•These case reports illustrate a novel epidermal growth factor receptor (EGFR)-mediated mechanism of resistance in patients with EGFR L858R mutations treated with osimertinib as front-line therapy who acquired the EGFR L718V (+)/T790M (–) resistance mutation identified by liquid biopsy after clinical progression on osimertinib, demonstrating potential clinical activity of afatinib in this setting.•These cases also emphasize the need to start to look for this genetic aberration and to confirm that afatinib is the right therapy or identify new drugs to overcome this mechanism of resistance and avoid sending these patients to chemotherapy instead to continuing with targeted therapy.

SESSION TITLE: Medical Student/Resident Lung Pathology SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Foreign body aspiration (FBA) is more common in children than adults, with 80% of incidents occurring in patients under 15 years of age. Unlike in children, FBA in adults has a very subtle presentation such as chronic cough or sputum production. We present the case of an aspirated almond presenting as a post-obstructive pneumonia concerning for occult malignancy. CASE PRESENTATION: A 59-year-old man with a 70-pack-year smoking history was admitted to the hospital due to persistent pneumonia. The patient reported ongoing symptoms for the past several months that were unresponsive to multiple courses of antibiotics in the outpatient setting, in addition, he reported a 40-pound weight loss in the past 8 months. His primary care physician ordered a low-dose CT scan of the chest to screen for lung cancer. This study revealed a new right upper lobe mass and the patient was referred to pulmonology for further evaluation. A PET scan was ordered at that time, however due to the recurrence of fever, shortness of breath, and productive cough, the patient presented to the emergency room. On admission, he was febrile with a significant leukocytosis and mild hyponatremia. Chest x-ray showed a diffuse infiltrate of the right lung with the densest consolidation seen in the right upper lobe. These findings were corroborated by CT angiography of the chest, and the patient was started on IV antibiotics and nebulizers. Also upon admission, oncology and radiation oncology were consulted in anticipation for a cancer diagnosis given the patient’s smoking history and recent weight loss. PET scan was re-ordered for staging, and a discussion on the likelihood of a cancer diagnosis was emphasized. Subsequently, the patient underwent rigid bronchoscopy at which time the mass was visualized and biopsies collected. The initial frozen section was suggestive of chondromatous tumor such as a hamartoma, but permanent sections revealed vegetative matter. Upon further questioning, the patient recalled aspirating a piece of almond several years ago. He was discharged and underwent flexible fiberoptic bronchoscopy and removal of a foreign body at which time his pneumonia resolved. Follow-up imaging revealed resolution of consolidation and absence of right upper lobe obstruction. DISCUSSION: Through mental shortcuts and previous experiences, post-obstructive pneumonia in a smoker with weight loss was assumed to be related to cancer. Premature consults and imaging studies were ordered due to these assumptions which ultimately resulted in excessive healthcare expenditures and exposing patient to potential adverse side effects of medications and invasive procedures. CONCLUSIONS: FBA in adults is rare and presentation can be non-specific but should be considered as a differential diagnosis in any patient with post-obstructive pneumonia to avoid anchoring in a diagnosis of cancer and potentially miss a treatable condition. Reference #1: Baharloo F, Veyckemans F, Francis C, Biettlot MP, Rodenstein DO. Tracheobronchial foreign bodies: presentation and management in children and adults. Chest. 1999;115(5):1357-1362. doi:10.1378/chest.115.5.1357 Reference #2: Biswas Roy S, Ross MD, Madan N, et al. Aspirated Almond Masquerading as an Obstructing Endobronchial Mass Suspicious for Lung Cancer. Case Rep Pulmonol. 2018;2018:3742036. Published 2018 Jun 7. doi:10.1155/2018/3742036 DISCLOSURES: No relevant relationships by Maya Lucas, source=Web Response no disclosure on file for Michel Velez

