*March 2019* This is an overview (written by Donald Ox) of the current EGFR TKIs and acquired resistance leading to the effectiveness of the afatinib + cetuximab combo treatment especially useful for T790M negative patients who developed acquired resistance to Iressa/Tarceva/Afatinib, as many in our group queried about their options other than chemo.

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are common in lung cancers patients who are non-smokers/never-smokers, and some of these patients’ tumors have been reported to be very responsive to 1st-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib (Iressa) in clinical trials since 2003. EGFR, a receptor tyrosine kinase (RTK) mutated or overexpressed in many types of cancers, plays a key role in tumor cell proliferation and vascularization. Since 15%-60% of non-small cell lung cancer (NSCLC) adenocarcinoma express EGFR mutations depending on various factors such as race, sex, ethnicity, and smoking history, EGFR has become a key therapeutic target for treating NSCLC adenocarcinoma, especially for non-smokers/never-smokers. Clinical trials have indicated that for advanced NSCLC patients with EGFR-mutations, first-line treatment with an EGFR TKI is superior to the traditional platinum-based cytotoxic chemotherapy, as well as to the immunotherapy using PD-1/PD-L1 check-point inhibitors, like Keytruda. Therefore, EGFR mutation testing should be mandatory for NSCLC patients. However, about 10% patients not testing EGFR-positive also responded well to EGFR-targeting TKIs, suggesting that selection of treatment based solely on somatic mutations using a FDA approved EGFR test kit is not always adequate.

Unfortunately, advanced NSCLC patients who responded to either the treatment of first-generation TKIs (i.e., gefitinib or erlotinib) or the second-generation TKIs (e.g., afatinib or dacomitinib) will mostly develop acquired resistance within a few years, some from further mutation on the EGFR protein. Preclinical studies as well as patients’ re-biopsies have revealed that the EGFR T790M point mutations arise in ~50-60% of these cases, as the cancer cells acquired the abilities to avoid apoptosis and continue proliferation as secondary-resistant cancer cells. Third-generation TKIs, such as osimertinib (Tagrisso), therefore, has been developed and approved by the FDA in late 2016 as the treatment choice for patients with the T790M mutation who have had disease progression following prior EGFR TKI therapies; it has now also been approved by the FDA in 2018 as a 1st-line treatment option for EGFR-mutated NSCLC patients. However, the acquired resistance to osimertinib also tends to develop within a year or two, and it can be very complex so oncologists world-wide are looking for effective clinical treatment options. Progression on second-line or third-line osimertinib treatment revealed that the biology of patients who retain T790M and those who lose T790M appears to be fundamentally different. Those who retain T790M seem to develop another acquired mutation; about half of those patients will develop C797S mutation, which prevents osimertinib from binding at the ATP cleft to be effective. However, in patients whose tumors that lose T790M, patients can develop a broad range of different resistance mechanisms, including MET amplification and mutations in PI3 kinase, etc. These patients may also develop KRAS mutations, fusions in RET, BRAF, FGFR3, as well as in ALK, NTRK, and ROS1 mutations. In tumors that retain T790M, the progress-free survival (PFS) time on osimertinib often exceeda one year. Patients who lost T790M, however, may have significantly lower PFS on osimertinib, suggesting that those competing mechanisms of resistance were already present in those patients when T790M was detected, even though more studies are needed to understand the details. Only in some specific cases where the C797S mutation developed on the trans-site of the T790M, new dual-TKIs treatment such as erlotinib combined with osimertinib appears to be effective in controlling the disease progression for some time. Therefore, a bit more data from clinical trials is urgently needed to address the acquired resistance induced by osimertinib, especially since it has become the favorite front-line treatment option for EGFR-mutant NSCLC patients by numerous oncologists world-wide. We at the EGFR resisters group will be constantly monitoring the latest development and report the promising clinical data and treatment options in our newsletter.

For example, recent novel treatment options with cetuximab (Erbitux) targeting the inhibition of the EGFR receptor for EGFR-mutant NSCLC have shown interesting promises for overcoming the acquired resistance from first-generation and second-generation EGFR TKIs.  When cetuximab is used in combination with afatinib, they both inhibit the EGFR pathway and this dual-inhibition has demonstrated a synergistic potency for anti-tumor activity, and induced antibody-dependent cell cytotoxicity (ADCC) in patients. In this somewhat “old” paper published in 2014, the experts reported promising trial data done from this novel targeted treatment option for EGFR-mutant NSCLC patients by dual-EGFR inhibition, and this combo treatment has proven to be effective in overcoming the acquired resistance of first-generation and second-generation EGFR TKIs clinically with manageable toxicity. This phase 1b study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib (Tarceva) or gefitinib (Iressa). Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3–6.4); median duration of confirmed objective response was 5.7 months (range, 1.8–24.4). Therapy-related grade ¾ adverse events occurred in 44%/2% of patients. Afatinib/cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations. This combo is known to cause considerable skin toxicity so patients usually should reduce the afatinib dose to 30 mg daily, and start the biweekly cetuximab dose significantly lower than the trial dosage 500 mg/m2. This combo can be a treatment option to Tarceva/Iressa resistance if patients did not develop T790M mutation.  In fact, my wife has used this combo therapy for three years and four months after she progressed on Tarceva ! We see our dermatologist quite often to make sure the skin toxicity can be manageable.