There are four oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) now approved for treatment of both treatment-naïve and previously treated advanced non-small cell lung cancer (NSCLC). With the increasing use of these therapies, researchers are investigating mechanisms of resistance to these agents as well as ways to minimize or prevent resistance and treat patients with resistant tumors.

At the 11th Annual New York Lung Cancer Symposium, held on November 12, 2016, in New York City, Roman Perez-Soler, MD, chairman of the department of oncology and professor of medicine and molecular pharmacology at the Albert Einstein College of Medicine, spoke about what is currently understood about resistance to EGFR-targeted therapies and how to treat this population of patients.

“Resistance is a continuous variable that can be defined in several ways,” said Perez-Soler. Two of the ways resistance can be defined based on response to therapy or the duration of response to treatment, either less or more than a 3-month progression-free survival. The genetic mechanisms of resistance may be compound specific, EGFR mutation-specific or EGFR-independent. Patients may have de novo resistance to these agents that is simply not evaluated including mutations in p53, the T790M EGFR mutation, and amplifications in the AXL and MET genes.

After identification of secondary T790M mutations in exon 20 of EGFR, which confers resistance by increasing the affinity of the EGFR protein for ATP, researchers found  that this mutation accounts for about half of all resistance to the EGFR TKIs erlotinib (Tarceva) and gefitinib (Iressa).¹

In a 2011 analyses of the natural history of patients with acquired T90M mutations, researchers showed that patients with this mutation have relatively indolent progression and a favorable prognosis.² “Some of the resistance mutations may confer a shorter progression-free survival [PFS], but do not necessarily confer a growth advantage or more virulent disease,” said Perez-Soler.

Osimertinib (Tagrisso) was specifically developed to target the T790M mutation and is now approved for those patients with molecularly detectable EGFR T790M mutations. “Osimertinib will work in the first-line setting if the patient has a de novo T790M mutation,” said Perez-Soler. At the recent European Society of Medical Oncology (ESMO) 2016 Congress, researchers demonstrated that of 30 treatment-naïve patients, 77% responded to treatment and that the median PFS has not yet been reached (LBA#1 ESMO 2016).

Patients who progress on an EGFR TKI likely have heterogeneous tumors with both resistant and sensitive tumor cells. Two options for these patients are continuing the initial EGFR TKI treatment and adding a second agent in combination or a starting therapy with osimertinib.

“With osimertinib, there is no more rash, which is a big issue for patients, and the PFS is equivalent to the other TKIs,” said Perez-Soler.

Still, tumors will continue to evolve resistance to this later-generation TKI. The currently known mechanisms of resistance include the C797S EGFR mutation, which has been seen in approximately one-third of patients.^{3, 4} Already, there are novel selective EGFR inhibitors in development including EAI045, which has shown the ability to overcome both T90M and C797S resistance mutations in combination with cetuximab, so far in mouse xenograft lung tumor models.⁵

To track the evolution of tumor resistance, sequential biopsies are necessary; yet sampling a patient’s tumor directly is both invasive and does not capture the patient’s entire tumor landscape. Increasingly, liquid biopsies, which sample cell-free DNA (cfDNA) from the blood or plasma of patients, are being used to track resistance mutations in lung cancer patients both in the clinic and research settings. “Liquid biopsies are the way to go and we are gaining sensitivity with these assays,” said Perez-Soler. There are many more mutations that can be captured from the dying cells shed into the blood from tumors that can “reveal the heterogeneity of resistance.”

References:

Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008 Feb 12; 105(6): 2070–2075.

Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011 Mar 15;17(6):1616-22.

Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015 Jun; 21(6): 560–562.

Piotrowska Z, Sequist LV. Treatment of EGFR-Mutant Lung Cancers After Progression in Patients Receiving First-Line EGFR Tyrosine Kinase Inhibitors : A Review. JAMA Oncol. 2016 Jul 1;2(7):948-54.

Jia Y, Yun CH, Park E, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016 May 25;534(7605):129-32.