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Accounting for up to 10% of all EGFR mutations in patients with non-small cell lung cancer (NSCLC), exon 20 insertion (ex20ins) is a rare mutation in the epidermal growth factor receptor (EGFR) gene associated with poor response to tyrosine kinase inhibitors.¹

鈥淔or the majority of people with advanced EGFR-mutated NSCLC, we have highly effective targeted treatment options,鈥� says Jeffrey Melson Clarke, MD, a medical oncologist at Duke Health, and Associate Professor of Medicine at Duke University School of Medicine, Durham, NC. Dr. Clarke is not affiliated with the study.

鈥淗owever, for a minority with EGFR exon 20-mutated disease,鈥� he added, 鈥渢hese treatments don鈥檛 work nearly as well and prognosis is worse as a result. Other commonly used drugs for lung cancer acting on the immune system are usually less effective in this population, as well.鈥�

To create benchmarks and help gauge future progress in drug development for patients with EGFR ex20ins NSCLC, the International Association for the Study of Lung Cancer and the American Society of Clinical Oncology CancerLinQ sought to evaluate the characteristics, treatment patterns, and overall survival of this patient population. 

The researchers, who published their study in a recent issue of JTO Clinical and Research Reports, described EGFR ex20ins to be a 鈥渄istinct clinical challenge in patients with NSCLC鈥� and to be 鈥渁ssociated with a higher propensity for brain metastases and a relatively modest overall survival.鈥�¹

Assessing CancerLinQ data

The American Society of Clinical Oncology CancerLinQ Discovery database was used to identify individuals initially diagnosed from 1995-2018 with NSCLC and EGFR ex20ins mutations. CancerLinQ is a health technology platform containing structured and unstructured data from 63 participating oncology organizations and practices across the United States.

Data were assessed on patient demographics, tumor characteristics, treatment patterns, and outcomes. Kaplan-Meier curves were used to evaluate overall survival, the primary outcome.

A snapshot of EGFR ex20ins NSCLC

The study analyzed data from 357 patients (median age 68 years); 54% were female, 63% White, and 9% Black. Overall, 62% had Stage 4 disease and 30% had brain metastasis. The authors pointed out that their analysis is one of the largest datasets in patients with EGFR ex20ins NSCLC.

A total of 54% had received chemotherapy, 15% immune checkpoint inhibitors (ICIs), and 12% targeted agents. Among those with brain metastasis, 16% were treated with ICIs, 18% with targeted agents, and 59% with chemotherapy. 

Overall survival

Median overall survival was 23.8 months. Multivariable analysis revealed that:

• Risk of death was significantly lower among patients treated with ICIs (HR 0.67, 95% CI 0.49 to 0.93; P=.018), chemotherapy (HR 0.59, 95% CI 0.45 to 0.77; P<.001), and targeted agents (HR 0.52, 95% CI 0.36 to 0.74; P<.001) as well as among those who underwent surgery (HR 0.56, 95% CI 0.43 to 0.74; P<.001), compared with those who did not receive these treatments.
• Women had a significantly higher risk of death compared with men (HR 1.47, 95% CI 1.18 to 1.84; P<.001).
• Black patients had a significantly lower risk of death compared with White patients (HR 0.62, 95% CI 0.42 to 0.91; P=.016).
• Patients in the Midwest region of the United States had a significantly lower risk of death compared to the South (HR 0.62, 95% CI 0.46 to 0.85; P=.003). 

A look at Stage 4 NSCLC

Among those with Stage 4 disease, 51% were female, 64% White, and 9% Black; 37% had brain metastasis. A total of 18% received ICIs, 14% targeted agents, and 60% chemotherapy. 

Median overall survival was 16.8 months for those with Stage 4 disease. Overall survival was significantly better among patients with Stage 4 disease receiving treatment with:

• Targeted agents (median 20.6 months vs 16.1 months; P=.02). 
• ICIs (median 29.1 vs 14.7 months; P=.01).
• ICI plus chemotherapy versus those treated with chemotherapy alone (median 29.1 vs 16.5 months; P=.05). 

The authors also indicated that, according to multivariable analyses of stage 4 patients: 

• Those treated with ICIs (HR 0.65, 95% CI 0.45 to 0.95; P=.026), targeted agents (HR 0.40, 95% CI 0.24 to 0.65, P<.001), chemotherapy (HR 0.54, 95% CI 0.38 to 0.76; P<.001), and surgery (HR 0.52, 95% CI 0.35 to 0.78; P=.001) had significantly improved survival compared with those who did not receive these therapies. 
• Risk of death was higher among women than among men (HR 1.46, 95% CI 1.09 to 1.95; P=.012)
• Risk of death was lower among Black patients versus White (HR 0.55. 95% CI 0.34 to 0.92; P=.021) 
• Risk of death was lower among patients with Stage 4 disease from the Midwest region of the United States compared to the South (HR 0.66, 95% CI 0.43 to 0.99; P=.046). 

Interpreting the results

The authors noted that their results regarding improved survival among patients with EGFR ex20ins NSCLC receiving targeted therapies 鈥渋s relatively modest and consistent with previous reports.鈥� They also noted that their finding of a survival benefit with immunotherapy in combination with chemotherapy could have been 鈥渟trongly biased by patient selection.鈥�

Several other limitations were mentioned, including, for example, the potential for missed patients with EGFR ex20ins due to underperformed molecular testing and the lack of information on the particular reasons guiding treatment decisions. 

鈥淏ecause of these limitations, as with any real-world data sets, we were unable to perform analyses at a more granular level for treatment efficacy using many possible confounding factors,鈥� the authors wrote in their report. 

Despite the study limitations, the authors commented, population-level findings 鈥渕ay provide the best information to guide research and patient care.鈥� 

鈥淲e have seen the development of new targeted treatments recently for EGFR exon 20,鈥� Dr. Clarke told 番茄社区, 鈥渁nd there are multiple new promising agents in clinical trials.鈥�

Published: June 28, 2024