouth daily is generally very well tolerated, with leading side effects of diarrhea in 42%, rash in 41%, and dry skin in 31% of patients—although these side effects were rarely grade 3 or higher.

An additional development in this setting of acquired resistance in EGFR mutation-positive advanced NSCLC came just days after the approval of osimertinib. Although rociletinib had been granted a priority review as treatment for T790M-positive acquired resistance to prior EGFR TKI therapy,[6] an FDA decision for this agent is now delayed by several months after a very recent report that the confirmed ORR was—at 28% and 34% for the 500-mg and 625-mg dose cohorts, respectively—lower than previously expected on the basis of initial reports that included unconfirmed responses.

The approval of osimertinib presents a clear treatment option for patients with T790M-positive acquired resistance, but how should the remaining 40%-50% of patients with T790M-negative acquired resistance be treated? Conventional chemotherapy remains a very appropriate consideration, potentially tailored to small cell histology for the minority who demonstrate this transformation. In addition, the first clinical trials focused on patients with T790M-negative acquired resistance are also now being initiated, including one focusing on the hypoxia-induced pan-HER inhibitor TH-4000.[7]

The practice of repeat biopsy after progression on an EGFR TKI should now become a new standard of care, and with this we will identify larger numbers of patients in this newly defined T790M-negative subgroup for whom we can hope novel treatment options emerge. For now, at least, the approval of osimertinib offers a highly active, generally very well tolerated new treatment option for patients identified as having T790M mutation-positive acquired resistance.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.