Lung cancer remains the leading cause of cancer-related deaths in Europe, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. NSCLC is a heterogeneous disease encompassing various oncogenic alterations. Among them, EGFR exon 20 insertion mutations, constituting 0.3–2.2% of NSCLC cases, rank as the third most common EGFR alteration after exon 19 deletions and the L858R point mutation in exon 21, also known as “typical” EGFR alterations. Recent advancements in understanding the molecular pathogenesis of NSCLC have led to significant breakthroughs in targeted therapies, revolutionizing treatment options for patients with specific genetic alterations. This article presents the outcomes of a Virtual Meeting conducted on the online platform (provided Within3©) from September 19 to October 30, 2022. The meeting focused on addressing the challenges in the diagnosis and treatment of NSCLC patients with EGFR exon 20 insertion mutations. The participants consisted of healthcare professionals from ten Central and Eastern European countries who shared their experiences and opinions on various aspects, including epidemiology, treatment options, and diagnostic approaches employed in their respective healthcare institutions. The discussions were facilitated through open-ended and multiple-choice questions. The primary objective of this article is to provide an overview of the identified challenges associated with the diagnosis and treatment of this heterogeneous disease, based on the assessments of the meeting participants. Among the major emerging challenges discussed, the reimbursement issues concerning next-generation sequencing (NGS), a recommended method in NSCLC molecular diagnosis, and the availability of approved targeted treatments to enhance patient outcomes were of paramount importance. Furthermore, fostering community awareness of lung cancer and promoting harmonized lung cancer care were identified as areas deserving greater attention. Notably, the rapidly evolving treatment landscape, particularly with NGS for NSCLC patients with genomic alterations like EGFR , ALK , RET , MET , NTRK , and ROS1 , necessitates prioritizing the development of new drugs, even for the relatively smaller subgroup with exon 20 insertion mutations.

Large cell neuroendocrine carcinoma of the lung (LCNEC) is currently classified as a rare lung cancer subtype, but given the high incidence of lung cancer, the overall number of cases is considerable. The pathologic diagnosis of LCNEC is mainly based on the microscopic appearance of the tumor cells, the mitotic rate, the amount of intra-tumoral necrosis, and the presence of positive neuroendocrine markers identified by immunohistochemistry. Recently, a subdivision into two main categories was proposed based on mutation signatures involving the RB1, TP53, KRAS, and STK11/LKB1 genes, into SCLC-like (small cell lung cancer-like) and NSCLC-like (non-small cell lung cancer-like) LCNEC. In terms of treatment, surgery is still the best option for resectable, stage I-IIIA cases. Chemotherapy and radiotherapy have conflicting evidence. Etoposide/platinum remains the standard chemotherapy regimen. However, based on the newly proposed LCNEC subtypes, some retrospective series report better outcomes using a pathology-driven chemotherapy approach. Encouraging outcomes have also been reported for immunotherapy and targeted therapy, but the real impact of these strategies is still being determined in the absence of adequate prospective clinical trials. The current paper scrutinized the epidemiology, reviewed the reliability of pathologic diagnosis, discussed the need for molecular subtyping, and reviewed the heterogeneity of treatment algorithms in LCNEC.

BACKGROUND:Discrepancies between the outcomes of cancer patients between Western European and Central and Eastern European (CEE) countries have often been observed. Despite the enormous economic and civilizational progress made in these countries after the abolishment of the communist regime, structural problems persist.SUMMARY:The present article reviews the domains of medical oncology education, human resources in oncology, cancer care, and clinical research in CEE in order to comprehensively assess the current situation and needs, describe important initiatives, and also propose ways to improving cancer outcomes in the region. Activities are under way to address these issues in national action plans to divert funding into oncology-related education, research, the purchase of equipment, and the attainment of modern hospital organization and structures.KEY MESSAGE:Over the past more than 30 years, CEE countries have made enormous economic and societal progress. Nevertheless, challenges especially in the health care sector persist.

