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Enriqueta Felip



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    ES04 - Liquid Biopsies in Lung Cancer (ID 772)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 203 BD
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      ES04.04 - Guiding Second Line Treatment in ALK + Patients (Sequence of Drugs, Rebiopsy?) (ID 11368)

      16:20 - 16:40  |  Presenting Author(s): Enriqueta Felip

      • Abstract

      Abstract not provided

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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.03 - Immunotherapy for Non-Small Cell Lung Cancers (NSCLC) with Oncogenic Driver Mutations: New Results from the Global IMMUNOTARGET Registry (ID 13187)

      13:40 - 13:45  |  Author(s): Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Background

      Prospective data on immunotherapy for NSCLC with oncogenic driver mutations are limited. We recently reported first results from the global IMMUNOTARGET registry (Mazières, ASCO 2018). Here, we present new data for PD-L1 and mutation subgroups.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In 2017, we started an international retrospective registry study ("IMMUNOTARGET") for patients with advanced NSCLC, known driver mutations (KRAS, EGFR, ALK, ROS1, BRAF, HER2, MET and RET) and PD-L1 immune checkpoint inhibitor therapy. The registry is approved by University of Toulouse and Swissethics, and funded by University of Toulouse and Cantonal Hospital of Lucerne. Anonymized real-world data submitted to the coordinating center include: patient and tumor characteristics, mutation test methods and results, systemic therapy lines, immune related adverse events, best response by RECIST, survival, and tumor PD-L1 expression (optional). Statistical calculations including best response, median PFS and OS are done at University of Toulouse.

      4c3880bb027f159e801041b1021e88e8 Result

      In April 2018, the registry included 551 pts from Europe, USA, Israel and Australia. Patients were 50% male/female, 28% current smokers, median age 60 years (range 28-83), 85% had PS0/1. Most (73%) tumors were stage IV at diagnosis, almost all (96%) were adenocarcinomas. Molecular classification by dominant driver mutation: KRAS=271 (49%), EGFR=125 (23%), BRAF=43 (8%), MET=36 (7%), HER2=29 (5%), ALK=23 (4%), RET=16 (3%), ROS1=7 (1%), 1 (0.2%) not classified (ALK+RET+MET). Most pts received nivolumab (466) or pembrolizumab (48) and were treated with immunotherapy in second or third line (67%). The median number of cycles was 5 (range 1-68). Fifty (11%) pts had grade 3-5 toxicity. Median OS from start of immunotherapy was 13.3 months, median PFS was 2.8 months. Best response was PR/CR in: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. Percentage of PD-L1 positive cells was available for 177 pts: 0%=71 (40%), 1-49%=46 (26%), 50-100%=60 (34%). Median % of positive cells was highest for ROS1 (90%), BRAF (50%), MET (30%) and RET (26%) mutant tumors. PD-L1 positivity was predictive for improved PFS in KRAS and EGFR mutant tumors. PD-L1 status was known in 18 tumors with ALK, ROS1 or RET rearrangements: 5 had 0%, 4 had 1-49% and 9 had 50%-100%. No tumor remissions were observed in this subgroup. The registry remains open, updated results will be presented at the conference.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although response rates were lower than in KRAS mutant NSCLC, individual tumors with other driver mutations responded to immunotherapy. PD-L1 expression may not accurately predict clinical benefit from immunotherapy in some molecular subgroups, better markers are needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA08 - Clinical Trials in Brain Metastases (ID 906)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
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      MA08.05 - Brain Penetration of Lorlatinib and Cumulative Incidence Rates for CNS and Non CNS Progression from a Phase 1/2 Study (ID 12760)

      15:45 - 15:50  |  Author(s): Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Background

