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D. Spigel



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.08 - A phase 2 randomized open-label study of ramucirumab (IMC 1121B; RAM) in combination with first-line platinum-based chemotherapy in patients (pts) with recurrent or advanced non-small cell lung cancer (NSCLC): final results from non-squamous (NSQ) pts (NCT01160744) (ID 1471)

      16:15 - 17:45  |  Author(s): D. Spigel

      • Abstract
      • Presentation
      • Slides

      Background
      Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in NSCLC pathogenesis. RAM is a human IgG1 monoclonal receptor targeted antibody that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study investigates RAM in combination with first-line platinum-pemetrexed chemotherapy in advanced NSCLC.

      Methods
      Eligible patients had Stage IIIb/IV NSCLC, ECOG PS ≤ 2, and no prior chemotherapy or VEGF/VEGFR therapy for metastatic disease. Non-squamous (NSQ) pts with advanced NSCLC were randomized 1:1 to either Arm A: pemetrexed + carboplatin/cisplatin (PEM + Cb/Cis) followed by PEM maintenance or Arm B: Ramucirumab 10 mg/kg + pemetrexed + carboplatin or cisplatin (RAM + PEM + Cb/Cis), followed by RAM + PEM maintenance once every 3 weeks. Patients received the first-line therapy from 4 to 6 cycles (21-day cycle); patients without evidence of disease progression entered a maintenance phase. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), change in tumor size, duration of response, and safety.

      Results
      From Oct 2010 to 2012, 140 pts were randomized (PEM + Cb/Cis: 71; RAM + PEM + Cb/Cis: 69). Overall, baseline patient characteristics were balanced between arms. The median PFS was 5.6 m PEM + Cb/Cis and 7.2 m for RAM + PEM + Cb/Cis; HR 0.75 (90% CI, 0.55, 1.03; p =0.132). ORR (CR + PR) was 38% for PEM + Cb/Cis and 49.3% including one complete response in the RAM + PEM + Cb/Cis arm (p=0.18). Disease control rate (CR + PR + SD) was 70% PEM + Cb/Cis and 86% for RAM + PEM + Cb/Cis ( p = 0.031). Median OS at the time of final PFS analysis was 10.4 m for PEM + Cb/Cis and 13.9 m for RAM + PEM + Cb/Cis; HR 0.83 (90% CI, 0.56, 1.22; p=0.43). Grade ≥ 3 adverse events (AEs) occurring in >10% of patients on RAM containing arm were: anemia, neutropenia, thrombocytopenia, nausea, fatigue, back pain, and hypertension.

      Conclusion
      While the primary endpoint of significant prolongation of PFS was not met, RAM has evidence of clinical activity in combination with PEM + Cb/Cis in patients with NSQ NSCLC. Addition of RAM to PEM + Cb/Cis did not result in excessive or unexpected toxicity.

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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.07 - The prevalence of MET expression by immunohistochemistry (IHC) in the MetLung (OAM4971g) trial: a randomized, placebo-controlled, phase III study with erlotinib + onartuzumab (MetMAb) vs erlotinib + placebo in patients with previously treated non-small cell lung cancer (NSCLC) (ID 2709)

      10:30 - 12:00  |  Author(s): D. Spigel

      • Abstract
      • Presentation
      • Slides

      Background
      MET signaling is correlated with a poor prognosis in multiple tumor types, including NSCLC. A randomized, controlled, phase II clinical trial demonstrated a PFS and OS benefit of inhibiting MET signaling with erlotinib + onartuzumab, a humanized monovalent antibody to the MET receptor, in patients whose NSCLC over-expressed MET by IHC (in press). A phase III trial (OAM4971g) is ongoing to confirm the benefit of onartuzumab when combined with erlotinib in patients with previously treated NSCLC whose tumors over-express MET by IHC (2+/3+ only). Here, we present the prevalence rates of MET expression and EGFR mutation status for patients whose tumor tissues were screened and for those enrolled in the phase III study.

      Methods
      Archival or fresh biopsy tumor specimens were submitted to a central laboratory for both MET IHC and EGFR mutation assessment. MET IHC status was determined using the CONFIRM SP44 anti-MET monoclonal antibody (Ventana Medical Systems, Inc., Tucson, AZ). Patients were selected based on expression of MET by IHC, as defined by moderate or strong staining in at least 50% of tumor cells (clinical score 2+/3+). The cobas[®]EGFR mutation test was used to stratify enrollment.

      Results
      Between November 2011 and June 2013, 1605 tumor tissue samples were submitted for MET IHC and EGFR activating mutation analysis, from 188 clinical study centers. The majority of screened and enrolled patients were over 60 years of age, Caucasian, male, and had non-squamous NSCLC histology (see table). MET IHC results are available for 1474 (92%) of all submitted samples: IHC 0 (n=118, 8%), IHC 1+ (n=619, 42%), IHC 2+ (n=575, 39%), IHC 3+ (n=162, 11%). The incidence of MET IHC 2+/3+ in screened patient subgroups is as follows: non-squamous 52.5%; squamous 29.2%; non-Asian 45.9%; Asian 48%; EGFR wild type 50.3%; EGFR mutant 57.5%. Table: Patient characteristics for screened and enrolled patients in the OAM4971g study