e15013 Background: Analysis ofcell-free circulating tumor RNA (cfRNA) extracted from plasma of cancer patients (pts) provides a means of measuring dynamic changes in gene expression as well as levels of cfRNA, allowing us the evaluation of disease status and prediction of outcomes to anti-tumoral therapy. Methods: Blood was drawn from pts under various treatments (tx) every 6-8 weeks, at the same time that CT scans were done. CfRNA was extracted from the resulting plasma and reverse transcribed with random hexamers to cDNA. Levels of cfRNA were quantitated by RT-qPCR and correlated with pt response (CR/PR/SD/PD), as determined by CT scans. Results: 96 pts (48 breast, 30 lung and 18 colon cancer) were enrolled in a 2-year study. Breast: 34 pts completed the first two cycles of tx. Of these, 8/11 pts with PD showed increasing (INC) levels of cfRNA, 16/17 pts with SD showed either no change (NC) or a decrease (DEC) in levels of cfRNA, and 4/6 pts with PR had DEC cfRNA (82% concordance between cfRNA and pt response). Of pts with PR, 3 were treated with HER2 inhibitors and in 2 of these pts, HER2 cfRNA expression levels disappeared. Lung: 23 pts completed the first two cycles of tx. Of these, 6/8 pts with PD showed INC levels of cfRNA, 8/12 pts with SD showed either NC or DEC cfRNA, and 3/3 pts with PR had DEC cfRNA, corresponding to 74% concordance between cfRNA and pt response. Among 7 pts treated with immunotherapy, 3/3 pts with PD showed INC PD-L1 expression (PDL-1), 3/3 pts with SD had NC in PD-L1, and 1 pt with PR showed DEC PD-L1, corresponding to 100% correlation between PD-L1 and response. Colon: 11/18 pts completed the first 2 cycles. Of these, 2/3 pts with PD showed INC cfRNA, and 3/4 pts with SD showed DEC cfRNA, as did 4/4 pts with PR (82% concordance between cfRNA and response). Conclusions: A significant concordance was observed between clinical response and changes in cfRNA levels in breast, lung and colon cancer pts (82%, 74% and 82%). Levels of PD-L1 correlated with response in 7/7 lung pts, and HER2 expression correlated with response in 2/3 breast pts. We conclude that cfRNA levels can indicate tx response, and PD-L1 and HER2 could be used to monitor response to immunotherapy and HER2 inhibitors.

11550 Background: There is an unmet need to evaluate tumor response by other means than radiology tests. Changes in gene expression, allele-fractions of mutations, PDL-1 expression and levels of cell free DNA [DNA] or RNA [RNA] in plasma might be useful for monitoring disease state and predicting outcome to anti-tumoral therapy. Methods: We measured serial levels of plasma DNA/RNA in metastatic patients (pts) with NSCLC and breast cancers undergoing treatment and correlated them with response (CR/PR/SD/PD) seen by CT scans. We also monitored PD-L1 expression in NSCLC pts treated with immunotherapy. DNA/RNA were extracted from plasma. RNA was reverse transcribed with random primers to cDNA. Levels of DNA/RNA were determined by RT-qPCR. Results: 52 pts were enrolled (28 breast/24 NSCLC). Breast group: 39% (11/28) were Caucasian (NHW) and 36% (10/28) Hispanic (H). 20 pts completed first two cycles of therapy: 2 pts had PR and showed no change (NC) or decrease (DEC) in levels of DNA/RNA. 11pts achieved SD, 9 had NC levels of DNA/RNA. Pts with PD: 5/6 underwent significant increase (INC) in DNA/RNA levels. Overall, among breast pts, there was an 84% (16/19) agreement between response and levels of DNA/RNA. These were correlated with one another ( r = 0.7002, p< 0.0001). NSCLC group: 71% (16/24) were NHW and 25% (6/24) H. Non-SQCC were 87% (21/24). 20 pts had CT scans. One pt had PR with DEC levels of DNA/RNA. 10 pts achieved SD, all showed DEC or NC levels of DNA/RNA. 8 pts had PD, 6 of them had INC in DNA/RNA levels even 7 weeks prior to PD. Among NSCLC pts, there was a 90% (17/19) agreement in response and levels of DNA/RNA. These were correlated with one another ( r= 0.6231, p< 0.0001). In 5 pts PD-L1 expression remained stable when CT scans showed SD or PR. Conclusions: There is a strong correlation between clinical responses with changes in plasma levels of DNA/RNA in pts with NSCLC (90%) and breast cancer (84%). Some of these were documented weeks before imaging was done. cfRNA is as effective as cfDNA as predictive tool for response. Plasma PDL-1 expression is a new tool to monitor immunotherapy response.