      The potent, selective, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) lorlatinib was designed to penetrate the blood-brain barrier (BBB). In a phase 1/2 study, lorlatinib showed robust clinical activity in patients with ALK-positive non-small cell lung cancer (NSCLC), most of whom had CNS metastases and failed ≥1 ALK TKI. In preclinical studies, lorlatinib demonstrated high BBB permeability with rapid brain uptake in vivo and significant activity against ALK-positive intracranial tumor models.1,2 To assess brain penetration of lorlatinib in a clinical setting, we report exploratory analyses from a phase 1/2 study (NCT01970865), evaluating CSF-to-plasma concentration ratios from a small sample of patients and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and deaths for pretreated patients with ALK-positive NSCLC ± baseline CNS metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Across the ongoing phase 1/2 study, 5 patients at lorlatinib 100 mg QD starting dose underwent CSF sampling. Patients with ALK-positive NSCLC with ≥1 prior ALK TKI were analysed for progressive disease, categorized as either CNS or non-CNS progression, based on independent central review. CIRs for patients in expansion cohorts EXP2–5 from the phase 2 portion of the phase 1/2 study (N=198) were calculated using competing risks methodology.

      4c3880bb027f159e801041b1021e88e8 Result

      In patients (n=5), mean CSF-to-plasma concentration ratio was 0.73 (SD 0.14). The table shows CIRs at 6 and 12 months.

      Months Cumulative Incidence Probability
      Patients with ≥1 prior ALK TKIa CNS Progression

      Non-CNS

      Progression

      Death
      All patients (n=198)

      6 mos

      12 mos

      0.13

      0.18

      0.25

      0.37

      0.05

      NE
      Patients with baseline CNS metastases (n=131)

      6 mos

      12 mos

      0.14

      0.22

      0.21

      0.31

      NE

      NE
      Patients with no baseline CNS metastases (n=67)

      6 mos

      12 mos

      NE

      NE

      0.32

      0.49

      0.05

      NE

      aPatients in expansion cohorts EXP2–5 from the phase 2 study

      NE, not evaluable
      8eea62084ca7e541d918e823422bd82e Conclusion

      Lorlatinib showed high BBB permeability as evidenced by a high mean CSF-to-plasma concentration ratio, in line with preclinical rat studies showing CNS penetration. This translated into high activity against CNS metastases as suggested by the numerically higher probability of the first progression event being extracranial rather than intracranial, including in patients with a history of CNS metastases.

      References

      1. Collier, et al. Mol Imaging 2017;16:1–3.

      2. Zou, et al. Cancer Cell 2015;28:70–81.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA12 - Novel Therapies in MET, RET and BRAF (ID 921)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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      OA12.01 - Phase II Data for the MET Inhibitor Tepotinib in Patients with Advanced NSCLC and MET Exon 14-Skipping Mutations (ID 12896)

      15:15 - 15:25  |  Presenting Author(s): Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Background

      A subset (3%) of NSCLCs harbor mutations of the MET proto-oncogene that cause MET exon 14 skipping (METex14) and accumulation of active MET lacking a juxtamembrane domain. We report interim data from a single-arm phase II trial (NCT02864992) investigating the efficacy and safety of the potent, selective tyrosine-protein kinase MET inhibitor tepotinib in patients with METex14-skipping mutation-positive (METex14+) NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Recruitment of ≤120 adult patients with advanced METex14+ NSCLC without EGFR-activating mutations or ALK rearrangements is ongoing. METex14+ mutations are identified in FPE tumor (T) material and/or plasma (L; 60 patients each, overlap anticipated) by a central laboratory. Patients receive tepotinib 500mg QD until disease progression, intolerable toxicity, or withdrawal. Primary endpoint: objective response rate (ORR). Secondary endpoints include safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Forty-one patients have been treated to date; data are available for 34 (median age 73.5 years; 23 male; 24/8 Caucasian/Asian; prior lines of therapy: 0, n=12; 1, n=11; 2, n=10; 3, n=1; stage IVA, n=4; stage IV, n=29; stage IIIB, n=1). Treatment is ongoing in 24 patients. Based on investigator assessment, 13/22 (59.1%) evaluable patients responded: 1 had a confirmed complete response; 12 had a confirmed partial response (PR); 3 (13.6%) had stable disease for ≥12 weeks (SD). Based on independent review, 9/22 (40.9%) had a confirmed PR; 5 (22.7%) had SD. Duration of response >12 months in 2 patients. Twenty (58.8%) patients have experienced tepotinib-related treatment-emergent adverse events (TRTEAEs), including serious TRTEAEs in 3 (8.8%): pneumonia =1, generalized oedema=1, interstitial lung disease=1, and grade ≥3 TRTEAEs in 6 (17.6%): generalized oedema=1, pneumonia=1, ALT increased=1, AST increased=1, amylase increased=2, gamma GT increased=1, lipase increased=1, hyperkalemia=1; no TRTEAEs were grade ≥4 or led to death. Five (14.7%) patients have died.

