Overcoming Resistance to Osimertinib Remains Key Challenge for Treatment Strategies in NSCLC

As one of the main challenges faced by cli­nicians who treat non—small cell lung cancer (NSCLC), drug resistance continues to thwart efforts to mitigate disease progression. This is especially true for the class of drugs called tyrosine kinase inhibitors (TKIs), which inhibit adenosine triphosphate at the binding site of tyrosine kinase.

A recent review article by Alessandro Leonetti and colleagues¹provides a comprehensive overview of resistance mechanisms to osimertinib (Tagrisso) and suggests strategies and insights to overcome resistance to this agent. Although patients treated with the first-generation TKIs gefitinib (Iressa) and erlotinib (Tarceva) and second-generation afatinib (Giotrif) enjoy a relatively high objective response rate (ORR) that ranges between 60% and 70%, most patients experience resistance, with progression-free survival (PFS) ranging from 9 to 15 months.^1,2

““This review reflects the urgent need of eluci­dating the complexity of resistance mechanisms to osimertinib, which is the current standard frontline treatment of patients with EGFR-mutated NSCLC,” corresponding author Elisa Giovannetti, MD, PhD, scientific researcher in the Department of Medical Oncology at Amsterdam University Medical Center, Vrije Universiteit Amsterdam, in the Netherlands, said in an interview withTargeted Therapies in Oncology. “The final goal is to provide a better under­standing of the limitations and novel opportunities to tackle tumor resistance.”

The main culprit in the development of TKI resis­tance is the T790M mutation inEGFRexon 20.³The only currently approved third-generation TKI, osimertinib, selectively targetsEGFRmutations and is indicated in patients who are T790M positive. Although the agent has robust clinical activity, similar to earlier generation TKIs, patients unfortu­nately develop secondary resistance.

The wide spectrum of resistance mechanisms observed in NSCLC may be due to the disease’s molecular heterogeneity. The authors note that many coexisting molecular alterations have been observed in a considerable percentage of patients, both when osimertinib is used in the frontline setting and after resistance develops from the use of previous TKIs.

Acquired resistance mechanisms to EGFR TKIs can be broadly grouped intoEGFR-dependent orEGFR-independent mechanisms. The scenario of resistance mechanisms to osimertinib includes a number of aberrations, which can develop based on the setting in which osimertinib is administered. Despite being partially overlapping, the frequency of these aberrations differs when osimertinib is given in the first- or second-line setting (FIGURE). “In the figure, different molecular aberrations might coexist in the same patient, thus reflecting the complexity of tumor machinery,” Giovannetti wrote.

“An acquired EGFR C797S mutation emerges less frequently after first-line osimertinib (7%) compared [with] second-line (10%-26%). On the contrary, acquired MAPK-PI3K mutations have been identified in higher percentages after failure of frontline osimertinib compared with second-line settings. Notably, among allEGFR-independent mechanisms of resistance,METamplification constitutes the most common cause of bypass pathway activation in both clinical settings, even though with different frequencies,” Giovannetti said. Further, in approximately half of the cases of first-line osimertinib failure, the molecular mecha­nism responsible for resistance remains unknown.

As a greater understanding of the mechanisms of resistance is reached, community oncologists could consider prompt detection of molecular aber­rations that arise during the natural course of the disease. The results of these studies could more efficiently guide treatment strategies that counteract tumor progression.

One emerging tool, circulating tumor DNA (ctDNA), could allow noninvasive on-treatment monitoring of disease response. Giovannetti noted, however, that this tool could miss “potential nonge­netic mechanisms of resistance driven by histologic/ phenotypic transformation and may underestimate gene amplifications.”

When determining T790M status, [ctDNA] anal­ysis could be useful for detecting T790M loss, which is usually associated with osimertinib failure due to competing resistance mechanisms. “Nonetheless, considering that osimertinib is currently given in the first line, regardless of T790M status, the detection of T790M mutation might have less clinical impor­tance in this setting,” Giovannetti wrote.

In light of osimertinib resistance, clinicians have explored other strategies, including revisiting the use of first-generation EGFR TKIs. In their review, the authors note that first-generation EGFR TKIs could play a role in T790M wild-type tumors that develop C797S as a resistance mechanism to osim­ertinib administered in the first-line setting or if the tumor loses T790M in the second-line setting. When this happens, tumor cells may develop resistance to osimertinib but retain sensitivity to other first-generation TKIs. Combinations of first-generation TKIs and osimertinib offer another treatment option that can be explored when C797S mutation develops.

Another option involves alternating dose regimens versus intermittent dosing to selec­tively eliminate drug-resistant clones with a second effective agent, after treatment with a first-choice drug, which is responsible for resistance. In comparison, with inter­mittent dosing, cancer cells that harbored acquired resistance to the first-choice drug may have a disadvantage in the absence of drug, resulting in fewer drug-resistant clones during the therapeutic holiday.

In a recent study, osimertinib plus inter­mittent selumetinib (MEK1/MEK2 inhibitor) demonstrated preliminary antitumor activity in patients withEGFR-mutated NSCLC who progressed to prior EGFR TKI, according to the results of the TATTON trial.⁴