Cell-free circulating tumor DNA (ctDNA) and RNA (ctRNA) can be extracted from plasma of cancer patients (pts). Measuring dynamic changes in gene expression, allele-fractions of mutations and levels of nucleic acids per ml of plasma in metastatic patients has shown great potential for monitoring disease state and predicting outcome to antitumoral therapy in advance of imaging. We designed a clinical trial to measure gene levels of plasma ctDNA and ctRNA in metastatic pts with NSCLC, breast, and GI malignancies under treatment and correlate the levels with CT scans done assessing response for one-year clinical trial. CtDNA/ctRNA were extracted from plasma separated from patient whole-blood draws shipped at ambient temperature. CtRNA was reverse transcribed with random primers to cDNA. Levels of ctDNA/ctRNA were determined by real-time qPCR. Results of ctDNA/ctRNA tests were compared with responses (CR, PR, SD or PD) as determined by the CT scans. Levels of PD-L1 expression relative to β–actin were determined by qPCR. We have enrolled 39 pts and we are presenting data from 15 pts with NSCLC. The first-line treatments were Carboplatin (40%, 6/15), Opdivo (26.7%, 4/15), Afatinib (13.3%, 2/15), Ceritinib (6.7%, 1/15), Crizotinib (6.7%, 1/15), and Taxotere/Cyramza (6.7%, 1/15). Histological subtypes were 73.3% (11/15) adeno, 20% (3/15) squamous, and 6.7% (1/15) other. The majority of patients were Caucasian (66.7%, 10/15), Hispanic (26.7%, 4/15), and African American (6.7%, 1/15). Levels of ctDNA and ctRNA were significantly correlated with one another across patient blood draws (r = 0.5781, p < 0.0001). After the first 2 cycles of therapy, 9 of the 15 patients achieved SD, of whom 8 were analyzed for ctDNA/ctRNA levels. In 7/8 of pts who had SD indicated by CT scan, CtDNA/ctRNA levels were stable, while the 2 PD pts showed significant increases in levels of ctDNA/ctRNA 4.8 weeks prior to progression. In the 2 SD pts treated with Opdivo, PD-L1 expression was stable during the cycles when CT scans also indicated an SD status. In almost 90% of the pts, constant ctDNA/ctRNA levels correlated with stable disease status as seen by CT; moreover, in 2 pts changes in the levels of both ct nucleic acids predicted progression about 5 weeks before CT scans. Importantly, the concordance between cDNA and cfRNA suggest that cfRNA can just as effective as cfDNA as a prognostic tool, while adding the extra dimension of gene expression.

1048 Background: A preferred NAC regimen for HER2-negative BC is DDAC for 4 cycles followed by 12 weeks of T. RDI of 1 indicates that all intended doses are given at the scheduled interval. While large randomized studies are lacking, few studies indicated improved pCR and/or RDI when taxanes are given first. We hypothesize that tolerability and RDI are improved when T is given before DDAC. To our knowledge, this is the first study evaluating the impact of sequence on tolerability and RDI when using DDAC/weekly T. Methods: This IRB-approved, retrospective chart review included pts with stage II-III HER2-negative BC who received DDAC/weekly T NAC at our institution between August 2012 and May 2014. The sequence was based on physician preference. Conventional sequence group (CS) included pts who received weekly T after DDAC; reverse sequence group (RS) received T before DDAC. Our primary outcomes were rate of pCR and tolerability/RDI. Results: We identified 27 pts in CS and 29 pts in RS. No statistical differences between groups with respect to age, ethnicity or tumor characteristics (ER, PR, Ki67) were found. The RS had numerically more pts with stage III (p = 0.054). The table lists results relevant to the primary objectives. Conclusions: T before DDAC was associated with more pts tolerating the T maximum dose intensity (T-RDI = 1) without compromising DDAC-RDI or pCR. More pts experienced a T dose reduction (T-DR) in CS. The difference in tolerability of T cannot be explained by a specific toxicity but rather by a multitude of complications observed in CS. The most common reason for decreased T-RDI was peripheral neuropathy (PN) in both groups. Interestingly, significantly more pts in CS required pharmacologic intervention (Rx) for PN. Our study confirms the findings of others with respect to administering taxanes before antracyclines and provides specific evidence to support sequencing weekly T before DDAC. Outcome, # (%) CS (N = 27) RS (N = 29) p T-RDI = 1 11 (40.7) 20 (69) 0.034 DDAC-RDI = 1 22 (81.5) 21 (72.4) 0.422 T-DR 11 (40.7) 5 (17.2) 0.049 pCR 5 (18.5) 5 (17.2) 0.587 Rx for PN 16 (59.3) 9 (31) 0.034