      0022_figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Tepotinib 500mg QD has promising activity in METex14+ NSCLC, with a favorable safety profile.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.09 - Pathology (Not CME Accredited Session) (ID 941)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.09-09 - Evaluation of a Novel ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in NSCLC Patients (ID 12744)

      16:45 - 18:00  |  Author(s): Enriqueta Felip

      • Abstract

      Background

      After the approval of crizotinib in ROS1 rearranged NSCLCs, the importance of accurately identifying those patients has never been greater. Although the recently updated guideline for molecular testing supports the use of ROS1 IHC as a screening test, to the best of our knowledge, only one ROS1 clone is commercially available and most published comparison studies involve a relatively small numer of positive cases. This situation prompted us to investigate a novel ROS1 IHC antibody in a large series of ROS1 positive NSCLCs samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Thirty-nine ROS1 FISH-positive (i.e., gold standard) samples from patients with NSCLCs procured at 22 hospitals were used for this study. In addition, 20 consecutive ROS1 FISH-negative samples from NSCLCs diagnosed at the referral institution were included as negative controls. The material available for all tumors had been formalin-fixed and paraffin-embedded. The specifics of formalin fixation were unknown. All specimens were independently screened for ROS1 expression by two IHC antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 provided by Ventana Medical Systems, Inc.) according to previously published methodology or the manufacturer´s instructions. FISH-validated ROS1-positive external controls were included in all the slides. The slides were reviewed by two pathologists blinded to FISH results. The results of both ROS1 IHC assays were evaluated using a modified H-score: strong cytoplasmic staining (3+), clearly visible using a ×2 or ×4 objective; moderate staining (2+), requiring a ×10 or ×20 objective to be clearly seen; and weak staining (1+), cannot be seen until a ×40 objective is used. Both anti-ROS1 IHC staining results were finally interpreted using a binary scoring system: positive (3+ or 2+) or negative (1+ or 0).

      4c3880bb027f159e801041b1021e88e8 Result

      In ROS1 FISH-negative cases, positive immunoreactivity (3+ or 2+) was observed in 25% and 5% of samples by SP384 and D4D6, respectively. In ROS1 FISH-positive cases, positive expression above the threshold was always present with both antibodies except for one sample that was only stained with SP384. In 4 positive cases (10.3%) by SP384 and 22 positive tumors (56.4%) by D4D6, we noted significant intratumoral heterogeneity, ranging from weak to strong protein expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have studied a very large series of ROS1 FISH-positive NSCLCs with a novel IHC clone, which showed excellent sensitivity. The predominantly homogeneous and intense staining may support the use of a dichotomous scoring approach, before confirmation with FISH or a molecular method.