      Screened (n=1605) Enrolled (n=443)
      Age (years)
      n 1482 442
      Median 63.0 62.5
      Range 24–89 24–84
      Race
      n 1482 443
      White 1187 (80.1%) 316 (71.3%)
      Asian 185 (12.5%) 72 (16.3%)
      Black or African American 44 (3.0%) 11 (2.5%)
      Sex
      n 1483 443
      Male 937 (63.2%) 244 (55.1%)
      Histology
      n 1451 440
      Non-squamous 1096 (75.5%) 374 (85.0%)
      MET IHC score
      n 1474 443
      3+ 162 (11.0%) 97 (21.9%)
      2+ 575 (39.0%) 346 (78.1%)
      1+ 619 (42.0%) 0 (0.0%)
      0 118 (8.0%) 0 (0.0%)
      EGFR activating mutation
      n 1422 443
      Yes 114 (8.0%) 46 (10.4%)
      No 1308 (92.0%) 397 (89.6%)

      Conclusion
      In this large population, the prevalence of MET IHC 2+/3+ was 50% in screened samples, consistent with prior IHC results for MET prevalence. The prevalence of MET IHC 2+/3+ was higher in non-squamous vs squamous tissue samples, but equally distributed across ethnicity and EGFR mutation status. The ongoing OAM4971g study will prospectively confirm whether blocking MET signaling in patients with MET IHC 2+/3+ over-expressing NSCLC provides clinically meaningful benefit in all enrolled patients and in important clinical subpopulations.

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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      MO18.01 - An analysis of the relationship of clinical activity to baseline EGFR status, PD-L1 expression and prior treatment history in patients with non-small cell lung cancer (NSCLC) following PD-L1 blockade with MPDL3280A (anti-PDL1) (ID 2347)

      16:15 - 17:45  |  Author(s): D. Spigel

      • Abstract
      • Presentation
      • Slides

      Background
      NSCLC may utilize PD-L1 overexpression to escape immune surveillance. This mechanism has been suggested by recent clinical studies showing that NSCLC can respond to PD-L1/PD-1 blockade. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 from binding to its receptors, PD-1 and B7.1.

      Methods
      Patients received MPDL3280A IV q3w for up to 1 year in a Phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tissue was analyzed centrally for PD-L1 expression by IHC.

      Results
      As of Feb 1, 2013, 52 NSCLC patients were evaluable for safety and treated at doses of 0.03-20 mg/kg. The median age of patients was 61 years (range, 24-83). 17 (33%) of patients were ECOG PS 0 and 35 (67%) of patients were ECOG PS 1. Prior treatments included surgery (89%), radiotherapy (54%) and systemic therapy (98%). 15% of patients received 1 prior regimen, 21% received 2 and 62% received ≥3. Additionally, 14%, 62% and 25% of patients were EGFR-mutation positive, EGFR WT and EGFR status unknown/undetermined, respectively, and 12%, 40% and 48% of patients were KRAS-mutation positive, KRAS WT and KRAS status unknown/undetermined, respectively. Patients received treatment with MPDL3280A for a median duration of 106 days (range 1-450). Treatment-related Gr3/4 AEs occurred in 12% of patients, including fatigue (4%) and hypoxia (4%). 1 patient experienced a Gr3/4 immune-related AE (Gr3 hyperglycemia). No Gr3-5 pneumonitis or diarrhea was reported. 41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy. An ORR of 22% (9/41) was observed in patients (squamous [n=9]/nonsquamous [n=31]) with a duration of response range of 1+ to 214+ days. Additional patients had nonconventional responses after apparent radiographic progression but were considered to have progressive disease in this analysis. All responses were ongoing or improving at data cutoff. The 24-week PFS was 46%. ORR by patient characteristics was also examined. The ORR for patients with ≤2 prior therapies was 23% (4/17) and 23% (5/22) for patients with >2 prior therapies. Additionally, the response for former/current smokers was 23% (8/35) versus 17% (1/6) for never smokers. Between EGFR-mutation positive and EGFR WT patients, the ORRs also did not differ (25% [1/4] and 19% [5/26], respectively). In contrast, PD-L1 status was associated with ORR response as patients with PD-L1–positive tumors had an ORR of 80% (4/5) and patients with PD-L1–negative tumors had an ORR of 14% (4/28). Updated data, including responses by KRAS status, will be presented.

      Conclusion
      Treatment with MPDL3280A was generally well tolerated, with no cases of Gr3-5 pneumonitis. Rapid and durable responses were observed, including in an EGFR-mutation positive patient. Responses to MPDL3280A did not appear influenced by the number of prior treatment regimens but did appear to be associated with PD-L1 tumor status. Additional studies have been initiated in NSCLC.

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      MO18.03 - Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial (ID 2356)

      16:15 - 17:45  |  Author(s): D. Spigel

      • Abstract
      • Presentation
      • Slides

      Background
      Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian S, et al. New Engl J Med. 2012;366:2443-54). We present long-term safety and efficacy outcomes from a phase 1 study of nivolumab, a fully human IgG4 PD-1 receptor blocking monoclonal antibody, in patients with advanced NSCLC.

      Methods
      NSCLC patients enrolled between 2008–2012 received nivolumab 1, 3, and 10 mg/kg IV Q2W on either dose escalation or subsequent expansion cohorts. Tumors were assessed (RECIST 1.0) after each 4-dose cycle. Protocol was amended (Jan. 23, 2012) to explore nivolumab’s potential to deliver prolonged overall survival (OS) for the initial and expansion cohorts and the overall population.