Background: The efficacy of FOLFIRINOX for metastatic pancreatic cancer has led to its use in patients with earlier stages of disease. This study retrospectively analyzed a cohort of patients with locally-advanced pancreatic cancer (LAPC) treated with FOLFIRINOX.Methods: Between 2008 and 2013, 51 treatment-naive patients with LAPC at a single institution received first-line FOLFIRINOX with neoadjuvant intent, at the full dose as described in the PRODIGE 4/ACCORD 11 study. Combined chemoradiation was administered for those who remained unresectable after maximum response to chemotherapy. The primary outcome measure was overall survival (OS), and secondary outcomes were progression-free survival (PFS) and margin-negative (RU) resection rate, and toxicity profile.Results: A total of 429 cycles of FOLFIRINOX were given with a median of 8 cycles (range 2-29) per patient; 66% of cycles were full dose. After chemotherapy, 27(53%) received chemoradiation. The median OS was 35.4 months (95% CI 25.8-45). Ten (4 borderline resectable and 6 unresectable) patients had successful RU resections; those who had RU resections had a significantly longer survival than those who did not (3-year OS rate 67% versus 21%, log rank p = 0.042). Increasing number of full-dose cycles was significantly associated with increased survival. The toxicity profile was similar to previous reports of this regimen.Conclusions: FOLFIRINOX is feasible as neoadjuvant therapy for LAPC. Although the RU resection rate was only 20%, the median OS of almost 3 years appears promising. Dose intensity and duration were associated with increased survival in this study, arguing against dose attenuated versions of this regimen. Copyright (C) 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

e15197 Background: Although no prospective data are available for the use of FOLFIRINOX in LAPC, in a retrospective study of 18 pts with UR or BR LAPC, neoadjuvant therapy with FOLFIRINOX with or without subsequent chemoradiation (CCRT) resulted in an R0 resection rate of 44% (Hosein et al, BMC Cancer 2012). In order to confirm these preliminary results, we analyzed a larger cohort of pts treated in a similar fashion with mature follow-up. Methods: We included consecutive pts from 2 centers with LAPC treated with first-line FOLFIRINOX with neoadjuvant intent. Pts were categorized as BR or UR using the NCCN criteria. Pts received FOLFIRINOX chemotherapy (at the full dose as described in the ACCORD-11 trial) until maximum response or tolerability, and then underwent surgery if their imaging suggested resectability. Pts then received CCRT if they were still UR or BR after FOLFIRINOX. The end points of this retrospective analysis were overall survival (OS), progression free survival (PFS), and R0 resection ra...

e15197 Background: Although no prospective data are available for the use of FOLFIRINOX in LAPC, in a retrospective study of 18 pts with UR or BR LAPC, neoadjuvant therapy with FOLFIRINOX with or without subsequent chemoradiation (CCRT) resulted in an R0 resection rate of 44% (Hosein et al, BMC Cancer 2012). In order to confirm these preliminary results, we analyzed a larger cohort of pts treated in a similar fashion with mature follow-up. Methods: We included consecutive pts from 2 centers with LAPC treated with first-line FOLFIRINOX with neoadjuvant intent. Pts were categorized as BR or UR using the NCCN criteria. Pts received FOLFIRINOX chemotherapy (at the full dose as described in the ACCORD-11 trial) until maximum response or tolerability, and then underwent surgery if their imaging suggested resectability. Pts then received CCRT if they were still UR or BR after FOLFIRINOX. The end points of this retrospective analysis were overall survival (OS), progression free survival (PFS), and R0 resection rate. Results: Between 2008 and 2013, 51 pts were included; 11 were BR and 40 were UR. The median age was 60 years (range 41–75), and all had an ECOG PS of 0 (20%) or 1 (80%). Most pts (63%) had pancreatic head tumors and 49% had biliary stents before therapy. A total of 429 cycles were given with a median of 8 (range 2–29); 27 (53%) went on to receive CCRT. Toxicities were similar to our previous report. After a median follow-up of 17 mo (range 2–56), the Kaplan-Meier median OS was 35 mo (95% CI 26–45), the 3-yr OS rate was 42% and the median PFS was 14 mo (95% CI 11–16). By imaging criteria, 13 (26%) were converted to resectability and 10 (4 BR and 6 UR) of these had successful R0 resections. Pts who had R0 resections had a significantly longer survival than pts who did not (3-yr OS rate 67% vs 21%, log rank p = 0.042). Conclusions: In this large retrospective study limited to pts with LAPC treated uniformly, the R0 resection rate with FOLFIRINOX was only 20%, but most of these pts were UR at baseline by NCCN criteria. The median OS of almost 3 yrs compares favorably to historical survival rates for LAPC pts. Prospective controlled trials testing this algorithm in LAPC are ongoing.