      Funding: I+D+I 2013-2016/Feder. ISCIII: PI14/01176

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-36 - Randomized Phase 2 Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer (ID 13960)

      16:45 - 18:00  |  Author(s): Enriqueta Felip

      • Abstract
      • Slides

      Background

      Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3), to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized Phase 1/2 study evaluated safety and efficacy of seribantumab in combination with erlotinib in advanced NSCLC. Here, we report the activity of seribantumab in combination with erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab plus erlotinib or erlotinib alone. Patients underwent pre-treatment core needle biopsy, and archived tumor samples were collected to support pre-specified biomarker analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      One hundred twenty-nine patients received seribantumab/erlotinib (n=85) or erlotinib alone (n=44). Median estimated PFS in the unselected ITT population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (HR=0.822; 95% CI, 0.37 to 1.828; P=0.63). In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab/erlotinib combination (HR=0.35; 95% CI, 0.16 to 0.76; P=0.008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97 to 4.76; P = 0.059).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, pre-defined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial is validating this finding in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216).

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.03 - Biology (Not CME Accredited Session) (ID 952)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.03-02 - Cell-Free DNA (cfDNA) Testing in Lung Adenocarcinoma (LUAC) Patients: Spanish Lung Liquid Versus Invasive Biopsy Program (SLLIP) (ID 12561)

      16:45 - 18:00  |  Author(s): Enriqueta Felip

      • Abstract
      • Slides

      Background

      Liquid biopsies are a revolution in cancer diagnostics as a minimally invasive alternative to tissue biopsy. cfDNA is used for the detection of biomarkers in LUAC patients if a tumor tissue sample is not available. We conducted the SLLIP study to prospectively validate Guardant360 for the detection of 7 targetable activating alterations (EGFR, ALK, ROS1, BRAF, MET, RET, and ERBB2) in LUAC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Blood samples from treatment-naïve stage IIIB-IV LUAC patients were analyzed using Guardant360, a next-generation sequencing panel covering 73 genes. The assay includes complete exon sequencing for 19 cancer genes, sequencing of critical exons in 54 genes, and detection of amplifications (18 genes), fusions (6 genes), and indels (23 genes) with high overall clinical sensitivity rates (85%) and ultra-high specificity (>99.9%). Indels and point mutations can be detected at a mutant allele fraction as low as 0.1%. Guardant360 was compared with tissue genotyping performed as standard of care, using a variety of “real life” techniques. The primary objective was to demonstrate the non-inferiority of Guardant360 versus tissue analysis for the detection of the 7 genetic alterations. The study is registered with ClinicalTrials.gov, number NCT03248089.

      4c3880bb027f159e801041b1021e88e8 Result

      186 LUAC patients were enrolled over a period of 11 months (August 2016-July 2017). Median age 64, 65% male, 72% smoker/ex-smokers, 85% ECOG performance status 0-1. Targetable activating alterations were detected by the Guardant360 assay and by tissue analysis in 25% (n=47) and 26% (n=49) of patients, respectively (non-inferiority P=0.268). Thirty patients (16%) had alterations identified by both modalities. None of the 186 patients was successfully tested in tissue for all 7 alterations. Of the 17 patients who were negative in tissue but for whom Guardant360 identified targetable alterations, 3 had BRAF V600E mutations. For none of these patients was BRAF tested in tissue. Clinical efficacy per biomarker and treatment modality are awaited.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Guardant360 cfDNA and tissue analysis detect relevant somatic tumor alterations at similar rates in LUAC patients. Under-genotyping in tissue is common but can be mitigated by the use of cfDNA next generation sequencing assays.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-27 - Ph II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Pembrolizumab in Patients with Advanced NSCLC (ID 14307)

      16:45 - 18:00  |  Author(s): Enriqueta Felip

      • Abstract

      Background

      Bemcentinib (BGB324) is a first-in-class, highly selective oral inhibitor of the AXL tyrosine kinase currently in phase II clinical development across several cancer types. AXL overexpression has been observed in pts failing anti-PD-1 therapy in several cancers whereas AXL inhibition via bemcentinib has shown synergistic effect with checkpoint blockade in pre-clinical models of NSCLC.