      Results
      129 pretreated NSCLC patients (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) were treated as of March 2013. Responses (CR/PR) occurred in 22 patients (17%) and were durable (estimated median response duration, 74.0 weeks [6.1+, 133.9+]), and ongoing in 55% (12/22) of patients. The highest objective response rate (ORR) was at 3 mg/kg (24%) across NSCLC histologies. Responses were rapid; 50% of patients (11/22) demonstrated response at first tumor assessment (8 weeks). Among 12 responders who discontinued therapy for reasons other than disease progression, 3 responded for ≥24 weeks post therapy discontinuation, and all 3 had not progressed at the time of this analysis. An additional 6 of the 122 patients (5%) demonstrated unconventional “immune-related” responses (based on target lesions), but were not included among responders. Survival benefit was demonstrated by 1-year and 2-year landmark OS rates (42% and 14%; Table). Median OS was 9.6 months across doses and 14.9 months at 3 mg/kg across histologies. Median OS across doses was similar for squamous/non-squamous patients. Any grade drug-related select adverse events (AEs) occurred in 41% (53/129) of patients (grade 3/4 select AEs, 5% [6/129]); most common being skin (16%), gastrointestinal (12%), and pulmonary (7%). Any grade drug-related pneumonitis occurred in 6% (8/129) of patients (grade 3/4 pneumonitis, 2% [3/129]), resulting in 2 deaths early in the trial, leading to increased emphasis on management algorithms. Characteristics and management of nivolumab-related pneumonitis will be summarized.

      Cohort Dose, mg/kg ORR[a] no. of patients/total no. of patients (%) [95% CI] Estimated median response duration, wk (range) Median OS,[b] mo (95% CI) OS rate, % (95% CI); patients at risk, n
      1 y 2 y
      NSCLC (n=129)[c] All doses 22/129 (17.1) [11.0, 24.7] 74.0 (6.1+, 133.9+) 9.6 (7.8, 12.4) 42 (33, 51); 43 14 (4, 24); 5
      1 1/33 (3.0) [0.1, 15.8] 63.9 (63.9, 63.9) 9.2 (5.6, 11.1)
      3 9/37 (24.3) [11.8, 41.2] NR (16.1+, 133.9+) 14.9 (9.5, NE)
      10 12/59 (20.3) [11.0, 32.8] 83.1 (6.1+, 117.1+) 9.2 (5.2, 12.4)
      Initial cohort (n=19) All doses 9.6 (4.5, 19.8) 42 (20, 64); 8 26 (7, 46); 5
      Expansion cohort (n=110) All doses 9.9 (7.8, 12.5) 42 (32, 51); 35
      Squamous (n=54) All doses 9/54 (16.7) [7.9, 29.3] NR (16.1, 133.9+) 9.2 (7.3, 12.5) 39 (25, 53); 16
      1 0/15 0 8.0 (2.6, 13.3)
      3 4/18 (22.2) [6.4, 47.6] NR (16.1, 133.9+) 9.5 (6.7, NE)
      10 5/21 (23.8) [8.2, 47.2] 83.1 (16.1, 117+) 10.5 (7.8, 12.5)
      Non-squamous (n=74) All doses 13/74 (17.6) [9.7, 28.2] 63.9 (6.1+, 74.0+) 10.1 (7.2, 13.7) 43 (31, 54); 26
      1 1/18 (5.6) [0.1, 27.3] 63.9 (63.9, 63.9) 9.9 (5.6, 22.7)
      3 5/19 (26.3) [9.1, 51.2] 74.0 (24.3, 74.0+) 18.2 (10.3, 18.2)
      10 7/37 (18.9) [8.0, 35.2] NR (6.1+, 65.7+) 7.4 (4.6, 12.4)
      [a]ORR = ([CR + PR] ÷ n) × 100.[b]OS estimates after 1 year reflect censoring and shorter follow-up for patients enrolling later in the study.[c]Non-squamous (n=74), squamous (n=54), and unknown histology (n=1) NE = not estimable; NR = not reached.

      Conclusion
      In advanced NSCLC patients, nivolumab produced durable responses and survival benefit (1-year OS rate, 42%), with a long-term safety profile acceptable for the outpatient setting, supporting ongoing development in phase 3 trials with survival endpoints. Additional follow-up on patient survival will be presented at the time of the meeting.

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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.09 - Molecular correlates of PD-L1 status and predictive biomarkers in patients with non-small cell lung cancer (NSCLC) treated with the anti-PDL1 antibody MPDL3280A (ID 1653)

      10:30 - 12:00  |  Author(s): D. Spigel

      • Abstract
      • Presentation
      • Slides

      Background
      In NSCLC, antitumor immune response may be inhibited by PD-L1 expression. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 binding to its receptors, PD-1 and B7.1.

      Methods
      Patients with squamous or nonsquamous NSCLC received MPDL3280A IV q3w up to 1 year as part of a phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tumor tissues were evaluated centrally by IHC for PD-L1 and CD8. A qPCR-based gene expression panel measuring ≈90 immune-related genes was used to characterize the tumor immune microenvironment at baseline and during MPDL3280A treatment.

      Results
      41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy with an ORR of 22%. Baseline tumor samples were available for IHC (n=33) and for gene expression analysis (n=29). Of patients with available tissue, 5 were PD-L1 tumor status positive and 28 were PD-L1 tumor status negative. Relationship between PD-L1 status and EGFR/KRAS status is described below (table). Elevated baseline PD-L1 expression was associated with response to MPDL3280A (80% ORR vs 14% ORR for PD-L1negative patients), and PD-L1 expression coordinated with CD8+ T cells. A Th1-type T-cell gene signature (including CD8, Granzyme-B and EOMES) was associated with treatment response. Non-responders exhibited at least a 2-fold higher ratio over CD8 of genes associated with immunosuppression, including RORC, FOXP3, TGFb1 and IL10 compared with responders. On treatment, responding tumors across indications showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 up-regulation.