The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.

ABSTRACT Aim: In a retrospective study of 18 pts with unresectable (UR) or borderline resectable (BR) LAPC, neoadjuvant therapy with FOLFIRINOX with or without subsequent chemoradiation (CCRT) resulted in an R0 resection rate (RR) of 44% (Hosein et al, BMC Cancer 2012). The reported 1-year progression-free survival (PFS) was 83 % and the 1-year overall survival (OS) was 100 %. Toxicity profile was tolerable. In order to confirm these preliminary results, we analyzed a large cohort of pts treated in a similar fashion with mature follow-up. Methods: Between 2008 and 2013, 51 treatment-naive pts with LAPC were treated with first-line FOLFIRINOX with neoadjuvant intent. Pts were categorized as BR or UR using the NCCN criteria. Pts received FOLFIRINOX chemotherapy (at the full dose as described in the ACCORD-11 trial) until maximum response or tolerability, and then underwent surgery if their imaging suggested resectability. Pts then received CCRT if they were still UR or BR after FOLFIRINOX. The end points of this retrospective analysis were OS, PFS, R0 RR and toxicity profile. Results: A total of 429 cycles were given with a median of 8 (range 2-29); 27 (53%) went on to receive CCRT. After a median follow-up of 17 mo (range 2-56), the Kaplan-Meier median OS was 35 mo (95% CI 26-45), the 3-yr OS rate was 42% and the median PFS was 14 mo (95% CI 11 – 16). By imaging criteria, 13 (26%) were converted to resectability and 10 (4 BR and 6 UR) of these had successful R0 resections. Pts who had R0 resections had a significantly longer survival than pts who did not (3-yr OS rate 67% vs 21%, log rank p = 0.042). Grade 1&2/3&4 chemotherapy-related toxicities were neutropenia (39%/20%), neutropenic fever (0%/12%), thrombocytopenia (53%/16%), anemia (63%/10%), fatigue (76%/6%), nausea (57%/4%) vomiting (22%/4%), neuropathy (53%/4%) and diarrhea (37%/10%). Conclusions: FOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. Although the resection rate was only 20%, the median OS of almost 3 years is appreciably longer than historical survival rates for this population. Prospective controlled trials testing this algorithm in LAPC are ongoing. Disclosure: All authors have declared no conflicts of interest.

Purpose of review This article reviews the most recent developments and implications in regard to isocitrate dehydrogenase mutations in chondrosarcoma, a disease in which currently available systemic therapies have proven inefficacious, with an emphasis on how disruption in normal cellular metabolism plays a role in oncogenesis. Recent findings The development of acquired isocitrate dehydrogenase-1/isocitrate dehydrogenase-2 mutations has been described in multiple tumors and more recently in chondrosarcomas. The impact of these mutations has been the focus of multiple research efforts during the last years, allowing us to better understand the impact of the mutation, including its interaction with other proteins, changes in expression of genes involved in tumor genesis, the oncogenic potential of 2-hydroxyglutarate, the impact on cellular proliferation and differentiation, and the influence on the epigenetic state of cells owing to changes in DNA and histone methylation patterns. New compounds targeting the mutation have been developed. Summary This mutation is the first of its kind described in chondrosarcoma, serving as an identifying marker of chondroid differentiation, and becoming the first molecular target with potential anticancer effect, translating into the development of therapies targeting these mutations currently being tested further in preclinical models and clinical trials.

For many decades, the use of chemotherapy as second-line therapy in non-small-cell lung cancer relied upon disease progression. Several studies have shown that four to six cycles of chemotherapy administered as front-line therapy treatment offers a survival advantage to patients; however, further chemotherapy beyond this initial treatment was more associated with side effects and no benefit in survival. Until 2009, second-line treatment for lung cancer was well established for three therapeutic agents: docetaxel, pemetrexed and erlotinib. Currently, the timeframe to use these agents has been challenged by two large randomized clinical trials in which pemetrexed OMEN trial) and erlotinib (Sequential Tarceva in Unresectable NSCLC [SATURN] trial) were used as 'maintenance' therapy and shown to impact progression-free survival and overall survival. This review focuses on the actual dilemma that medical oncologists face in clinical practice in terms of when and to whom maintenance therapy should be applied or if the 'watch and wait' approach prior to start second-line therapy is still advisable.

