Repeat Molecular Testing Is Beneficial in EGFR+ NSCLC With Acquired Resistance


Repeat histologic evaluation and molecular testing in patients with EGFR-mutant non–small cell lung cancer who develop acquired resistance to osimertinib can deliver pertinent information that can help guide subsequent treatment decisions.

Zosia Piotrowska, MD, MHS

Zosia Piotrowska, MD, MHS

Repeat histologic evaluation and molecular testing in patients with EGFR-mutant non–small cell lung cancer (NSCLC) who develop acquired resistance to osimertinib (Tagrisso) can deliver pertinent information that can help guide subsequent treatment decisions, according to Zosia Piotrowska, MD, MHS.1

“Can retesting inform subsequent treatment decisions? Does it pass that rule we learned in residency: Is this a test that might change our treatment? I think the answer here is ‘yes,’” Piotrowska, an assistant professor of medicine at Harvard Medical School, and an assistant in medicine at Massachusetts General Hospital, said in a presentation during the 19th Annual Winter Lung Cancer Conference®.

“If you don’t have a clinical trial, is [retesting] still worth doing? Even there, I think the answer is ‘yes,’ [so you can] look for histologic transformations that may guide your selection of chemotherapy, as well as some of these resistance mechanisms where a clinical trial is preferred,” Piotrowski added. “But if you’re running out of options, there are some off-label options that you may consider and discuss with your patient.”

First-line FDA-approved therapies for patients with common EGFR-sensitizing mutations like exon 19 deletions and L858R point mutations include osimertinib (Tagrisso) as the preferred frontline treatment, followed by erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), and dacomitinib (Vizimpro). For those with atypical EGFR mutations, which include L861Q, G719X, and S768I, among others, afatinib is available for use.

The frontline benefit with osimertinib was first demonstrated in the phase 3 FLAURA trial (NCT02296125), which served as the basis for the April 2018 FDA approval in this setting for patients with EGFR-mutant NSCLC. Here, osimertinib in comparison with gefitinib or erlotinib led to a median progression-free survival (PFS) of 18.9 months (95% CI, 15.2-21.4) vs 10.2 months (95% CI, 9.6-11.1), respectively (HR, 0.46; 95% CI, 0.37-0.57; P <.001).2 Additionally, the median overall survival (OS) was 38.6 months (95% CI, 34.5-41.8) with osimertinib vs 31.8 months (95% CI, 26.6-36.0) for erlotinib/gefitinib (HR, 0.799; 95% CI, 0.641-0.997; P = .0462).3

Despite this statistically significant benefit with osimertinib, Piotrowska added, “As you all know, these patients eventually progress on this therapy, and the question is: What do we do next for those patients?”

Overcoming Osimertinib Resistance to EGFR-Targeted Therapy

Retesting with tissue and/or liquid biopsy is an informative and appropriate next step upon resistance to osimertinib, Piotrowska said, adding that this will serve to detect resistance mechanisms to the third-generation EGFR TKI.

Resistance mechanisms to frontline osimertinib include histologic transformations to small cell lung cancer (SCLC) or squamous or pleomorphic NSCLC, as well as on-target resistance through C797S and other secondary EGFR mutations, which are generally seen in the single-digit numbers, Piotrowska noted. Off-target resistance mechanisms also exist, the most common being acquired MET amplification; others that are observed at a lower frequency include the development of acquired oncogenic fusions in ALK, RET, and BRAF, among others.

Transformation to SCLC occurs in 5% to 10% of patients who have developed resistance to osimertinib. Specifically, patients with baseline EGFR/TP53/RB1 co-mutations are 43 times more likely to undergo this transformation, according to Piotrowska.

Currently, for patients who experience transformed SCLC, the preferred treatment approach is carboplatin plus etoposide, with an unclear role for immunotherapy.

“I tend to favor chemotherapy alone for these patients to allow for the eventual reintroduction of osimertinib,” Piotrowska said. “Part of the reason for this is that we have seen in some patients that these can be heterogenous clones; you may still have a small cell component, so you want to leave the option for EGFR TKI therapy, as well.”

For patients who have secondary EGFR mutations, retesting may guide selection of EGFR inhibitors and lead to ongoing clinical trials. Meanwhile, acquired MET amplification could prompt the consideration of novel combinations with MET and EGFR inhibitors. For those with other acquired oncogenic drivers, EGFR TKIs combined with other TKIs have also showcased potential.

“There are many different treatment options [available to us], but you can only select between these options if you test these patients,” Piotrowska stressed.

The Tissue Vs Liquid Biopsy Debate

Although tissue biopsy is invasive and is associated with a longer turnaround time, it does remain the gold standard for the detection of resistance mechanisms, Piotrowska said. Moreover, because SCLC transformation is a concern in this patient population, the ability to detect this abnormality is an advantage.

Liquid biopsy is easier to obtain with a faster turnaround time, but Piotrowska noted that the sensitivity of it is dependent on the amount of DNA that is shed into circulation. Histologic transformation is also not able to be detected through liquid biopsy.

When examining the pros of cons of which testing modality to utilize, Piotrowska said that she prefers tissue biopsy but does consider liquid assays in select situations.

“If an EGFR mutation is detected [on liquid biopsy], then the circulating tumor DNA is likely adequate for the detection of many genomic resistance mechanisms, but it is less sensitive for the detection of fusions and amplifications,” Piotrowska explained. “For those patients in whom a tissue biopsy is not feasible, the liquid biopsy is [an acceptable] surrogate with the knowledge of those limitations.”

Targeting MET Amplification By Leveraging MET Plus EGFR Inhibition

To target MET amplification, approaches combining MET inhibitors with EGFR-directed therapy have been under investigation.

The phase 1b TATTON trial (NCT02143466), for example, evaluated osimertinib plus savolitinib (AZD6094) in patients with EGFR-mutant NSCLC who had MET amplification following osimertinib and showed efficacy signals. In a cohort of patients who previously received a third-generation EGFR TKI (n = 69), the objective response rate (ORR) with the combination was 30.0% (95% CI, 20.0%-43.0%) and the median PFS was 5.4 months (95% CI, 4.1-8.0).4

The phase 2 SAVANNAH trial (NCT03778229), which is testing the same combination in patients with EGFR-positive/MET-positive locally advanced or metastatic NSCLC who have progressed on prior osimertinib, is ongoing.

Novel EGFR TKIs Under Exploration

Efforts are also underway to target EGFR C797S, of which there are limited data with first-generation EGFR TKIs. BLU-945 and BLU-701 are both fourth-generation EGFR inhibitors with preclinical activity against this marker and are being studied in the phase 1/2 SYMPHONY (NCT04862780) and the phase 1/2 HARMONY (NCT05153408) trials, respectively.

Combination approaches may also be effective for targeting acquired fusions in RET, ALK, and others. Specifically, in a patient with EGFR-mutant advanced NSCLC who had an acquired RET fusion, the combination of osimertinib plus pralsetinib (Gavreto) resulted in a confirmed tumor shrinkage rate of 78%.5 Similarly, acquired ALK fusions are being targeted by osimertinib plus crizotinib (Xalkori), as well as osimertinib plus alectinib (Alecensa), in ongoing studies.6

Other combinations of interest include amivantamab, a bispecific antibody targeting EGFR/MET plus lazertinib, a third-generation EGFR TKI, in patients with TKI-resistant EGFR-positive NSCLC. In a phase 1 trial of the combination (NCT02609776) in 45 patients with osimertinib-relapsed, chemotherapy-naïve, EGFR-mutated NSCLC, the investigator-assessed ORR was 36% (95% CI, 22%-51%) at a median follow-up of 11.0 months (range, 1.0-15.0).7 The median duration of response (DOR) was 9.6 months (95% CI, 5.3–not reached); the DOR at 6 months or longer was 69%. The clinical benefit rate with the combination was 64% (95% CI, 49%-78%) and the median PFS was 4.9 months (95% CI, 3.7-9.5).

When evaluating for those with identified EGFR-/MET-based resistance, the ORR was 47% (n = 8/17); the ORR was 29% in those who did not have identified resistance (n = 8/28).

The investigational antibody-drug conjugate patritumab deruxtecan (U3-1402) has demonstrated activity across diverse resistance mechanisms.8 In a phase 1 trial (NCT03260491) of a group of 57 patients with NSCLC who had varying EGFR mutations and previously received platinum-based chemotherapy and an EGFR TKI, the ORR was 39% (95% CI, 26%-52%).

Finally, ORCHARD (NCT03944772) is a biomarker-directed platform trial that is biopsying patients upon osimertinib resistance and assigning them to different treatment options based on their identified, or lack thereof, mechanism of resistance. This research will help inform the understanding of subsequent treatments following the use with osimertinib, Piotrowska concluded.


  1. Piotrowska Z. Overcoming resistance to EGFR targeted therapy: is retesting informative? Presented at: 19th Annual Winter Lung Cancer Conference; February 4-6, 2022; Miami, FL.
  2. Ramalingam S, Reungwetwattana T, ChewaskulyongB, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Ann Oncol. 2017;28(suppl 5):v635. doi:10.1093/annonc/mdx440
  3. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Eng J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
  4. Sequist LV, Han J-Y, Ahn M-J, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 2020;21(3):373-386. doi:10.1016/S1470-2045(19)30785-5
  5. Piotrowska Z, Isozaki H, Lennerz JK, et al. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. 2018;8(12):1529-1539. doi:10.1158/2159-8290.CD-18-1022
  6. Offin M, Guo R, Wu SL, et al. Immunophenotype and response to immunotherapy of RET-rearranged lung cancers. JCO Precis Oncol. 2019;3:PO.18.00386. doi:10.1200/PO.18.00386
  7. Bauml J, Cho BC, Park K, et al. Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response. J Clin Oncol. 2021;39(suppl 15):9006. doi:10.1200/JCO.2021.39.15_suppl.9006
  8. Janne PA, Baik CS, Su W-C, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9007. doi:10.1200/JCO.2021.39.15_suppl.9007
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