      Conclusion
      PD-L1 expression and a Th1 driven T-cell gene signature correlated with response to MPDL3280A in NSCLC, and MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. Additionally, expression of immune suppressive factors in NSCLC tumors is associated with a lack of benefit from MPDL3280A. These data provide mechanistic insights into immunotherapy and patient selection for MPDL3280A monotherapy. Preliminary observations suggest clinical activity and molecular characteristics may be associated with PD-L1 tumor expression. Updated data will be presented. Table: Relationship between PD-L1 status and EGFR/KRAS mutational status

      PD-L1-Positive (n = 5) PD-L1-Negative (n = 28) PD-L1 Unknown (n = 7) Overall (n = 40)*
      EGFRm, n 1 2 1 4
      EGFR WT, n 2 20 4 26
      EGFR Unknown, n 2 6 2 10
      KRASm, n 1 4 1 6
      KRAS WT, n 2 8 3 13
      KRAS Unknown, n 2 16 3 21
      * 1 patient had missing data.

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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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      MO21.10 - Serial monitoring of plasma EGFR T790M levels and evaluation of EGFR mutational status in matched tissue and plasma from NSCLC patients treated with CO-1686 (ID 2498)

      10:30 - 12:00  |  Author(s): D. Spigel

      • Abstract
      • Presentation
      • Slides

      Background
      Background: We explored the minimally-invasive detection of EGFR mutations in circulating free DNA from plasma and studied the concordance of EGFR mutation status between matched plasma and tumor tissue in a cohort of newly diagnosed or relapsed patients with advanced NSCLC. CO-1686 is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M and the common initial activating mutations, while sparing wild-type EGFR. Promising clinical activity has recently been reported from an on-going Phase I/II trial.

      Methods
      Methods: Matched tumor tissue and blood from 80 Stage IIIB/IV NSCLC patients, 41 treated with CO-1686, were tested using two allele-specific PCR assays, the cobas® EGFR FFPET and cobas® EGFR blood tests. Each test detects 41 mutations in EGFR, including the T790M resistance mutation, exon 19 deletions and L858R. We also used BEAMing, a highly quantitative and sensitive technology based on digital PCR, to assess a subset of 18 patients treated with CO-1686. BEAMing was compared to cobas analysis at baseline, and also used to serially monitor plasma EGFR mutation levels in response to CO-1686.

      Results
      Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 76% (44/58) for activating mutations and 63% (17/27) for T790M. The cobas® EGFR blood test identified two patients with T790M mutations in plasma that were not detected in the corresponding tumor biopsy—likely because of tumor heterogeneity. The M1a/M1b status was known for 63 EGFR mutation-positive patients. Of the 44 with extrathoracic metastatic disease (M1b), 38 were found to have an activating mutation in plasma (86%). Conversely, only 53% (10/19) of EGFR mutation-positive patients with intrathoracic metastatic disease (M1a) had detectable activating mutations in plasma (p = 0.0081). For the 18 patients profiled by BEAMing, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 94% (17/18) for T790M and 83% (15/18) for activating mutations. Nine of the 18 patients had detectable baseline plasma T790M levels, and several patients treated with CO-1686 had an initial decrease in plasma T790M by BEAMing.

      Conclusion
      Conclusions: Using the cobas® EGFR blood test, a high proportion of EGFR mutations identified in tissue were also detected in plasma. Mutations were more readily detectable in the plasma of patients with M1b rather than M1a disease. These findings suggest that the cobas® EGFR blood test and BEAMing can be useful tools for the non-invasive assessment and monitoring of EGFR mutations in NSCLC patients.

      EGFR mutation Evaluable patients Patients with tissue mutations* Patients with plasma mutations** Patients with same mutation detected in tissue and plasma Positive Percent Agreement***
      L858R, del19, S768I, G719X, or ex20ins 80 58 44 44 76%
      T790M 80 27 19 17 63%
      * identified by the cobas® EGFR tissue test
      ** identified by the cobas® EGFR blood test
      ***agreement of blood and tissue mutation-positive results with tissue as reference; although tissue is reference, some mutations may be missed due to tumor heterogeneity

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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO24.07 - nab-Paclitaxel plus carboplatin in patients (pts) with squamous cell (SCC) non-small cell lung cancer (NSCLC): analysis of pts treated beyond 4 cycles in a pivotal phase 3 trial (ID 3438)

      10:30 - 12:00  |  Author(s): D. Spigel

      • Abstract
      • Presentation
      • Slides

      Background
      Continuous maintenance is defined as continuation of ≥ 1 first-line agents after 4-6 cycles of induction therapy in pts who have not progressed. In a pivotal phase 3 trial, first-line treatment to progression with nab-paclitaxel (nab-P, 130-nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C resulted in a 68% improvement in response rate (41% vs 24%; P < .001) and a trend toward improved survival (median, 10.7 vs 9.5 months; P = .808) in the subset of pts with SCC. This unplanned exploratory analysis examined outcomes in pts with SCC receiving > 4 cycles of nab-P/C to assess the feasibility of the nab-P/C regimen in the maintenance setting in SCC.

      Methods
      Pts with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on days 1, 8, 15 or sb-P 200 mg/m[2] on day 1 every 21 days; both arms received C AUC 6 on day 1. Overall response rate and progression-free survival (PFS) were determined by blinded centralized review. To allow comparison of the results of this analysis with maintenance studies, PFS is expressed from day 1 of cycle 5 (C5D1).