SUMMARY We know how important antiangiogenesis therapy can be in cancer treatment. However, it took some time before the first compound became approved. Currently, several agents are approved and used against cancer. Moreover, the possible number of clinical indications and agents that are in development is extraordinary. A lot of questions regarding angiogenesis in cancer still remain unanswered. One of the major weaknesses is the fact that most of the approved agents do not have a predictive or prognostic biomarker that can be used to tailor these novel agents in terms of inducing the best possible antitumor effect. Many of these new targeted agents inhibit several tumorigenesis pathways, but most of the time only one of these pathways is the main driver for cancer proliferation. In this article, we present the most current clinical information available in antiangiogenic therapy and the potential development in non-small-cell lung cancer.

The hedgehog (Hh) pathway is a critical regulator of vertebrate embryonic development and is involved in the function of processes such as stem cell maintenance and differentiation, tissue polarity and cell proliferation. Given how critical these functions are, it is not surprising that mutations in Hh pathway components are often implicated in the tumorigenesis of a variety of human cancers. Promotion of tumor growth has recently been shown by activated Hh signaling in the tumor itself, as well as by pathway activation within surrounding cells comprising the tumor microenvironment. Targeted disruption of various Hh pathway proteins has been successfully employed as an anticancer strategy with several synthetic Hh antagonists now available. Here, the molecular basis of Hh signaling, the therapeutic rationales for targeting this pathway and the current status of Hh pathway inhibitors in the clinic are reviewed.

Lung cancer incidence continues to rise and is the number one cause of cancer death in both men and women worldwide with projected 221,130 new cases and 156,940 deaths in the United States in 2011.1 Non-small cell lung cancer (NSCLC) represents more than 85% of the cases with most patients having either locally advanced or metastatic disease at the time of initial diagnosis, and approximately 60%-70% of them have an adenocarcinoma histologic subtype. In the last three years, we have seen several advances in the management of NSCLC, with several factors playing an important role in the treatment decision making process. Maintenance therapy has been added to the algorithm of NSCLC management and Pemetrexed has been studied as single agent or in combination in this setting with recent studies showing safety and improved progression free survival (PFS) and/or overall survival (OS), still the disease for the most part has a dismal outcome. More research work needs to be done to identify which patients truly benefit from these approaches, and to whom we should offer maintenance or switch maintenance vs. close observation.

e17564 Background: Pemetrexed (Pem) is commonly used as frontline +/- maintenance chemotherapy (MCTx) in patients (pts) with advanced non-squamous (ns) NSCLC. Due to Pem toxicity profile, pts can remain on therapy (tx) for prolonged periods of time. We are reporting an increase in the erythrocyte MCV without apparent clinical significance. Methods: 54 ns-NSCLC pts previously treated with Pem-based tx either as initial treatment followed by MCTx Pem alone or Pem/bevacizumab (Bev) or second line tx were analyzed for elevation of MCV from a normal baseline (80-98 fl). All pts were on daily folic acid (FA) and vitamin B12 (vitB12) supplementation at least every 3 cycles of Pem. Co-factors such as FA, vitB12, homocysteine (Hom), and methylmalonic acid (MMA) were measured on those pts still alive, on active MCTx, and available who had high MCV. Results: 54 pts were evaluable; 50 pts received platinum/Pem/Bev triplet as initial tx followed by Pem/Bev or Pem MCTx and 2 pts with Pem/Bev and Pem alone as second line, respectively. Median age: 63 yrs old (34-84); 32 pts were male and 31 pts (56%) Hispanic. 32 pts (58%) developed an elevated MCV (range: 98.1-114). For the entire cohort, median # cycles of Pem given 11 (range: 2-38). In those pts who had high MCV, the median # of Pem cycles given was 12 (range: 5-38). All pts had normal or low MCV prior to tx, but one. Unfortunately, 33 pts had progressed and are no longer on MCTx. 12 pts out of the 19 still on MCTx had high MCV. In 5/12 pts, we were able to measure their co-factor levels. All values were within normal limits. The MCVs of these 5 pts were: 101.6, 100, 102.1, 102.2, and 104.8 from baseline values of: 74.4, 89.3, 92.8, 89.7, and 89.6, respectively. Their Hbg levels were: 12.2, 13.2, 15.4, 11.4, and 11 g/dL, respectively with normal WBC (and differential) and platelets. Conclusions: Pem is an antifolate agent that is associated with folate depletion (due to TS inhibition) and macrocytosis. We are reporting here patients treated with Pem for long time with proper FA and vitB12 supplementation that have an increased MCV with no apparent signs of folate, vitB12, MMA, and Hom deficiency. This observation needs a lengthened follow-up.