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F. De Marinis



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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.01 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): VeriStrat analysis of longitudinal samples (ID 3122)

      10:30 - 10:35  |  Author(s): F. De Marinis

      • Abstract
      • Presentation
      • Slides

      Background
      2nd-line therapy for advanced NSCLC patients (pts) after progression on platinum-based regimens typically employs CT or E. A test for optimizing choice of treatment in these pts is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility. PROSE is a multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2nd- line NSCLC pts treated with E or CT. As reported at 2013 ASCO1, PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p value of 0.031, with VSG pts deriving similar overall survival (OS) benefit from both treatments (hazard ratio (HR) for E=1.06; p=0.71) and VSP pts benefitting more from CT than E (HR for E=1.72; p=0.02). Previous studies in EGFR-TKI-treated pts have shown that at progression around 30% of pre-treatment VSG pts have changed classification to VSP2. The present report discusses the exploratory analysis of longitudinal VS classifications generated during the PROSE study.

      Methods
      Of the 263 pts in the PROSE primary analysis population, 89 provided serum samples during treatment and 108 at progression, with 47 pts providing both. VS testing was performed on these longitudinal samples blinded to all clinical and treatment outcomes and pts and physicians remained blinded to VS results.

      Results
      VSG or VSP classifications were obtained for 89 pts from treatment samples (67 VSG / 22 VSP) and 107 pts (one sample was classified as indeterminate) from progression samples (59 VSG / 48 VSP). In pts with matched baseline and progression samples, the percentage of VSG classifications was lower at progression (55%) than at baseline (77%) (p < 0.001 ). Twenty eight pts (34%) classified at baseline as VSG changed to VSP at progression, in line with previous studies2, and this did not show any significant dependence on treatment. When treated with E, pts whose classification changed from VSG at baseline to VSP during treatment (n=6) had inferior PFS to the 25 pts who remained VSG (p=0.001, median PFS: 3.6 and 7.7 months (mos), respectively). Patients whose classification changed from VSG at baseline to VSP at progression on E (n=18) had numerically inferior OS (median 10.0 mos) compared with the 31 pts who remained VSG at progression (median 14.6 mos) and significantly superior OS (median 5.0 mos) compared with the 10 pts who were VSP at both time points (p<0.001).

      Conclusion
      The observed changes in VS classification at progression demonstrate the importance of obtaining a VS result prior to each line of therapy for which erlotinib is considered as a therapeutic option. The proportion of patients who are good candidates for erlotinib therapy (VSG) decreases from 2[nd] to 3[rd] line and the possible impact of this on treatment sequencing and monitoring for 2[nd] and higher line advanced NSCLC pts merits further studies.

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    MO26 - Anatomical Pathology II (ID 129)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO26.08 - The concomitant presence of echinoderm microtubule associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK) EML4-ALK fusion gene in EGFR-mutant non-small-cell lung cancer (NSCLC) patients treated with erlotinib or chemotherapy in the EURTAC trial</b> (ID 1109)

      11:10 - 11:15  |  Author(s): F. De Marinis

      • Abstract
      • Presentation
      • Slides

      Background
      Activating mutations in the epidermal growth factor receptor (EGFR) confer sensitivity to gefitinib and erlotinib in patients with NSCLC. However, response is often short-lived, and patients ultimately relapse, indicating that other concomitant actionable mutations could influence outcome in these patients. The EML4-ALK fusion gene has recently been identified in a subset of NSCLCs, but its specific role remains unclear. We have evaluated the frequency and impact of the concomitant presence of EML4-ALK in patients included in the randomized phase III EURTAC trial.

      Methods
      The EURTAC study enrolled 173 EGFR-mutant NSCLC patients who were randomized to receive erlotinib or standard chemotherapy with cisplatin or carboplatin plus docetaxel or gemcitabine. Tumor specimens were available from 95 of these patients for the analysis of EML4-ALK. EML4-ALK variants 1 and 3 (v1, v3) were analyzed by an independent single round of PCR followed by sequencing, using cDNA as a sample.