      In pts with advanced, pre-treated NSCLC, bemcentinib monotherapy led to disease stabilisation in 2 out of 8 pts including evidence of tumour reduction. Combination therapy of bemcentinib with EGFR inhibition indicated the potential of AXL blockade to reverse resistance to targeted therapy in advanced EGFR therapy resistant NSCLC. Evidence of immune activation following bemcentinib monotherapy was observed in AML patients.

      This open label, single-arm, two-stage Phase 2 study was designed to test whether AXL inhibition may increase the efficacy of pembrolizumab in patients with advanced, previously treated adenocarcinoma of the lung.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with documented Stage IV adenocarcinoma of the lung who had progressed on previous platinum chemotherapy and – if applicable – at least one line of licensed EGFR or ALK targeted therapy, received 200 mg/d bemcentinib po and 200 mg/q3wk pembrolizumab iv. Patients were required to consent to a fresh pre-treatment biopsy. Tumour assessments were done 9-weekly. The primary endpoint was ORR. Tumour biopsies were analysed for PD-L1 and AXL as well as immune cell populations. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in patients pre-dose and at C2D1.

      4c3880bb027f159e801041b1021e88e8 Result

      As of time of writing, the study had fully recruited its first stage. Of 24 patients enrolled, 14 were ongoing. 6 of 10 patients who had reached their first scan showed evidence of tumour shrinkage including 3 pts with partial responses in their target lesions. 2 patients had stable disease. There were no grade 4 treatment-related events. Dose reduction from 200 to 100 mg/d of bemcentinib as a consequence of adverse events was required in 12% of patients. Correlation of AXL and PD-L1 expression with response was evaluated. Soluble AXL plasma levels were increased following one cycle of treatment indicative of target engagement.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A preliminary analysis of response to combination treatment during the first stage of this study as well as biomarker correlation will be presented at the meeting. Clinical trial information: NCT03184571

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-45 - SHERLOC: A Phase 2 Study of Seribantumab in Combination with Docetaxel in Patients with Heregulin Positive, Advanced NSCLC (ID 11349)

      16:45 - 18:00  |  Author(s): Enriqueta Felip

      • Abstract
      • Slides

      Background

      HER3 and its ligand, heregulin (HRG), have been identified as a critical activator of PI3K and Akt signaling and a key pro-survival pathway in cancer cells. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. Preclinical data suggest that seribantumab reverses HRG-mediated drug resistance across multiple cancer models. In retrospective analyses of prior seribantumab Phase 2 studies, high levels of HRG mRNA appeared to predict poor outcome to standard of care (SOC) treatment. Addition of seribantumab to SOC appeared to improve progression-free survival (PFS) in patients with HRG positive (HRG+) tumors, consistent with the hypothesis that the blockade of HRG-induced HER3 signaling by seribantumab can restore drug sensitivity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the current randomized, open-label, international, Phase 2 study, patients with locally advanced or metastatic NSCLC histologically classified as adenocarcinoma are screened for HRG using an RNA in situ hybridization assay on a recent biopsy tissue sample. Approximately 100 HRG+ patients will be enrolled and randomized in a 2:1 ratio to receive seribantumab plus docetaxel (experimental treatment Arm), or docetaxel alone (control Arm). Eligible patients must have no EGFR and ALK mutations and have progressed following one to two SOC for locally advanced and/or metastatic disease, including platinum-based therapy and anti-PD-1/PD-L1 therapy where available and clinically indicated. Primary trial endpoint is PFS. Secondary endpoints include overall survival, objective response rate, time to progression, and pharmacokinetic profile. The study has ≥ 80% power to detect a 3-month improvement in median PFS over 3 months (hazard ratio ≤ 0.50), using a one-sided, stratified log-rank test at a significance level of 0.025. Study is ongoing and enrolling patients in seventy nine sites worldwide. Clinical trial information: NCT02387216

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 965)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.16-03 - CheckMate 816: A Phase 3 Trial of Neoadjuvant Nivolumab Plus Ipilimumab or Chemotherapy vs Chemotherapy in Early-Stage NSCLC (ID 12599)