      Results
      229 pts with SCC received nab-P/C and 221 received sb-P/C in this study. In the nab-P/C arm, 60% (n = 138) of pts with SCC were progression-free at the end of cycle 4 and entered cycle 5 (the study population). In these pts, the median PFS was 3.4 months (range 2.8 – 4.2) from C5D1. The median OS from randomization in these pts was 13.8 months (range 12.4 – 16.8). Survival at 1year was 59% (51% – 67%). The median number of treatment cycles was 7 (range 5 – 31). A total of 125 (91%), 64 (46%) and 35 (25%) pts were treated for up to 6, 8 and 10 cycles, respectively, with a median weekly dose of 75 mg/m[2 ]for nab-paclitaxel in each group, and carboplatin AUC of 6, 4.75, and 4.5, respectively. Preliminary safety findings in this population revealed that the most common grade 3/4 treatment-related adverse events were neutropenia (49%), anemia (31%), and thrombocytopenia (27%). The overall rate of grade 3 peripheral neuropathy in the nab-P/C arm was 4% (with no grade 4); 1%, 3%, and 0% of pts had grade 3 peripheral neuropathy at cycle 6, 8, and 10, respectively.

      Conclusion
      Continued treatment with nab-P/C to progression was feasible, well tolerated, and effective in pts with advanced SCC who had not progressed after 4 cycles of first-line therapy. Future randomized, prospective studies are warranted to further evaluate the activity of nab-P/C as maintenance therapy in SCC pts.

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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)

      10:30 - 12:00  |  Author(s): D. Spigel

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.10-004 - Exploratory Subset Analysis in African Americans from the PointBreak Study (Randomized Phase 3 Pemetrexed + Carboplatin + Bevacizumab Followed by Maintenance Pemetrexed + Bevacizumab Versus Paclitaxel + Carboplatin + Bevacizumab followed by Maintenance Bevacizumab in Patients with Stage IIIB/ IV   Nonsquamous Non-Small Cell Lung Cancer) (ID 249)

      09:30 - 16:30  |  Author(s): D. Spigel

      • Abstract

      Background
      African Americans (AA) have a higher rate of lung cancer than Caucasians per 100,000 population (74.7 versus 64.4) but are underrepresented in randomized clinical trials. In the PointBreak study, AAs were enrolled at the same rate as the US incidence of non-small cell lung cancer (NSCLC) for AAs in 2011 (13%; now 15% in 2013). Post-hoc analyses of the AA subgroup were conducted from this study to evaluate efficacy and safety, as well as these outcomes by treatment center.

      Methods
      All patients (N=939) were chemonaive with an ECOG performance status (PS) of 0/1. AAs were analyzed against Caucasians for efficacy/safety in the pemetrexed (Pem) arm only. Subgroup analyses of AAs alone were conducted for efficacy/safety (between arm comparisons) as well as academic versus community settings (pooled two treatment arms). Hazard ratios and p-values were derived from a multivariate Cox-PH model, adjusting for disease stage, gender, PS and measurable/nonmeasurable disease. Response rates and adverse events (AEs) were compared using the exact test.

      Results
      Patients had stage IIIb (with pleural effusion)/IV nonsquamous NSCLC, according to AJCC edition 6. There were 94 AAs (42 = Pem arm; 52 = Paclitaxel [Pac] arm) and 805 Caucasians in the treated population. Demographics were statistically comparable between AAs and Caucasians in the Pem Arm, respectively: 62%/53% male, 71%/53% ≤65 years, 98%/89% ever smokers, 81%/90% Stage IV disease, with ECOG PS of 0/1, 33%/67%, versus 44%/56%. Median OS was similar between AAs and Caucasians in the Pem arm at 12.4 versus 12.3 months. Median PFS for AAs and Caucasians was 4.6 months versus 6.0 months (HR 1.229 (0.864 – 1.749; p=0.251). Overall response rate (ORR) for AAs was higher, though not statistically, at 38.1% versus 33.3% (p=0.607). Efficacy among AAs was fairly similar with median OS for Pem arm at 12.4 versus 13.7 months for Pac arm (p=0.1208). Median PFS by arm was 4.6 versus 5.1 months (p=0.6699). ORR among AAs was 38% in both arms. AAs showed a heavy trend (80%) for enrollment in community centers (n=74) versus academic center (n=20). Efficacy among AAs by setting showed a higher median OS at academic sites at 16.5 months versus 11.4 months, p=0.1906 (HR=0.6605; 95% CI: 0.355 – 1.229). Median PFS was also higher at academic sites at 6.9 months versus 4.6 months, p=0.9149 (HR =0.9690; 95% CI: 0.544 – 1.726). Drug-related grade 3/4 AEs in the Pem arm showed higher percentages for Caucasians with the exception of neutropenia, as follows: anemia (7.3%/15.9%), thrombocytopenia (9.8%/25.5%), fatigue (4.9%/11.5%), neutropenia (31.7%/25.3%), febrile neutropenia (0%/1.6%). Among AAs in the Pem/Pac Arm respectively, drug-related grade 3/4 AEs were: anemia (7.3%/0%), thrombocytopenia (9.8%/4.0%), fatigue (4.9%/4.0%), neutropenia (31.7%/44.0%), and febrile neutropenia (0%/4.0%).

      Conclusion
      There were no significant differences between AAs and Caucasians for OS, PFS, and ORR. Among AAs, median OS was not superior for either arm. PFS and OS were similar for academic and community settings among AAs. Caucasians had a significantly higher incidence of Grade 3/4 thrombocytopenia (p=0.0217), but this should be interpreted with caution due to the sample size for the AAs.