      Results
      EML4-ALK was detected in 15 samples (15.79%). Nine tumors contained v1 (E13;A20) and six v3 (E6;A20). No significant differences were found in baseline characteristics between patients with and without EML4-ALK. Progression-free survival was 10.4 months (m) for patients harboring the EML4-ALK fusion gene compared to 7.1 m for those without EML4-ALK. Overall survival (OS) was not reached in patients with EML4-ALK, compared to 22.9 m in those without. Complete data on outcome according to treatment arm will be presented.

      Conclusion
      Our findings indicate that the EML4-ALK rearrangement is concomitant with EGFR mutations in a considerable number of NSCLC patients and may affect outcome.

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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O01.07 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): Secondary Endpoint Analysis (ID 3276)

      11:35 - 11:45  |  Author(s): F. De Marinis

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR-TKis are more effective in NSCLC patients with EGFR activating mutations. However, about 90% of non-Asian patients are EGFR wild type, and a test for optimizing treatment in pts with wild-type or in patients with undetectable EGFR mutation status or squamous histology is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility in retrospective studies. PROSE is the first completed multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2[nd]- line NSCLC pts treated with E or CT. As reported at 2013 ASCO[1], VSG pts derived similar overall survival (OS) benefit from both agents (hazard ratio (HR) for E=1.06; p=0.71) whereas CT was the superior option for VSP pts (HR for E=1.72; p=0.02). PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p-value of 0.031. The present report discusses the results for the secondary endpoints, PFS.

      Methods
      285 pts, stratified by ECOG-PS, smoking, and blinded pre-treatment VS classification, were randomized 1:1 to receive E or CT at standard doses. Primary endpoint was overall survival (OS) and the primary hypothesis was a significant interaction between VS status and treatment. Sample size was calculated based on an estimated 65%/35% VSG:VSP ratio and hazard ratio (HR) for interaction of 2.35, with a 2-sided α=0.05 and 90% power.

      Results
      263 pts (129 CT, 134 E) were included in the per protocol primary analysis. 68% of pts in CT arm and 72% in E arm were classified as VSG, and analysis was performed at 226 survival events.VSP classification was significantly correlated with worse PFS as compared to VSG, in overall comparison (HR=1.75, 95%CI: 1.34-2.95, P <0.001) , in the CT (HR = 1.69, 95%CI: 1.15-2.48, P <0.007) and the E (HR = 1.91, 95%CI: 1.340-2.80, P<0.001) arms, demonstrating its prognostic value also in PFS. In VSG median PFS was 4.8 months (m) on CT, and 2.5 m on E (HR = 1.26, 95% CI: 0.94-1.69, P =0.129); in VSP median PFS was 2.8 m on CT and 1.7 m on E (HR=1.51, 95% CI: 0.96-2.38, P =0.078). No statistical significant interaction was detected (p=0.44)

      Conclusion
      The analysis of PFS and OS indicates that the differential treatment benefit in OS related to VS classification is determined by the combination of prognostic and predictive properties of the test.

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    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O15.06 - Randomized Phase III Trial of Gemcitabine (G)/Carboplatin (C) with or without Iniparib (I) in Patients (Pts) with Previously Untreated Stage IV Squamous Lung Cancer (ID 3322)

      11:25 - 11:35  |  Author(s): F. De Marinis

      • Abstract
      • Presentation
      • Slides

      Background
      Iniparib is an agent originally thought to function as an inhibitor of the DNA repair enzyme PARP-1, which is overexpressed in squamous lung cancers. Promising phase II activity and safety were reported with iniparib in combination with GC in pts with metastatic triple-negative breast cancer (O’Shaughnessy, NEJM 2011); however, subsequent phase III data were negative. Further study of iniparib’s mechanism of action suggests that this agent induces DNA damage, cell cycle arrest in the G2/M phase, and potentiates DNA-damaging chemotherapies not through PARP inhibition. Herein we report the final results from an international Phase III trial (NCT01082549) of first-line chemotherapy and iniparib in pts with advanced squamous lung cancer.