"Background: REFLECT was a retrospective, non-interventional study conducted in eight countries, including eleven sites from Romania, on patients with advanced stage non-small cell carcinoma (NSCLC). Aim: To characterize clinical outcomes, treatments and the proportion of T790M EGFR mutation testing in patients with advanced non-small cell lung cancer (NSCLC) receiving first- or second-generation (1G/2G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs ) as first-line (1L) treatment in the Romanian cohort of an international study. Methods: Comprehensive data were retrieved from the medical records of ninety patients with EGFR-mutated advanced NSCLC treated with 1G/2G EGFR TKIs between January 2015 and June 2018. All analyses are descriptive. Results: The median age at lung cancer diagnosis in the Romanian cohort was 67.5 years, with 68% females. The distribution of EGFR TKIs was 50% erlotinib, 31% afatinib, and 19% gefitinib. First line treatment was stopped in 76 (84%) patients due to progression (79%), toxicities (3%), the patient’s decision (1%) or surgery (1%). The median progression- free survival on 1L treatment was 12.0 months (95% CI 10.3-15.6), and the median overall survival from the start of first line therapy was 26.4 months (95% CI 22.4-34.2). EGFR T790M mutation testing was performed on 69% of patients at the time of progression on 1L therapy, with 57% of patients testing positive. Second-line (2L) therapy was started in 63% of patients discontinuing 1L therapy. Third-line treatment was started in 50% of patients discontinuing 2L treatment. Conclusion: Survival results mirrored those of randomized trials. The suboptimal T790M testing rate (69%) underlines the importance of reflex testing procedures, while attrition rates on 1L (26%) emphasize the need for an upfront selection of the most effective treatments."

The targeted therapy with tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor mutation (EGFRm) in advanced non-small cell lung cancer (NSCLC) changed the treatment paradigm. REFLECT study (NCT04031898) explored EGFR/T790M testing and treatment patterns in EGFRm NSCLC patients receiving first- or second-generation (1G/2G) EGFR TKIs as front-line (1L) in eight countries. Pooled data from Central Eastern Europe (CEE) countries from this study (Bulgaria, Poland, Romania, Slovenia) are presented here. This physician-led chart review study was conducted in patients with confirmed-EGFRm NSCLC initiating 1L 1G/2G EGFR TKIs between 2015–2018. The CEE cohort included 389 patients receiving 1L erlotinib (37%), afatinib (34%), and gefitinib (29%). Overall, 320 (82%) patients discontinued 1L, and 298 (77%) progression events were registered. Median progression free survival on 1L TKIs was 14.0 (95% CI: 12.6–15.6) months. Median overall survival from 1L start was 26.6 (95% CI: 24.1–29.0) months. Attrition rate between 1L and next line was 30%. Among patients with 1L progression, 200 (67%) were tested for T790M and 58% were positive. This first CEE analysis of treatments and outcomes in EGFRm NSCLC patients highlights the importance of using the most efficacious therapies currently available in 1L to reduce attrition and improve patient outcomes.

During the last 30 years the developments in small cell lung cancer (SCLC) have been extremely scarce. Concurrent chemo-radiation associated with prophylactic cranial irradiation in case of complete clinical remission is standard in limited disease. In extensive disease, platinum/etoposide and topotecan remain the standard systemic approaches in the first- and second-line setting, respectively. The only notable improvement was communicated in the IMpower133 trial, by the addition of atezolizumab to the platinum/etoposide chemotherapy backbone. Against this background, the current article aims to review the most important abstracts presented at ASCO 2019 along with their potential impact for current clinical practice.

Many analyses of the efficacy of neoadjuvant treatment (NAT) for early breast cancer including a meta-analysis derived from 10 randomized trials came to the conclusion that patients who would achieve pathologic complete response (pCR) following NAT would experience significant improvement in disease-free and overall survival (OS). Thus, pCR was proposed as a surrogate endpoint for OS, with pCR representing a robust prognostic marker for survival at an individual level. In the current analysis, we argue that OS following NAT-induced pCR might have reflected the initial prognosis of patients mainly defined - among other factors - by the initial pathological lymph node status while being largely independent on the type of administrated treatment, thus pleading against the pCR surrogacy hypothesis. We therefore propose to redefine pCR as a surrogate endpoint of NAT trials by the involvement of additional biologic parameters.

This article is not intended to be a comprehensive review of all highlights presented at the recent ESMO Annual Meeting, but rather a summary from a personal point of view in three very different fields of oncology. Breast cancer and lung cancer are traditionally in the focus of interest, and again, relevant new data were presented. The third part of this overview is focused on novel treatment strategies in malignant lymphoma, a field that is also quickly evolving and traditionally underrepresented at meetings dealing with solid cancers.

ObjectivesPatritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that blocks activation by its ligand, heregulin (HRG). Preclinical studies have demonstrated the efficacy of patritumab in aberrantly high HRG-expressing non-small cell lung cancer (NSCLC). In the phase II randomized, placebo-controlled double-blind study HERALD (n=212 patients with NSCLC), patritumab plus erlotinib did not improve progression-free survival (PFS) compared with placebo plus erlotinib. The current study examined whether soluble HRG (sHRG) level in serum correlated with the efficacy of patritumab plus erlotinib.Materials and methodsSerum was obtained from participants prior to treatment (n=202). sHRG level was measured using a validated quantitative immune assay, and correlations with survival were blindly assessed.ResultssHRG level was various (−1346–11,772pg/mL). Participants were divided into the sHRG-high or -low subgroups at the concentration defining near the third quartile, 980pg/mL. Patritumab plus erlotinib significantly improved PFS relative to placebo in the sHRG-high subgroup (n=46, hazard ratio 0.42 [0.19–0.96], p=0.0327). In contrast, the HRG-low subgroup (n=148) had no improvement in PFS with patritumab.ConclusionsHRG seems to be a predictive biomarker for the efficacy of patritumab plus erlotinib in NSCLC patients.

Introduction: Necitumumab, a second-generation, recombinant human immunoglobulin G1 epidermal growth factor receptor antibody in the phase 3 SQUIRE trial (NCT00981058), increased survival benefit for patients randomized to receive necitumumab plus gemcitabine-cisplatin compared with those who received gemcitabine-cisplatin. Here we characterize health-related quality of life (HRQoL) and tolerability results.Methods: A total of 1093 patients with stage IV squamous non-small cell lung cancer were randomized 1:1 to receive necitumumab (800 mg absolute dose intravenously [IV]) plus gemcitabine-cisplatin (gemcitabine = 1250 mg/m(2) IV on days 1 and 8; cisplatin = 75 mg/m(2) IV on day 1) or gemcitabine-cisplatin alone (every 21 days) for up to six cycles. Patients receiving necitumumab plus gemcitabine-cisplatin without disease progression continued necitumumab until progression. HRQoL was measured by Eastern Cooperative Oncology Group performance status, the Lung Cancer Symptom Scale (LCSS), and the European Quality of Life Five-Dimensions questionnaire. Efficacy and LCSS outcomes were analyzed using the baseline maximum severity score of the LCSS. Tolerability was measured in terms of exposure to the study treatment and adverse events. Hospitalization rates were collected.Results: Most patients in both study arms similarly maintained Eastern Cooperative Oncology Group performance status and comparable LCSS and European Quality of Life Five-Dimensions questionnaire assessments. Patients with a higher baseline LCSS had a greater survival benefit on the necitumumab arm. Chemotherapy exposure was similar in both treatment arms; 51% of patients on the necitumumab plus gemcitabine-cisplatin arm continued on single-agent necitumumab. The most frequent grade 4 adverse events were neutropenia (6.1% versus 7.9%) and thrombocytopenia (3.2% versus 4.3%) in the necitumumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin arms, respectively. Hospitalizations were slightly higher with necitumumab plus gemcitabine-cisplatin (36.4%) than with gemcitabine-cisplatin (34.0%).Conclusions: The addition of necitumumab to gemcitabine-cisplatin was well tolerated, did not negatively affect HRQoL or toxicity, and particularly benefited patients with more severe baseline symptoms or lower HRQoL. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