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      P1.10-033 - Safety and Resource Use in PRONOUNCE: A randomized, phase 3, open-label study of Pemetrexed plus Carboplatin with maintenance Pemetrexed (PemC) and Paclitaxel plus Carboplatin plus Bevacizumab with maintenance Bevacizumab (PCB) in patients with advanced non-squamous (NS) non-small-cell lung cancer (NSCLC) (ID 1680)

      09:30 - 16:30  |  Author(s): D. Spigel

      • Abstract

      Background
      Two combination chemotherapy regimens were compared in a Phase 3, randomized, open-label United States only study. The two-drug regimen of pemetrexed/carboplatin followed by maintenance pemetrexed (PemC) was compared to the three-drug regimen of paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab (PCB). The primary endpoint of improved progress-free survival (PFS) without Grade 4 toxicity (G4PFS) for PemC over PCB was not met in PRONOUNCE, as reported by Zinner et al. (ASCO, 2013). No difference in PFS or overall survival (OS) for PemC vs. PCB was observed. Both regimens demonstrated tolerability, but toxicity profiles differed.

      Methods
      Patients 18+ years of age with Stage IV chemonaïve non-squamous non-small-cell lung cancer (NS-NSCLC) were randomized to PemC (n=182) or PCB (n=179). Safety data were compared for patients who received ≥1 dose of study treatment (PemC:171; PCB:166), and resource use including concomitant medications, transfusions, and hospitalizations was recorded. Measures were compared between arms using Fisher’s exact test, if not otherwise specified. Protocol-defined chemotherapy infusion time was 0.7 hours for PemC and 4-5 hours for PCB. For the primary endpoint of G4PFS, the G4 events were reported regardless of drug causality.

      Results
      Of 152 G4PFS events for PemC, 37 (24.3%) resulted from first occurrence of a G4 event. Of 144 G4PFS events for PCB, 64 (44.4%) resulted from first occurrence of a G4 event. The safety profile for the entire study demonstrated that patients on PemC experienced significantly more drug-related Grade 3/4 anemia (18.7% vs. 5.4%; p<0.001), Grade 3/4 thrombocytopenia (24.0% vs. 9.6%; p<0.001), and Grade 1/2 nausea (46.8% vs. 28.9%; p<0.001). Patients on PCB experienced significantly more drug-related Grade 3/4 neutropenia (24.6% vs. 48.8%; p<0.001) and Grade 1/2 alopecia (8.2% vs. 28.3%; p<0.001). There was a significantly higher rate of drug-related Grade 1/2 sensory neuropathy (8.2% vs. 30.1%; p<0.001), Grade 1/2 hypertension (0.0% vs. 9.6%; p<0.001), Grade 1/2 hemorrhage in pulmonary/upper respiratory (1.8% vs. 13.3%; p< 0.001) and Grade 1/2 joint pain (1.8% vs. 13.9%; p<0.001) with PCB. Patients on PemC required more red blood cell (RBC) transfusions (34.5% vs. 11.4%; p<0.001), but there was no difference in platelet transfusions (p=0.621). Erythropoietic stimulating agents (ESAs) were used more frequently (19.9% vs. 7.2%; p<0.001) in PemC, and granulocyte colony-stimulating factor (G-CSF) use was significantly higher with PCB (17.0% vs. 30.1%; p=0.005). Requirement for antibiotics (p=0.323) and antiemetics (p=0.574) did not differ between PemC and PCB. There were no differences between PemC and PCB in the number of patients with at least one hospitalization (34.5% vs. 31.9%; p=0.645), and the mean length of stay between PemC (8.2d +/- 6.79) and PCB (8.8d +/- 7.33) did not differ (p=0.682;Wilcoxon rank sum test).

      Conclusion
      The toxicity profiles of PemC and PCB were consistent with previous reports. Toxicities documented as important to patients were split, with mild-to-moderate nausea more common for PemC and alopecia, infection and neuropathy more frequent for PCB. Resource intense toxicities were also divided. Hospitalizations did not differ between treatments. ESAs and RBC transfusions were more common with PemC, and G-CSF use was more common with PCB. ClinicalTrials.gov identifier:NCT00948675

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-020 - Molecular Alterations in Advanced Lung Cancer: Genomic Sequencing in a Community Profiling Program of the Sarah Cannon Research Institute (SCRI) (ID 3357)

      09:30 - 16:30  |  Author(s): D. Spigel

      • Abstract

      Background
      In October 2012, SCRI launched a genomic sequencing program at a single community clinical research center in middle Tennessee to explore molecular alterations with proven or potential therapeutic significance for patients (pts) with advanced solid and hematologic tumors. Herein we report the findings from the lung cancer cohort tested to date.

      Methods
      Biospecimens from pts with advanced lung cancer (ECOG ≤ 2) who consented to molecular profiling were tested by Next-Generation Sequencing (NGS) with 1000X average coverage in a CLIA/CAP-certified laboratory. Oncogenic hotspot mutations in 35 genes were tested (copy number variation and translocation were not tested). Results were reported to the treating physician within 12 days of receipt of suitable tissue, and were used to inform treatment decisions. Molecular profiling results were stored in a database to enable correlation with clinical outcomes.