      Methods
      Pts were randomized 1:1 to GC or GCI. All pts received G 1000 mg/m[2] IV days (D) 1 and 8, and C AUC=5 IV D1 of each 21-D cycle. Iniparib was dosed 5.6 mg/kg IV D 1, 4, 8, and 11. All pts were assessed for response per RECIST 1.1 every 6 weeks. Pts without evidence of progressive disease (PD) or other reason for discontinuation could remain on treatment beyond 6 cycles. Accrual of 780 pts provides 89% power to detect an improvement in survival from 8 months (mos) anticipated with GC to 10.7 mos with GCI (HR of 0.75). Eligibility: Pts with newly diagnosed stage IV (M1a and M1b) squamous lung cancer, ECOG PS 0-1. Exclusion criteria included: history of recent cardiac disease, untreated brain metastases, and treatment for early-stage lung cancer within 12 months of study entry. The primary endpoint was overall survival (OS). Interim analyses for safety and futility were performed by an independent data safety monitoring board.

      Results
      780 pts were enrolled and randomized (GC, 390), (GCI, 390) from March 2010 to May 2012. Baseline characteristics were well balanced between groups (GC/GCI): median age 66 years (21-86); 74%/73% male; 30%/33% ECOG 0; 28%/33% current smokers; 66%/62% past smokers. The median number of cycles for GC/GCI were 4 (1-26)/5 (1-32). Dose reductions, dose intensity, and discontinuations due to tumor progression or adverse events were similar in both arms. The median OS for GC/GCI was 8.9 v. 8.9 months, HR 1.08 (0.92-1.28), p=.348. 1-year OS was 41 v. 40%. The median progression-free survival (PFS) for GC vs GCI was 4.9 v. 4.8 months, HR 0.99 (0.83-1.19), p=.92. The objective response rate (ORR) for GC v GCI was 34 v. 32%, p=.648. The safety profile was similar in both arms; anemia (28/26%), neutropenia (31/35%), thrombocytopenia (27/28%), and fatigue (6/9%).

      Conclusion
      The addition of iniparib did not improve the efficacy of GC in the treatment of pts with advanced squamous lung cancer. Further development of iniparib in squamous lung cancer is not recommended.

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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.03 - Cost-utility analysis of first-line treatment with erlotinib versus chemotherapy in EGFR-mutant advanced non-small-cell lung cancer (NSCLC): economic analysis of EURTAC trial (ID 1100)

      10:50 - 11:00  |  Author(s): F. De Marinis

      • Abstract
      • Presentation
      • Slides

      Background
      The impact of tyrosine kinase inhibitors (TKIs) in EGFR-mutant advanced NSCLC is poorly documented. Two studies (Jacob et al, ISPOR2010, Brown et al, Health Technol Assess, 2010) are based on modelisation and indirect comparisons. The present study reports a cost-utility analysis of a phase III randomized trial (EURTAC).

      Methods
      A three state Markov model (first line PFS, second line PD and death) was built. Clinical data and resource assessment (drugs, drug administration, adverse events, second-line treatment) were collected from the trial. Utility values were derived from Nafees et al, as previously published (Vergnenegre et al. JTO 2011). Incremental cost-utility ratios (ICUR) were calculated for the first-line treatment and the overall strategy until death from the perspective of different countries (2013 actualized euros). Sensitivity analyses researched the main cost drivers.

      Results
      The quality-adjusted life-years gained was 0.124 with erlotinib, which showed an improvement in the quality of life for these patients. Despite the extra treatment costs of second-line erlotinib in the chemotherapy arm, there was a cost benefit for erlotinib first, resulting in fewer patients receiving second-line pemetrexed along with other therapy. Cost gain in favor of first-line erlotinib was 8,918 Euros. The main results are depicted in Table1.

      First-line erlotinib First-line chemotherapy
      Average cost of first-line (euros 2013)
      Drugs 21,679 1030
      Administration 329 4,455
      Adverse events 546 2,686
      Cost of post-first progression care 40,467 67,281
      ICUR (erlotinib versus chemotherapy)
      ICUR France negative
      ICUR Spain negative
      ICUR Italy negative
      Sensitivity analyses will be presented at the meeting.

      Conclusion
      ICUR favored first-line erlotinib in EGFR-mutant patients with advanced NSCLC, which is the widely accepted treatment compared to chemotherapy. The cost-utility of the overall strategy remained beneficial in three different European countries. On behalf GFCP,GEPC and AIOT groups

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-032 - Sensitivity and meta-regression analysis exploring potential outcomes predictors in randomized trials (RCTs) evaluating the benefit of 1st-line tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma. (ID 1670)

      09:30 - 09:30  |  Author(s): F. De Marinis

      • Abstract

      Background
      Patients affected by lung adenocarcinoma carrying a EGFR sensitizing mutation of significantly benefit from TKIs in terms of progression free survival (PFS), activity and symptoms control. The potential predictive role of clinico-pathological predictors should be investigated in order to optimize the benefit of the currently available drugs.

      Methods
      A literature-based meta-regression and sensitivity analyses to investigate the differential effect of TKIs according to demographic and molecular factors, was accomplished, analyzing all RCTs exploring TKIs versus chemotherapy for 1[st]-line treatment of patients affected by EGFR mutant NSCLC.

      Results
      9 trials (3,741 patients) were identified (EGFR mutant: 1,797). 9 RCTs were evaluable for PFS (1,790 patients) and response (1,733 patients); 7/9 for survival (1,075 patients). With regard to PFS and response, a significant interaction according to ethnicity (Asian versus Caucasian versus mixed, p=0.006 [Cochrane-Q 10.275] and p=0.047 [6.129], respectively), and trial design (retrospective versus prospective EGFR analysis, p=0.024 [5.067] and p<0.0001 [13.633]), was found. No difference was observed in term of survival. A significant interaction for response was found, with an Odds Ratio in favour of afatinib, erlotinib and gefitinib (versus chemotherapy) of 2.70 (95% CI 2.11-3.45), 2.67 (95% CI 1.81-3.93) and 1.81 (95% CI 1.46-4.78).

      Interaction [Cochrane-Q] P value Interaction [Cochrane-Q] P value
      PFS Response
      Overall (ERL vs GEF vs AFA) [4.266] p=0.188 [9.924] p=0.007
      ERL vs AFA [3.321] p=0.068 [0.056] p=0.813
      ERL vs GEF [9.714] p=0.054 [5.169] p=0.023
      AFA vs GEF [0.002] p=0.962 [7.351] p=0.007

      Conclusion
      Although limited by the retrospective nature and the heterogeneity, these data indicate a differential effect of TKIs according to the design and the ethnicity, and in response according to TKIs. These data may constitute the background to develop a clinical predictive model to better estimate the expected benefit when using EGFR TKIs in patients with EGFR mutant NSCLC

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-033 - Afatinib in EGFR mutant non-small-cell lung cancer patients with acquired resistance to reversible EGFR-TKIs (ID 2285)

      09:30 - 09:30  |  Author(s): F. De Marinis

      • Abstract

      Background
      Afatinib, an irreversible EGFR-HER2 dual inhibitor, demonstrated superiority versus standard platinum-based chemotherapy as front-line therapy in non-small-cell lung cancer patients (NSCLC) with activating Epidermal Growth Factor Receptor (EGFR) mutations. In pretreated NSCLC afatinib failed to improve survival when compared to placebo in patients refractory to gefitinib or erlotinib and not selected for EGFR status. Aim of the present study was to evaluate clinical efficacy of afatinib in EGFR mutant NSCLC patients (pts) with secondary resistance to reversible EGFR-TKIs.

      Methods
      We retrospectively analyzed a cohort of 97 EGFR mutant lung cancer pts resistant to EGFR-TKI according to criteria used in the LUX-Lung 1 trial (Miller VA, Lancet Oncol 2012) and treated with Afatinib at the daily dose of 40-50 mg. The drug was given as compassionate use.

      Results
      The study included individuals with a median age of 62,5 year. The majority were females (N=63/64.9%), never/former smokers (N=94/96,9%), with good performance status (ECOG PS 0-1; N=90/90.2%) and pretreated with > 3 therapy lines (N=68/70.0%). EGFR status was assessed in tumor tissue obtained at the time of original diagnosis. The majority of pts (N=64, 66%) harbored a deletion in exon 19, while T790M mutation was detected in two cases including one case with double exon 19 and T790M mutation. Among the 95 pts evaluable for toxicity, 54.7% had any grade skin rash, including 11.6% with grade 3, and 50,5% had any grade of diarrhea, with grade 3 recorded in 10,5%. Among the 87 pts evaluable for efficacy, response rate (RR) was 11.5%, with a median progression free-survival and overall survival of 3.9 months and 7.3 months respectively. In 25 pts a tumor biopsy was repeated immediately before starting Afatinib therapy and 1 patient out of 5 individuals harboring T790M mutation showed a short extracerebral partial response, with following brain progression.