9071 Background: Patritumab (P) is a fully human anti-HER3 antibody that blocks activation by the ligand, heregulin (HRG), inducing receptor internalization. Preclinical study observed its efficacy in non-small cell lung cancer (NSCLC) with high level of HRG expression (Yonesaka et al, ASCO2014). Phase II randomized, placebo-controlled double-blind study HERALD assessed the efficacy of low or high dose P combination with erlotinib (E) in NSCLC (von Pawel et al, ASCO2014). P + E could not detect PFS improvement compared with placebo (Pbo) + E in ITT population (n = 212). However, P + E significantly improved PFS in subgroup with high level of HRG mRNA. Currently, we examined whether soluble HRG (sHRG) level in serum could correlate with the efficacy of P + E. Methods: Serum was obtained from NSCLC subjects enrolled in HERALD study prior to treatment (n = 194). sHRG level in serum was measured by a validated quantitative immune assay, and blindly assessed about the correlation with survival. The hypothesis is subjects with high level of sHRG demonstrate an improved PFS when treated with P + E compared with Pbo + E. The cut off value was set at primarily third quarter in the blinded sample set. Estimates of the hazard ratio (HR) and the 95% confidence intervals (CIs) of pooled high and low dose P + E were calculated using a stratified Cox’s proportional hazards model. Results: sHRG was detectable in 36% of subjects (0-11772 pg/mL). PFS was significantly improved in the sHRG high subgroup ( > 980 pg/mL, n = 46) when treated with P + E compared with Pbo + E (HR 0.41 [0.18-0.90], p = 0.02). In contrast, the HRG low subgroup ( < 980 pg/ml, n = 148) showed no improvement in PFS (HR 1.05 [0.70-1.57], p = 0.82) with P + E. Further, elevated cutoff value improved HR (Table). Efficacy of P was independently predicted by sHRG compared to tumor HRG mRNA. Conclusions: P + E showed improved PFS in the HRG high subgroup, but not in the HRG low subgroup. Soluble HRG appears to be a predictive biomarker for P + E in NSCLC patients. Clinical trial information: NCT01211483.sHRG cut-off value (pg / mL) N HR for PFS p-value 0 66 0.58 0.08 980 (Q3) 46 0.41 0.02 1622.5 39 0.31 0.01 2000 34 0.28 0.008 3000 30 0.24 0.006 4000 27 0.26 0.01 5000 23 0.40 0.13

Until last year, the international guidelines recommended the use of docetaxel in advanced prostate cancer (PC) at the time of progression following androgen deprivation therapy (ADT). Nevertheless, two randomized phase III trials, CHAARTED and STAMPEDE, delivered level I evidence showing that upfront introduction of docetaxel, during the androgen sensitive course of disease, is able to significantly improve the patients' overall survival. As such, this strategy was rapidly included in the current guideline recommendations, with slightly different indications in the ESMO as compared to the NCCN version. Side effects of chemotherapy along with the possible higher benefit in high vs low-volume metastatic disease should be taken into consideration when choosing this alternative. The present paper makes a review of the current data supporting the new indication of docetaxel, and provides detailed information in order to assist the clinician in deciding the best treatment for patients with advanced PC.

BACKGROUND:Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). METHODS:We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. FINDINGS:Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. INTERPRETATION:Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. FUNDING:Eli Lilly and Company.

8008^ Background: Necitumumab (N), a human IgG1 anti-EGFR monoclonal antibody, inhibits ligand-binding and receptor activation. EGFR is detectable in the vast majority of advanced sq-NSCLC tumors. Methods: Pts with pathologically proven stage IV sq-NSCLC were randomized 1:1 to GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) plus N (800 mg iv, days 1 and 8) (GC+N arm), or GC alone (GC arm) every 21 days for up to 6 cycles. GC+N pts with no progression continued on N alone until progressive disease or intolerable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. EGFR protein expression level by immunohistochemistry (H-score) in tumor tissue was an exploratory analysis. Planned sample size was 1080 pts, with 90% power and a 2-sided alpha level of 0.05. Results: 1,093 pts were randomized (n=545, GC+N; n=548, GC). Baseline characteristics were balanced between GC+N and GC, respectively, including males (82.6% and 83.6%), ECOG PS 0/1 (91.0% and 91.2%), and PS 2 (9.0% and 8.6%). Exposure to chemotherapy was similar in both arms; median dose intensity (DI) for G and C was 86% and 95%, respectively, and DI for N was 94%. 51% of GC+N pts continued N alone for a median of 4 additional cycles. The addition of N to GC statistically significantly improved OS (HR=0.84, p=0.012) and PFS (HR=0.85, p=0.020); mOS was 11.5 vs 9.9 mo in GC and mPFS was 5.7 vs 5.5 mo in GC. ORR was 31% vs 29% in GC (p=0.400), and the disease control rate (DCR) was 82% vs 77% in GC (p=0.043). Post-progression anticancer therapy was similar (47% vs 45%). Several prespecified subgroup analyses of OS and PFS showed a consistent treatment effect, including pts with ECOG PS 2. Grade ≥3 adverse events with GC+N (measured by preferred MedDRA terms) that showed a >2% increase over GC were hypomagnesemia (8.7% vs 1.1%) and skin rash (3.7% vs 0.2%). Conclusions: The addition of N to GC statistically significantly improved OS, PFS, and DCR. The safety profile of GC+N is acceptable. Clinical trial information: NCT00981058.