      Results
      As of May 31 2013, a total of 594 tumor samples were profiled, 143 (24%) of which were from pts with lung cancer. 23% (33/143) of the lung samples were inadequate for assay. Of the 110 lung samples with sufficient tissue, 47 (43%) were found to have at least 1 identifiable mutation: 30 (27%) single mutations and 17 (16%) multiple mutations. The mutation frequency by histology was adenocarcinoma 63% (34/54 pts), squamous 19% (4/21 pts), large cell 67% (4/6 pts), and small-cell 8% (1/13 pts). The most frequent mutations from this 35-gene panel were KRAS and EGFR (18% and 14%, respectively). Other genetic alterations identified included STK11 6%, MET 5%, RUNX1 4%, FGFR3 3%, BRAF 2%, MEK1 2%, PIK3CA 2%, WT1 1%, SMO 1%, KIT 1%, GNAS 1% and FGFR4 1%.

      Breakdown of KRAS and EGFR Mutations
      Gene Codons Tested Mutation Codons Detected Number of Mutations % of Detected Mutations
      KRAS 12, 13, 61, 146 12 19 95%
      61 1 5%
      EGFR 709-719, exon 19 deletion, 768-790, exon 20 insertion, 833, 858-861 769 2 13%
      796 1 7%
      833 1 7%
      852 1 7%
      858 3 20%
      Deletion 7 40%
      Insertion 1 7%

      Conclusion
      This program confirms the feasibility of molecular profiling in the community setting to assist medical oncologists in treatment decisions for pts with lung cancer, including enrollment in clinical trials.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-005 - Randomized Phase II Study of Pemetrexed v. Pemetrexed/Bevacizumab v. Carboplatin/Pemetrexed/Bevacizumab in Patients with Previously Untreated Advanced Non-Squamous Non-Small-Cell Lung Cancer and Poor Performance Status (ID 894)

      09:30 - 16:30  |  Author(s): D. Spigel

      • Abstract

      Background
      Pemetrexed (Pem) and bevacizumab (Bev) have each been shown to improve survival in patients (pts) with advanced non-squamous non-small-cell lung cancer (NSCLC) (Scagliotti JCO 2008, Sandler NEJM 2006). Recent evidence suggests these agents can be safely combined and given with carboplatin (Cb) in the first-line setting with encouraging activity (Patel, ASTRO 2012). However, the efficacy and safety of these agents in pts with poor performance status (PS) are unknown. Herein, we report a prospective randomized phase II study of first-line pem v. pem/bev v. cb/pem/bev in pts with advanced NSCLC and poor PS.

      Methods
      Key eligibility included: pts with newly diagnosed advanced non-squamous NSCLC (IIIB or IV), an Eastern Cooperative Oncology Group (ECOG) PS of 2, and measurable disease per RECIST v.1.1. Pts were randomized 1:1:1 to receive either Pem 500mg/m[2] IV (Arm 1), Pem 500mg/m[2] IV and Bev 15mg/kg IV (Arm 2), or Pem 500mg/m[2] IV, Bev 15mg/kg IV, and Cb AUC=5 IV (Arm 3). Cycles were 21 days, with reimaging every 2 cycles. Pts on Arm 3 received a maximum of 4 cycles (12 weeks) of Cb. All pts continued Pem or Pem/Bev until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.

      Results
      Between June 2009 and May 2013, 155 pts were randomized. Summary demographic data are available for 142 pts (median age: 72 years, adenocarcinoma, 80%, males, 59%) in Arms 1, 2, and 3; 97%, 98%, and 88% of pts were current or former smokers, respectively. The most common treatment-related grade 3/4 toxicities are presented below. ORRs for Arms 1, 2, and 3 were 15%, 24%, and 40%, respectively. While modest efficacy was observed in Arm 1, recent data (Lilenbaum, et al. 2012) suggesting a significant OS advantage in pts receiving Pem in combination with Cb vs. Pem alone led to closure of this arm in early 2013. A subset analysis examining pts older or younger than 70 years found that the younger population treated on Arm 1 had inferior ORRs to older pts treated on Arm 3 (7% v. 26%, respectively).

      Grade 3/4 Toxicity Arm 1 (N=48) Arm 2 (N=49) Arm 3 (N=45)
      Hematologic
      Hemoglobin 5 (10%) 1 (2%) 5 (11%)
      Leukocytes 0 1 (2%) 4 (9%)
      Neutrophils 3 (6%) 4 (8%) 8 (18%)
      Platelets 0 2 (4%) 10 (22%)
      Non-hematologic
      Anorexia 1 (2%) 0 0
      Cardiac ischemia/infarction 0 1 (2%) 0
      CNS ischemia 0 1 (2%) 1 (2%)
      Deep vein thrombosis 0 1 (2%) 1 (2%)
      Dehydration 2 (4%) 2 (4%) 0
      Diarrhea 0 2 (4%) 1 (2%)
      Dyspnea 0 2 (4%) 2 (4%)
      Fatigue 10 (21%) 9 (18%) 9 (20%)
      Epistaxis 0 1 (2%) 0
      Hypertension 0 2 (4%) 2 (4%)
      Muscle weakness 4 (8%) 3 (6%) 4 (9%)
      Nausea 0 0 2 (4%)
      Proteinuria 0 0 1 (2%)
      Pulmonary embolism 1 (2%) 1 (2%) 2 (4%)
      Vomiting 0 2 (4%) 1 (2%)

      Conclusion
      This is the largest prospective trial of bevacizumab in poor PS pts with advanced NSCLC. All three regimens were safe and well-tolerated. ORRs with Pem/Bev +/- Cb were encouraging and comparable to historical outcomes in patients with better PS. PFS and OS data will be presented.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-043 - nab-Paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): an economic analysis (ID 2479)