      Conclusion
      Our findings suggest that afatinib is modestly effective in EGFR mutant NSCLC with acquired resistance to reversible EGFR-TKIs.

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    P2.08 - Poster Session 2 - Radiotherapy (ID 198)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P2.08-019 - Palliative radiation during pemetrexed plus cisplatin first-line treatment or pemetrexed continuation maintenance treatment in advanced nonsquamous non-small cell lung cancer (NSCLC): A report of patient safety in the PARAMOUNT trial (ID 2364)

      09:30 - 09:30  |  Author(s): F. De Marinis

      • Abstract

      Background
      Patient (pt) safety is of utmost concern to radiation oncologists. Pemetrexed (Pem) is an effective and well-tolerated treatment for advanced nonsquamous NSCLC. The safety of palliative radiation (XRT) during Pem treatment was studied in this subset of pts in the PARAMOUNT trial.

      Methods
      In PARAMOUNT, a randomized, double-blind study, 939 pts received 4 cycles of induction Pem (500 mg/m[2]) + cisplatin (Cis) (75 mg/m[2]) on day 1 every 21 days. Patients without progressive disease (PD) and with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1 (n=539) were then randomized (2:1) to maintenance Pem (500 mg/m[2], day 1) + best supportive care (BSC) (Arm A) or placebo + BSC (Arm B) until PD. Best supportive care (BSC) was defined as treatment without a specific antineoplastic regimen and included palliative XRT to extrathoracic structures. Safety was assessed via the incidence of adverse events (AEs) by maximum grade (Gr; CTCAE, v3).

      Results
      The 55 pts who received palliative XRT to extrathoracic structures during treatment had stage IV nonsquamous NSCLC. The majority of pts were male (58%), with an ECOG PS of 1 (75%). Patients’ median age was 61 yrs (range, 32-74) yrs, with 13% of pts ≥70 yrs. The most common location irradiated was bone (43/55 pts). Non-bone locations were: lymph node (3), mediastinum (2), chest (2), and adrenal gland, intraocular, lung, brain, and abdomen (1 each). Forty-five pts received XRT during Pem+Cis induction, 3 of whom also received XRT during maintenance. Seven pts (Arm A) and 6 pts (Arm B) received palliative XRT during maintenance. Total XRT doses ranged from 8-66 Gy. The time interval between day 1 of last chemotherapy cycle and the start of palliative XRT ranged from 0-28 days. Of 55 pts, 12 (22%) had ≥1 AE(s) during XRT considered possibly related to Pem and/or XRT (Table 1). All pts except 1 experienced the AE during induction. The most common AE was Gr 2 anemia. Three pts had Gr 3/4 anemia. Five pts had nonhematologic toxicities. One pt in Arm B, who received a total dose of 20 Gy in the hip during maintenance treatment, had pneumonitis. No AEs were reported for pts who received palliative XRT during Pem maintenance treatment.

      Table 1: AEs during palliative XRT or within 2 weeks after the end of the last fraction in both phases of the PARAMOUNT trial.
      Pts receiving palliative XRT (N=55)
      Patients with AEs during induction and/or maintenance (n=12, 22%)
      Toxicity Gr 1, n (%) Gr 2, n (%) Gr 3-4, n (%)
      Hematologic
      Hemoglobin 1 (1.8) 4 (7.3) 3 (5.5)
      Leukocytes 0 2 (3.6) 1 (1.8)
      Platelets 0 1 (1.8) 0
      Nonhematologic
      Rash/dermatitis 1 (1.8) 1 (1.8) 0
      Rash/desquamation 1 (1.8) 1 (1.8) 0
      Pneumonitis 0 0 1 (1.8)*
      *Pneumonitis was the only event reported for a pt during the maintenance phase. The pt was assigned to placebo.