Background: P is a fully human anti-HER3 antibody that inhibits HER3 binding with its ligand heregulin (HRG). Preclinically, P enhances anti-tumor activity with EGFR inhibitors, prevents HER3 reactivation after anti-EGFR treatment, and inhibits HRG- dependent activation. Phase Ib showed that P, with E (150mg/day PO), was tolerated at 18mg/kg IV q3w.

This phase II study evaluated the addition of mapatumumab, a tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) agonist, to carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer (NSCLC). Patients were randomized to receive paclitaxel and carboplatin either with or without mapatumumab. No clinical benefit from adding mapatumumab to carboplatin and paclitaxel in unselected patients with NSCLC was observed. The possibility of subgroups sensitive to mapatumumab is discussed.Background: This phase II study examined the efficacy of mapatumumab in combination with paclitaxel and carboplatin in patients with non-small-cell lung cancer (NSCLC). Patients and Methods: Patients with stage IIIB or stage IV advanced primary NSCLC were randomly assigned (1:1:1) to receive up to 6 courses of standard-dose paclitaxel and carboplatin or a combination of paclitaxel, carboplatin, and mapatumumab (10 mg/kg or 30 mg/kg). Primary efficacy end points were overall response rate and median progression-free survival (PFS). Secondary efficacy end points included disease control rate, overall survival (OS), time to response, and duration of response. Exploratory studies included evaluation of historical biopsy materials for TRAIL-R1 expression by immunohistochemical analysis and serum levels of M30, a marker of apoptosis, before and after the first 2 doses of mapatumumab. Safety parameters, including adverse events (AEs), laboratory tests, and immunogenicity, were assessed. Results: The majority of patients had stage IV disease (79%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%); baseline characteristics were similar across treatment arms. No improvements in response or disease control rates, PFS, or OS were gained from the addition of mapatumumab. Adverse events in the mapatumumab arms were generally consistent with toxicities seen in the carboplatin and paclitaxel control arm. Levels of M30 were highly variable, and consistent patterns were not seen across treatment arms. Conclusion: This study showed no clinical benefit from adding mapatumumab to carboplatin and paclitaxel in unselected patients with NSCLC. The combination was generally well tolerated. The possibility of subgroups sensitive to mapatumumab is discussed.

SUMMARY Pemetrexed, a multitargeted antifolate agent, is currently used in the treatment of non-small-cell lung cancer. Strong evidence has shown a treatment-by-histology interaction, with pemetrexed acting significantly better in the nonsquamous cell subtype. Therefore, all pemetrexed indications are restricted to this histology. Associated initially with somewhat high toxicity, the use of vitamin supplementation and corticoid premedication turned pemetrexed into one of the most convenient chemotherapy agents. At present pemetrexed is recommended as one of the preferred platinum partners in first line and as a single agent in the second-line setting for nonsquamous histology. The particular efficacy/toxicity profile has confirmed pemetrexed as the only chemotherapy agent approved for both continuation and switch maintenance therapy.

Updated long-term, low-grade (grade 1/2) safety and quality of life (QoL) results from the randomized, double-blind Maintenance phase of the PARAMOUNT trial are reported. These results showed a low incidence of low-grade adverse events and uncompromised QoL, demonstrating a well-tolerated safety profile for long-term pemetrexed maintenance. Introduction: In the PARAMOUNT ("A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non-Small-Cell Lung Cancer") trial, patients with advanced nonsquamous non-small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL. Materials and Methods: Patients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m(2), day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed. Results: A median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean +/- SD 7.9 +/- 8.3; placebo 1-38; mean +/- SD 5.0 +/- 5.2), with 28% of pemetrexed and 12% of placebo patients receiving >= 10 maintenance cycles. The pemetrexed dose intensity was 94%. More. patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P =.005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms. Conclusion: PARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved.