adenocarcinoma , the most common type of lung cancer , accounts for nearly half of all non - small cell lung cancer ( nsclc ) cases . with more than a million deaths per year , it is the leading cause of worldwide cancer - related mortality . a common molecular subset of nsclc , associated with 10 and 30% of nsclcs in north american / european and east asian countries , respectively , harbors activating mutations in the epidermal growth factor receptor ( egfr ) . the two most common egfr mutations are exon 19 deletions and the l858r point mutation , with exon 19 deletions leading to a longer survival following treatment with egfr tyrosine kinase inhibitors ( tkis ) compared with those with the l858r mutation . despite the dramatic efficacy of these tkis , including erlotinib , gefitinib , and afatinib , in 70% of egfr - mutant nsclcs , the remaining 30% exhibit de novo resistance   and , even among initial responders , acquired resistance is inevitable , usually in less than 1 year . the present report describes the case of a patient with acquired resistance to carboplatin / pemetrexed and erlotinib who demonstrated massive necrosis during treatment with the systemically nontoxic epi - immunotherapeutic agent , rrx-001 [ 9 , 10 , 11 ] , in the context of a clinical trial called triple threat ( nct02489903 ) . the objective of this trial is to investigate resensitization to platinum doublet chemotherapy in patients with nsclc , sclc , and high - grade neuroendocrine tumors . a 49-year - old white male us air force master sergeant and never smoker was initially diagnosed with clinical stage iiia ( t3 , n1 , m0 ) egfr - positive ( exon 19 deletion ) nsclc in june 2014 in the left upper lobe of the lung , for which he underwent upper lobectomy followed by four cycles of carboplatin ( auc = 5 ) and pemetrexed ( 500 mg / m ) that finished on october 29 , 2014 . on december 1 , 2014 , due to complaints of upper abdominal pain and weight loss , a metastasis to the abdomen was discovered . surgical resection was undertaken , and pathology confirmed an egfr - positive metastasis from the primary lung cancer . in june 2014 , a computed tomography ( ct ) scan demonstrated a new mass in the pancreas . cytology samples obtained via fine needle aspiration ( fna ) demonstrated the presence of an egfr exon 19 mutation - positive lung adenocarcinoma . treatment with erlotinib ( 150 mg daily ) was initiated on december 22 , 2014 . approximately 6 months after starting erlotinib in july 2015 , restaging ct revealed disease progression . another fna of the mass demonstrated persistence of the egfr exon 19 mutation . in august 2015 , the patient was enrolled on a phase ii clinical trial with th-4000 , a hypoxia - activated egfr / her2 inhibitor , for patients who failed erlotinib therapy . approximately 8 weeks later , restaging ct demonstrated disease progression , with a doubling in the size of the mass . on october 8 , 2015 , despite a 20-lb weight loss and a decline in performance status due to the size of the mass , he enrolled on the triple threat trial ( nct02489903 ) and received 4 mg of once weekly rrx-001 . five weeks later , due to progressively worsening abdominal pain , he was imaged with pet / ct , which demonstrated an enlarged necrotic mass in the head of the pancreas with a thin capsule of apparently viable tumor ( fig . image - guided aspiration of the mass yielded 200 ml of fluid , which was sent for cytology . the fluid content was positive for a predominance of necrotic debris with cd8 + t - cell infiltration . a comparison of cellularity , necrosis , and t - cell infiltrate before and after treatment with rrx-001 is demonstrated graphically in figure 2 , and the degree of necrosis in figure 3 . on november 10 , 2015 , due to this early pseudoprogression or apparent growth of the tumor from extensive necrosis , defined as recist v.1.1 progression , the patient was restarted on platinum doublets ( cisplatin / pemetrexed ) per protocol . since the tumor is at least partially liquefied centrally , a percutaneous drainage catheter was placed leading to significant symptomatic improvement . while the prognosis for patients with egfr - mutant nsclc that have progressed on prior tki therapy remains grim , evidence of efficacy with checkpoint inhibitors in nsclc suggests that rrx-001 , which induces antitumor immune responses , may provide a new treatment direction for nsclc in general and egfr - mutant nsclc in particular , since the latter is reported to be associated with programmed death - ligand 1 ( pd - l1 ) expression . more detailed investigations of the functions of t and b cells and pd-1/l1 expression in the antitumor effects of rrx-001 are warranted to characterize the immune profile of these responders , which , in turn , may suggest new combination strategies to enhance the cancer immunity cycle . as an epi - immunotherapeutic agent , rrx-001 , like the dna methyltransferase inhibitors decitabine   and azacytidine [ 16 , 17 ] , although , in this study , patients received rrx-001 as monotherapy , the systemic non - toxicity of rrx-001 , as well as the preclinical   and preliminary clinical evidence of immune reactivation in combination with nivolumab in a phase i dose - escalation trial called primetime ( nct02518958 ) , potentially provides a rationale for triple therapy with rrx-001 , egfr - tkis , and anti - pd-1/pd - l1 antibodies in egfr - mutant nsclc .
we present the case of a 49-year - old male with metastatic epidermal growth factor receptor ( egfr ) mutation - positive adenocarcinoma of the lung that continues to outlive stage iv diagnosis of non - small cell lung cancer after treatment with rrx-001 , an experimental anticancer agent with epigenetic and immunologic activity , in the context of a phase ii clinical trial called triple threat . 
 currently , no adequate treatment options exist for patients with egfr mutation - positive tumors who have failed a 1st - generation tyrosine kinase inhibitor ( erlotinib or gefitinib ) treatment and do not develop a resistant mutation . 
 biopsy of a large pancreatic metastasis after rrx-001 demonstrated extensive necrosis with cd3 + and cd8 + immune cell infiltration that appears to correlate with prolonged survival despite end - stage disease . 
 these results suggest that the mode of action of rrx-001 is related to immune stimulation in addition to epigenetic inhibition .