      Conclusion
      Conclusions: In PARAMOUNT, palliative XRT is well tolerated and can be safely administered at low and high doses during Pem+Cis chemotherapy or Pem monotherapy to pts with advanced nonsquamous NSCLC.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-037 - Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after completing at least 4 cycles of pemetrexed plus cisplatin induction treatment: a cross-trial analysis of two phase III trials (ID 2449)

      09:30 - 09:30  |  Author(s): F. De Marinis

      • Abstract

      Background
      In a phase III trial, JMDB, the subgroup of patients with nonsquamous histology showed a significant improvement in survival after treatment with first-line pemetrexed + cisplatin (pem 500 mg/m[2] + cis 75 mg/m[2] every 21 days for a maximum of 6 cycles). In PARAMOUNT, a double-blind, placebo-controlled, phase III trial, 539 patients with advanced nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 were randomized to maintenance pem or placebo after completing 4 cycles of pem+cis without disease progression.

      Methods
      We compared patients from the two randomized arms of PARAMOUNT with a selected homogeneous population from JMDB: 346 patients with advanced nonsquamous NSCLC and an ECOG PS of 0 or 1 who completed at least 4 cycles of pem+cis without disease progression. Efficacy outcomes included overall survival (OS) and progression-free survival (PFS) measured from the start of treatment with pem+cis and analyzed by Kaplan-Meier and Cox methods. Rates of toxicities were calculated without formal statistical comparison.

      Results
      Outcomes for the JMDB homogeneous group were similar to the PARAMOUNT placebo arm (PFS: 6.24 vs 5.59, p=0.117; OS: 14.23 vs 13.96, p=0.979). The PARAMOUNT pem group had statistically superior efficacy compared with the JMDB homogeneous group (PFS: 7.46 vs 6.24 p<0.00001; OS: 16.89 vs 14.23 p=0.003). Patients who received pem maintenance displayed numerically higher incidences of drug-related serious adverse events (SAEs) compared with JMDB patients who received ≥4 cycles of pem+cis (10.6% vs 2.9%); grade 3/4 anemia and fatigue were higher in the pem arm of PARAMOUNT. A comparable number of patients (approximately 2/3) on both arms of PARAMOUNT and on JMDB received post-discontinuation systemic therapy (PDT). Results are summarized in Table 1. Table 1: Summary of survival, post-discontinuation systemic therapy , and selected drug-related adverse events in the PARAMOUNT pem and placebo arms and the JMDB homogeneous group

      PARAMOUNT pem arm (n=359) PARAMOUNT placebo arm (n=180) JMDB homogeneous group (n=346)
      PFS
      Median (95% CI), mos 7.46 (6.90-8.57) 5.59 (5.45-5.95) 6.24 (5.91-6.54)
      Cox unadjusted HR (95% CI) 0.66 (0.56-0.77)* 0.86 (0.72-1.04)**
      Unadjusted log-rank p-value <0.00001* 0.117**
      OS
      Median (95% CI), mos 16.89 (15.77-18.99) 13.96 (12.88-15.51) 14.23 (12.94-15.05)
      Cox unadjusted HR (95% CI) 0.75 (0.63-0.91)* 1.00 (0.81-1.24)**
      Unadjusted log-rank p-value 0.003* 0.979**
      Received any PDT, n % 231 (64.3) 129 (71.7) 207 (59.8)
      Patients with ≥1 drug-related SAE, n (%) 38 (10.6) 8 (4.4) 10 (2.9)
      Hematologic grade 3/4 toxicities, n (%)
      Anemia Hemoglobin decreased Hemoglobin 16 (4.5) 2 (0.6) 0 (0.0) 2 (1.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 10 (2.9)
      Neutropenia Neutophils/granulocytes 17 (4.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 18 (5.2)
      Nonhematologic grade 3/4 toxicities, n (%)
      Fatigue 11 (3.1) 2 (1.1) 5 (1.4)
      *PARAMOUNT pem arm vs JMDB homogeneous group; **PARAMOUNT placebo arm vs JMDB homogeneous group. Abbreviations: PDT=post-discontinuation systemic therapy; PFS: progression-free survival; OS: overall survival; SAE: serious adverse event

      Conclusion
      The PARAMOUNT placebo arm showed results consistent with the JMDB homogeneous group treated with pem+cis. The addition of pem continuation maintenance treatment results in a statistically significant increase in OS and PFS. Although there was an increase in the incidence of grade 3/4 toxicities with longer exposure to pem+cis or maintenance pem, the overall incidence remains low, underscoring the relative safety of these treatment regimens.