Dr Yu Shares Updates of Prevention Efforts in EGFR-Mutant Lung Cancer

Helena Yu, MD, Memorial Sloan Kettering Cancer Center, New York, New York, presented updates of small cell histologic transformation in epidermal growth factor receptor (EGFR)-mutant lung cancers.

EGFR mutations are detected in 15% of non-small cell lung cancers (NSCLC) and highlight a subset of patients who can benefit from specialized, targeted therapies. Dr Yu identified multiple randomized studies that demonstrate improved disease control with EGFR inhibitors compared to standard of care, platinum doublet first-line chemotherapy.

Several FDA approved first-line treatments for patients with EGFR+ lung cancers include erlotinib, afatinib, gefitinib, and dacomitinib. Currently, there is no superior option for treatment amongst early generation EGFR inhibitors. The median progression-free survival (PFS) rate is 8-15 months for these regimens.

Dr Yu described osimertinib as a third-generation, irreversible, mutant-specific EGFR-TKI, wherein the FLAURA trial in 2018 showed osimertinib demonstrated superior efficacy to standardized EGFR-TKIs. However, almost all lung cancers develop resistance to osimertinib, meaning cancer can grow and spread beyond management.

“After earlier generation EGFR-TKIs, acquired resistance occurred where we saw T790M as a mechanism of resistance and then utilized osimertinib later on in the first-line setting. We need to understand what mechanisms of resistance to osimertinib are. The question is, is acquired resistance to first-line osimertinib different than later-line osimertinib?” said Dr Yu.

Almost all EGFR+ lung cancers are adenocarcinoma. It is rare for de novo EGFR+ SCLC to be reported. Histologic transformation is a mechanism of resistance to EGFR-TKI as transformation results in loss of dependence on EGFR signaling. Once transformations start, only targeting EGFR is no longer effective. Various treatments are required to best treat transformed SCLC.

“We combined data from 8 institutions to look at clinical outcomes after 67 patients with EGFR+ SCLC underwent histologic transformation,” continued Dr Yu.

87% of patients had adenocarcinoma at diagnosis and 13% were de novo small cell or mixed histology. All patients retained EGFR mutation in transformed SCLC tumors. Common, concurrent mutations were TP53, RB1, and PIK3CA.

The median time from initial diagnosis of metastatic disease to transformation was 17.8 months (95% CI, 14.3-26.2). Platinum etoposide therapy was the most common regimen with a clinical response rate of 54% and median PFS of 3.4 months. There were no responses to immunotherapy, which was attempted in a majority of patients.

Taxanes were most often used with a clinical response rate of 50% and a median PFS of 2.7 months. Median overall survival (OS) from time of SCLC transformation was 10.9 months.

Unfortunately, there are no current strategies or treatments available to reverse histologic transformation. There are significant efforts to focus on prevention.

A current trial at Memorial Sloan Kettering Cancer Center selects patients at risk based on genomics (EGFR/RP1/TP53 genotype) and adds small-cell directed chemotherapy prior to transformation to eradicate small-cell subclones. 

“We are starting those patients on osimertinib care, but we are actually adding in small-cell directed chemotherapy to platinum etoposide treatment in order to try to remove the small-cell subclone that is predisposed to histologic transformation,” continued Dr Yu.

Dr Yu explained that molecular analyses will be performed at different timepoints to identify changes in subclones over treatment and molecular determinants of transformation.

In conclusion, within lung cancer, histologic transformation is primarily seen as a mechanism of resistance to EGFR-TKI therapy in patients with EGFR-mutant lung cancer. More frequent histologic transformations are observable on targeted EGFR inhibition with newer EGFR inhibitors. Histologic transformation can only be identified with a tumor biopsy.

After SCLC transformation, platinum etoposide chemotherapy and taxanes have demonstrated some efficacy while immunotherapy is non-applicable. A continuation of EGFR-TKIs can be successful in some cases where adenocarcinoma subclones may still be present.

Dr Yu concluded as transformation cannot be reversed and clinicians are aware of at-risk genotypes, efforts should primarily focus on prevention of SCLC transformation. – Alexa Stoia