Estelamari Rodriguez, MD, MPH, associate director, Community Outreach – Thoracic Oncology, Sylvester Comprehensive Cancer Center, discusses the benefits of the TKIs afatinib (Gilotrif) and osimertinib (Tagrisso) in patients with lung cancer with uncommon 

 mutations can fall into several categories. Sensitizing 

 exon 20 insertion mutations are 2 distinct groups, and all other 

 mutations, Rodriguez says. Historically, patients with lung cancer with uncommon 

 mutations have had unfavorable outcomes with first- and second-generation TKIs, Rodriguez notes.

However, data support the use of the TKI afatinib in patients with lung cancer with uncommon 

 mutations, and in 2018, the agent was approved by the FDA in this population based on findings from the phase 2 LUX-Lung 2 (NCT00525148) and phase 3 LUX-Lung 3 (NCT00949650) and LUX-Lung 6 (NCT01121393) trials. Since afatinib is an irreversible EGFR receptor inhibitor, it has activity against several uncommon 

 mutations, Rodriguez explains. Although this agent causes more rash and diarrhea than other TKIs, these are manageable with dose adjustments and supportive care.

Additionally, osimertinib in under global investigation as a first-line therapy for patients with lung cancer with uncommon 

 resistance mutations such as T790M, with a high degree of mutant receptor activity and fewer adverse effects than other TKIs, Rodriguez says.

Targeted therapies are optimal frontline treatment options for patients with molecularly driven cancers, such as those with 

-mutant lung cancers, in whom chemotherapy can often be reserved for later lines, Rodriguez emphasizes. Another benefit of afatinib and osimertinib is their ability to penetrate the central nervous system barrier, which is a common site of progression in patients with lung cancers with uncommon 

 mutations, Rodriguez notes. Afatinib is approved by the FDA in this population, and data support the use of osimertinib in these patients as well, Rodriguez concludes.

Videos

Estelamari Rodriguez, MD, MPH, discusses the benefits of the TKIs afatinib and osimertinib in patients with lung cancer with uncommon EGFR mutations.

Dr Rodriguez on TKIs in Lung Cancers With Uncommon EGFR Mutations

Tarek M. Mekhail, MD, MSc, FRCSI, FRCSEd, medical director, Thoracic Oncology Program, AdventHealth Cancer Institute, associate professor, the University of Central Florida, discusses the prevalence of uncommon 

 mutations in patients with lung cancer, research needs for these patients, and how the findings from the phase 3 LUX-Lung 3 (NCT00949650) and LUX-Lung 6 (NCT01121393) trials support the use of afatinib (Gilotrif) in this population.

Dr Mekhail on the Prevalence of Uncommon 

 mutations are becoming increasingly recognized through next-generation sequencing, Mekhail says. Around 6% of all patients with lung cancer will have a form of an uncommon 

 mutation, Mekhail notes. However, limited data exist regarding drug activity in this population, as most clinical trials investigating first-, second-, and third-generation TKIs in patients with lung cancer have excluded those with uncommon 

Dr Mekhail on LUX-Lung 3 and LUX-Lung 6 in Lung Cancers with Uncommon 

The LUX-Lung 3 and Lux-Lung6 trials have provided information regarding the treatment of patients with lung cancer with uncommon 

 mutations. LUX-Lung 3 investigated the efficacy and safety of afatinib vs pemetrexed (Alimta) and cisplatin in patients with 

-mutant advanced lung adenocarcinoma, including those with uncommon 

 mutations. In this trial, treatment with afatinib led to a median progression-free survival (PFS) of 11.1 months vs 6.9 months in those who received pemetrexed plus cisplatin and an overall response rate (ORR) of 56% vs 23%, respectively. The median duration of disease control was 13.6 months and 8.1 months in the afatinib and chemotherapy arms, respectively. LUX-Lung 6 evaluated the safety and efficacy of afatinib vs cisplatin and gemcitabine in Asian patients with advanced non–small cell lung cancer harboring 

 mutations. In this trial, patients who received afatinib achieved a median PFS of 11.0 months vs 5.6 months in those who received the chemotherapy combination. The ORR was 66.9% and 23.0% in patients who received afatinib and chemotherapy, respectively. Additionally, the disease control rate (DCR) was 92.6% and 76.2% in the afatinib and chemotherapy arms, respectively.

Although the findings from these trials showed variable response rates, DCRs, and PFS, each trial had encouraging ORR, DCR, and PFS data, Mekhail emphasizes. The results from these trials support the use of afatinib in patients with lung cancer with uncommon 

Tarek M. Mekhail, MD, MSc, FRCSI, FRCSEd, discusses the prevalence of uncommon EGFR mutations in patients with lung cancer, research needs for these patients, and how the findings from the phase 3 LUX-Lung 3 and LUX-Lung 6 trials support the use of afatinib in this population.

Dr Mekhail on Afatinib in Lung Cancers With Uncommon EGFR Mutations

Martin F. Dietrich, MD, PhD, medical oncologist, Florida Cancer Specialists & Research Institute, discusses how mutational profiling can inform subsequent treatment selection for patients with non–small cell lung cancer (NSCLC).

Current molecular testing practices in lung cancer have been substantially influenced by the expansion of actionable targeted alterations, as well as associated treatment options.

Patient risk-factors such as advanced age or heavy smoking are not predictive of specific rare mutations, and there is currently no viable tool for predicting a patient’s mutational probability according to individual characteristics, Dietrich begins.

Therefore, the optimal strategy for identifying rare mutations in patients with NSCLC is to include them in early clinical assessments, Dietrich explains. Since there are several effective first-line therapeutics for the treatment of patients with NSCLC, many of these mutations are not identified until later in the disease course, if at all, he adds. There is a clear algorithm for the use of these first-line options for common mutations like 

, Dietrich continues. Although there are also agents approved for mutations like 

, it is more difficult to determine their proper sequencing, Dietrich states.

In clinical practice, the selection of targeted therapies vs immunotherapies can be divided by 

 specifically may be associated with higher mutational burden and smoking, he notes. However, there is some overlap according to disease biology, and some mutations cannot be definitively clustered due to a lack of phase 3 data, Dietrich qualifies. For example, targeted therapies appear to provide more benefit for patients with NSCLC exhibiting a 

 fusion based on observational studies and biological analysis, he details.

Accordingly, patients who may or may not be enriched for specific mutations should not be selected out. Instead, all patients should undergo next-generation sequencing using both DNA- and RNA-based platforms regardless of disease stage, Dietrich concludes.

Martin F. Dietrich, MD, PhD, discusses how mutational profiling can inform subsequent treatment selection for patients with non–small cell lung cancer. 

My Treatment Approach: Utilizing Test Results to Inform Clinical Decisions in NSCLC | Supplements and Featured Publications

Dr Rodriguez on TKIs in Lung Cancers With Uncommon EGFR Mutations

Dr Mekhail on Afatinib in Lung Cancers With Uncommon EGFR Mutations

Dr Dietrich on the Importance of Mutational Profiling in NSCLC Treatment