Treatment exceeds expectations in a patient with non-small cell lung adenocarcinoma with an EGFR exon 20 mutation

Introduction

Lung cancer is the second most common cancer in the United States. ¹ There was an estimated 222,500 new cases in 2017 alone. ¹ Lung cancer is divided into two broad categories – small cell and non-small cell lung cancer (NSCLC). NSCLC is the most common type and a difficult cancer to treat especially in patients with stage IV disease. The average five-year survival rate for stage IVA is 10% and for stage IVB is 1%. ² However, new drugs, including tyrosine kinase inhibitors (TKIs) which target epidermal growth factor receptor (EGFR) mutations, have provided better treatment options for these patients. EGFR mutations are estimated to occur in approximately 11–17% of Caucasian patients with NSCLC. The most common EGFR mutations are the exon 19 deletion and the L858R point mutation in exon 21. These two mutations are known to respond well to treatment with TKIs. Less common EGFR mutations include the exon 20 insertion, G719X mutation, and T790M mutation. ³ These less common mutations are felt to be resistant to TKIs. Exon 20 insertions are thought to occur in 1.5–2.5% of all NSCLCs, but make up for 10% of the known EGFR mutations. ⁴ They are the more common of the rare mutations and are not responsive to TKIs. The exon 20 insertion itself is also quite variable, with up to 13 different insertions found to date. ⁵

Case

This is a case of a 78-year-old man with advanced non-small cell lung carcinoma who has surpassed expected survival after multiple treatments. The patient, who initially presented with cough and hemoptysis, had a computed tomography (CT scan) of his chest which showed a 6 × 3.6 cm left lower lobe lung mass as well as bilateral hilar adenopathy, paratracheal adenopathy, and multiple bilateral pulmonary nodules. Initially, there was concern for an infectious etiology; however, CT-guided biopsy revealed malignant cells consistent with a non-small cell adenocarcinoma of the lung. The patient was found to have an EGFR insertion mutation at exon 20, and he did not have an anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS-1) mutation. At the time of his diagnosis in 2014, it was unclear what the implications of his exon 20 mutation were in regards to the EGFR inhibitors. The patient was elderly and had high volume disease, so erlotinib was started as a reasonable way to treat the tumor while limiting toxicity. When he did not respond, and more importantly, when he did not have rapid progression two months after initiation, it was decided that the patient could tolerate chemotherapy and therefore receive more effective anti-tumor treatment. For the following six months, he was treated with carboplatin at an Area under the curve (AUC) of 5 and paclitaxel at 175 mg/m², with good response. After completion of this chemotherapy regimen, the patient was placed on pemetrexed maintenance and completed 34 cycles at reduced dose of 350 mg/m² due to mild azotemia. Three years into treatment, he had progression seen on imaging with moderate interval increase in bilateral lung lesions. At this point, he was started on nivolumab for 10 cycles. However, he again had progression and an increase in his carcinoembryonic antigen tumor marker. He was started on chemotherapy with docetaxel at 60 mg/m² and continues to remain on docetaxel with a good performance status (ECOG score of 1). Currently, he is 50 months out from initial diagnosis of his metastatic non-small cell lung adenocarcinoma.

Discussion

Molecular testing in lung cancer treatment allows for a more targeted chemotherapy regimen for many patients. Those with advanced cancer and EGFR mutations are being found to have heterogeneous outcomes based on the exact mutation. Our patient had an exon 20 insertion which usually confers a poor prognostic outcome, but he has exceeded expectations. Long survival is very uncommon with this disease and an exon 20 insertion given its usually high fatality rate. Therefore, this case is an example of possible treatment options for patients with this type of mutation. Multiple trials have shown that the rarer EGFR mutations do not respond to TKIs, and that better regimens need to be studied. For example, Pilotto et al. reported in a review of the BE-POSITIVE trial data, that in the subgroup of patients with exon 20 alterations, there was no objective response to TKI treatment, and a median overall survival was 15.44 months. ⁶ O’Kane et al. report that a review of 12 major retrospective studies showed that the majority of patients with the exon 20 insertion were resistant to TKIs. They also showed that the patients treated with platinum doublets had a higher superior median overall survival of 31 months. ⁴ Another retrospective study performed in India showed that patients with exon 20 mutations had a poorer overall survival. ⁷ Afatanib is one of the TKIs and has been approved since 2013 for use in patients with metastatic NSCLC who have an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation. ⁸ However, after a recent prospective study involving data from the LUX-LUNG 2, LUX-LUNG3, and LUX-Lung 6 trials, it has been found that there may be additional other mutations also sensitive to treatment with afatanib that were previously not considered sensitive. Afatanib was found to be most effective with EGFR mutations in Ser 768IIe, Leu861Gln, and Gly719Xaa and less effective with exon 20 insertions and Thr790Met mutations. ⁷ Therefore, in January of 2018, the FDA approved afatanib also for the treatment of metastatic NCSLC in patients with the first three mutations (S768I, L861Q, and/or G719X).

A recent meta-analysis showed that carboplatin plus pemetrexed for elderly incurable chemo-naïve NSCLC can be a good option. They report a median overall survival of 14.9 months and progression-free survival of 5.4 months. ⁹ Other studies also suggest that chemotherapy is likely a better option for patients with exon 20 mutations and metastatic cancer who will likely not respond to typical TKI treatment. ⁸

This case report demonstrates that treatment of patients who have exon 20 mutations with platinum doublet chemotherapy with carboplatin and paclitaxel followed by maintenance pemetrexed may be a good option, since they do not respond to TKIs as well. The patient discussed here surpassed the majority of expected overall survival. He is doing well almost four years after his initial diagnosis. Given new data regarding the lack of response in exon 20 mutations to TKIs, responses to other chemotherapeutic regimens need to be examined on a larger scale. Further studies need to be done to evaluate more closely these uncommon EGFR mutations and identify the best course of treatment. The case also emphasizes the importance of determining in each patient his or her exact mutation for the most effective guidance of the treatment.