      09:30 - 16:30  |  Author(s): D. Spigel

      • Abstract

      Background
      In a phase III trial in first-line, advanced NSCLC, nab-paclitaxel + carboplatin (nab-P/C) significantly increased tumor response rates, with comparable overall survival (OS) vs solvent-based paclitaxel + carboplatin (sb-P/C). However, nab-P/C improved OS in prespecified, stratified subgroups of pts, including those aged ≥­ 70 y (19.9 vs 10.4 mo; P = 0.009) and in North American pts, (12.7 vs 9.8 mo; P = 0.008). Based on the data from this trial, nab-P/C was approved by the US Food and Drug Administration (FDA) as a first-line treatment in advanced NSCLC, a condition for which no drug has demonstrated a clinically meaningful survival advantage vs platinum doublets in an unselected population in FDA registration trials. Here, we report results of a cost-effectiveness analysis that was conducted from the US payer perspective, with resource use data collected during the trial.

      Methods
      Cost-of-care estimates were applied to patient-level data on chemotherapy, drug delivery, patient monitoring, supportive care drugs, and treatment of dose-limiting toxicity. Cost-effectiveness outcomes were presented as incremental cost per life year ($/LY) gained with nab-P.

      Results
      Use of colony stimulating factors and treatment discontinuations due to toxicity were comparable between experimental and control arms. Taxane dose intensity was higher with nab-P vs sb-P (79.6% vs 61.8%). For all pts, the nab-P/C group had a $25,868 higher cost compared with sb-P/C ($35,179 vs $9,310) and an incremental $/LY gained in excess of $100K, comparable with $/LY gained estimates published for other recently approved NSCLC agents. However, in the subsets of pts aged ≥ 70 y and those from North America, the cost differential was reduced to $18,244 and $19,941, respectively. $/LY gained was reduced to $23,000 and $83,000, respectively, which compares favorably with published incremental $/LY gained for other NSCLC agents based on their OS advantage in patient subpopulations. Similar results were observed in a post hoc analysis of the subgroup of pts aged ≥ 60 y.

      Conclusion
      Weekly nab-P/C can be considered a clinically and economically attractive treatment option for US payers for first-line advanced NSCLC, particularly in the North American and elderly subsets. Future clinical trials are needed to validate these findings.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-014 - Safety, pharmacokinetics, and activity of the anti-NaPi2b antibody-drug conjugate DNIB0600A: A Phase I study in patients with non-small cell lung cancer and platinum-resistant ovarian cancer (ID 1477)

      09:30 - 16:30  |  Author(s): D. Spigel

      • Abstract

      Background
      NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter highly expressed in non-small cell lung cancer (NSCLC) and ovarian cancer (OC). DNIB0600A is an antibody-drug conjugate consisting of a humanized anti-NaPi2b IgG1 monoclonal antibody and the anti-mitotic agent MMAE.

      Methods
      This study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to patients (pts) with non-squamous NSCLC or platinum-resistant, non-mucinous OC. A traditional 3+3 design was used for dose escalation followed by expansions in NSCLC and OC at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue by immunohistochemistry (IHC). Anti-tumor activity was evaluated per RECIST 1.1.

      Results
      As of 1 May 2013, 65 pts have enrolled (35 NSCLC; 30 OC), median age 62 (range 39-85), PS 0-1, median number of prior regimens 2 (1-8) in NSCLC pts, and 5 (1-12) in OC pts. Pts received a median of 4 (range 1-25) doses of DNIB0600A. One pt experienced a DLT (Grade 3 dyspnea) at 1.8 mg/kg; however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Two patients had Grade 1 and 2 infusion-related reactions. The most common related AEs (all grades) were fatigue (55%), nausea (35%), peripheral neuropathy (32%), decreased appetite (29%), vomiting (25%), alopecia (20%), and diarrhea, dysgeusia, headache, and pain (each 15%). The majority of these AEs were Grade 1 and Grade 2. Two patients had serious AEs (SAE) which led to discontinuation (dyspnea; dehydration and hyperglycemia). Four other related SAEs (nausea, upper respiratory tract infection, abdominal pain, and headache) were noted in 2 pts. Preliminary PK results support a q3w dosing regimen with no accumulation observed. Expansion at 2.4 mg/kg was selected based on cumulative safety data and a benefit/risk assessment performed at time of expansion. Exposures of analytes monitored were dose-proportional over all dose levels, and no PK difference was observed between NSCLC or OC pts. Approximately 60% of NSCLC and 90% of OC pts expressed high levels (IHC 2+/3+) of NaPi2b. Anti-tumor activity with DNIB0600A was associated with tumor NaPi2b expression for both NSCLC and OC. Of the 40 pts with NaPi2b IHC Score of 2+ or 3+, treated at dose levels 1.8-2.8 mg/kg, 10 pts had a confirmed partial response (PR); 2 of 18 NSCLC and 8 of 22 OC pts, respectively. Additionally, 3 NSCLC and 3 OC pts have unconfirmed PRs. No pt was enrolled with NaPi2b IHC Score of 1+; no pt responded among the 13 pts with NaPi2b IHC Score of 0, treated at dose levels 1.8-2.8 mg/kg

      Conclusion
      DNIB0600A administered q3w has an encouraging safety, tolerability, and PK profile and evidence of anti-tumor activity in NSCLC and OC pts whose tumors express NaPi2b detectable by IHC. This data supports further clinical evaluation of DNIB0600A in NSCLC and OC together with a companion diagnostic.