Discussion

• This case describes the course of treatment for an elderly patient with good initial performance status, an EGFR L858R mutation and high PD-L1 expression score.
• The patient was diagnosed with metastatic disease, and first-line treatment selection (clinical trial) was based on tumor marker status (EGFR L858R). Tissue was obtained by endobronchial biopsy, and testing was performed by the pathology group.
• While on trial protocol, the patient developed skin rash, indicating response to therapy¹ and remained on therapy for approximately 6 months before progressing in the left mandibular body. Rash improved over time with doxycycline (up to 100 mg daily). Despite an EGFR L858R mutation, the response to erlotinib was relatively short.
• Decision was made to re-biopsy the patient in the hopes of finding a new targetable mutation, such as EGFR T790M. More than 50% of patients with EGFR mutation who become resistant to therapy will harbor a T790M mutation.^2,3 
• Unfortunately, this patient did not have an EGFR T790M mutation, but results of next-generation sequencing indicated a 100% PD-L1 tumor proportion score (TPS).
• At the time of treatment, pembrolizumab⁴ was approved as an immunotherapy option for patients whose tumor had high PD-L1 TPS and had previous treatment with EGFR/ALK aberrations. Positive PD-L1 TPS was defined as ≥ 50%. If this patient’s PD-L1 score was < 50%, then platinum-based chemotherapy would have been recommended.
• The patient received 200 mg of IV pembrolizumab over 30-minute infusions on day 1 of a 21-day cycle. While on pembrolizumab, this patient experienced minimal toxicity. However, toxicity commonly associated with immune checkpoint inhibitors include dermatitis, hypophysitis, enterocolitis, elevated liver function and diarrhea. Additionally, patients who experience immune-related adverse events tend to have improved treatment outcomes.⁵
• After four cycles, the patient was reassessed. Stable disease was reported in her chest, and new central nervous system disease was identified. She was treated with SRS and continued pembrolizumab treatment for two additional cycles before having disease progression in the chest, despite the new brain metastasis. SRS was selected over whole brain radiation because of single site of disease and fewer comorbidities.  Pembrolizumab was continued as the patient only had new oligometastatic progression. Dose and schedule of pembrolizumab were not altered.
• Scans were obtained after cycle 6 was completed and identified progressive disease in the right hemithorax. At this point, the patient was re-biopsied for T790M mutation using a serum-based assay.  Liquid biopsies are good options for assaying several gene aberrations in patients with non–small cell lung cancer and are FDA approved in this indication. One advantage of using a liquid biopsy is that it allows for assessment of ctDNA in the bloodstream and may be more representative of the entire tumor burden.
• With no T790M mutation identified with liquid biopsy, the patient went on to salvage chemotherapy with carboplatin/pemetrexed. Of note, the patient continued to have an EGFR L858R mutation. Some studies have suggested re-treatment with an EGFR TKI after progression on EGFR TKI and chemotherapy, particularly in patients with no other treatment options.^6-8
• As of December 2017, the patient had received three cycles of carboplatin/pemetrexed without progression. However, a dose reduction for carboplatin is planned because of low hemoglobin.

• 1. Liu H-b, Wu Y, Lv T-f, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS ONE. 2013;8(1):e55128.
• 2. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-792.
• 3. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73.
• 4. Pembrolizumab (Keytruda) Checkpoint Inhibitor. U.S. Food and Drug Administration website. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm526430.htm. Updated October 25, 2016. Accessed December 8, 2017.
• 5. Fujii T, Colen RR, Bilen MA, et al. Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience [published online ahead of print November 21, 2017]. Invest New Drugs. doi:10.1007/s10637-017-0534-0.
• 6. Chang GC, Tseng CH, Hsu KH, et al. Predictive factors for EGFR-tyrosine kinase inhibitor retreatment in patients with EGFR-mutated non-small-cell lung cancer - A multicenter retrospective SEQUENCE study. Lung Cancer. 2017;104:58-64.
• 7. Cappuzzo F, Morabito A, Normanno N, et al. Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer. Lung Cancer. 2016;99:31-37.
• 8. Xia GH, Zeng Y, Fang Y, et al. Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI. Cancer Biol Med. 2014;11(4):270-276.