      16:45 - 18:00  |  Presenting Author(s): Enriqueta Felip

      • Abstract
      • Slides

      Background

      Approximately 20–25% of patients with NSCLC are diagnosed with early or localized disease, which has a relapse rate of 30–80% with surgery. Although neoadjuvant chemotherapy can reduce the risk of relapse, it only provides a pathological complete response (pCR; no viable tumor cells) rate of 4%. The neoadjuvant setting presents abundant tumor-associated neoantigens derived from the primary tumor that may allow immunotherapy to prime a long-lasting immune response. Clinical trial results support the use of immuno-oncology agents as neoadjuvant treatment for early-stage NSCLC. In a pilot study in patients with untreated, surgically resectable early-stage (stage I–IIIA) NSCLC, nivolumab (a fully human PD-1 immune checkpoint inhibitor antibody) administered as neoadjuvant treatment (3 mg/kg for 2 cycles during the 4 weeks prior to surgery) induced a pCR in 10% of patients and a major pathological response (MPR; ≤10% residual viable tumor cells in resected primary tumor) in 45% of patients, did not delay surgery, and was associated with an acceptable safety profile. Combining immuno-oncology agents with distinct mechanisms of action, such as PD-1 and CTLA-4 inhibitors, offers the possibility of a synergistic response and may improve antitumor activity compared with either agent alone. The combination of an immuno-oncology agent and chemotherapy may also offer synergistic activity, given that chemotherapy results in tumor cell death and subsequent antigen release that can activate an immune response. Promising results have been noted with nivolumab plus ipilimumab (a CTLA-4 immune checkpoint inhibitor antibody) and nivolumab plus chemotherapy in patients with treatment-naïve stage IIIB/IV NSCLC in the multicohort phase 1 CheckMate 012 study. CheckMate 816 (NCT02998528) is a phase 3 study evaluating nivolumab plus ipilimumab, nivolumab plus platinum-doublet chemotherapy, and platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Approximately 642 patients aged ≥18 years with early-stage (stages IB–IIIA) resectable NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, Asia, and Africa. Patients are ineligible if they have active autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Patients will be randomized (1:1:1) to receive neoadjuvant nivolumab plus ipilimumab, nivolumab plus platinum-doublet chemotherapy, or platinum-doublet chemotherapy. Primary endpoints are event-free survival and pCR. Key secondary endpoints are overall survival and MPR (<10% residual tumor in lung and lymph nodes). The start date was January 2017. The estimated primary completion date is May 2023.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-11 - Association of the Lung Immune Prognostic Index (LIPI) with Outcomes for Immune Checkpoint Inhibitors in Diffuse SCLC Patients (ID 14200)

      12:00 - 13:30  |  Author(s): Enriqueta Felip

      • Abstract

      Background

      Pretreatment LIPI (Lung Immune Prognostic Index), based on derived NLR (neutrophils/[leucocytes-neutrophils] ratio) and lactate dehydrogenase (LDH) has been associated with outcomes for immune checkpoint inhibitors (ICI) in advanced NSCLC patients. We tested whether LIPI has the same role in diffuse small cell lung cancer (SCLC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Baseline dNLR and LDH and clinical data were retrospectively collected in SCLC patients, treated with ICI (PD1 inhibitor, PDL1 inhibitors +/- CTLA4 inhibitor) from April 2014 to Jan. 2018 (N=66) from 6 European centers. LIPI was calculated combining dNLR and LDH, stratifying 3 risk groups: good (dNLR<3+LDH<upper limit of normal (ULN), intermediate (dNLR>3 or LDH>ULN), poor (dNLR>3+LDH>ULN). The primary endpoint was overall survival (OS), and secondary endpoint was progression-free survival (PFS).

      4c3880bb027f159e801041b1021e88e8 Result

      Fifty-three patients (80%) were males, 58 (88%) smokers and all patients had PS ≤1, with median age 63 years (41-82). PDL1 was ≥ 1% by immunohistochemistry in 6 patients, and unknown in 60 patients. The median of prior lines was 1 (0-6). Platinum-based therapy was the prior line in 63 (95%) patients, with ORR of 88%. The median PFS and OS with ICI were 2.7 months (m) [95% CI 1.87-4.43] and 10.3 m [95% CI 5.8-12.6]. dNLR was greater than 3 in 16 (25%) and LDH> Upper Limit of Normal (ULN) in 33 (50%) patients. Based on both, LIPI stratified the population in 3 groups: 26 patients as good (40%), 29 (45%) as intermediate and 10 (15%) as poor LIPI risk groups. LIPI was an independent factor for OS (HR 2.77, 95% CI 1.07-7.14, P=0.03) and PFS (HR 3.13, 1.37-7.16, P=0.01). Median OS for good, intermediate, and poor risk groups were 11.4 m [95% CI 5.5-27.3], 11 m [95% CI 6.8-not-reached (NR)] and 2.3 m [95% CI 0.7-NR], respectively (P=0.004). Median PFS for good, intermediate, and poor risk groups were 3 m [95% CI 1.9-12.6], 2.8 m [95% CI 1.6-6.0 and 1.2 m [95% CI 0.47-NR], respectively (P=0.004).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Baseline LIPI poor risk group is associated with poor outcomes for ICI in diffuse SCLC patients. LIPI effect in a validation cohort is currently evaluated.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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      PL02.03 - Brigatinib vs Crizotinib in Patients With ALK Inhibitor-Naive Advanced ALK+ NSCLC: First Report of a Phase 3 Trial (ALTA-1L) (ID 11155)

      08:30 - 08:40  |  Author(s): Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Background

      Brigatinib has robust efficacy in crizotinib-resistant ALK+ NSCLC, exhibiting median progression-free survival (mPFS) of 16.7 months. We report results of the first interim analysis from the ALTA-1L study of brigatinib vs crizotinib in ALK TKI-naive, ALK+ NSCLC (NCT02737501).

      This open-label, multicenter study enrolled patients with stage IIIB/IV ALK+ NSCLC based on local ALK testing (FDA approved/other). Eligible patients had ECOG PS 0–2, ≤1 prior systemic therapy for locally advanced/metastatic NSCLC, and no prior ALK inhibitor. Asymptomatic CNS metastases were allowed. All patients had systematic CNS imaging. Patients were randomized 1:1 to brigatinib 180 mg QD with 7-day lead-in at 90 mg or crizotinib 250 mg BID. Primary endpoint: blinded independent review committee (BIRC)-assessed PFS (RECIST v1.1). Secondary efficacy endpoints included BIRC-assessed objective response rate (ORR), intracranial ORR (iORR), and intracranial PFS (iPFS). Interim analyses were planned at 50% and 75% of planned PFS events (n=198).

      275 patients were randomized (brigatinib/crizotinib, n=137/138); median age (years) 58/60. 26%/27% received prior chemotherapy for advanced disease, and 29%/30% had baseline brain metastases. At data cut-off (19 February 2018), median follow-up brigatinib/crizotinib: 11.0/9.25 months; with 99 PFS events, brigatinib met the prespecified threshold for statistical superiority vs crizotinib in the primary endpoint, BIRC-assessed PFS (HR 0.49, 95% CI 0.33–0.74, log-rank P=0.0007); brigatinib mPFS was not reached (95% CI NR–NR) vs crizotinib 9.8 months (95% CI 9.0–12.9). Investigator-assessed PFS HR 0.45 (95% CI 0.30–0.68), log-rank P=0.0001. Table shows additional efficacy data. Most common treatment-emergent AEs grade ≥3: brigatinib: increased CPK (16.2%), increased lipase (13.2%), hypertension (9.6%); crizotinib: increased ALT (9.5%), AST (5.8%), and lipase (5.1%). Any grade ILD/pneumonitis: brigatinib, 3.7%; crizotinib, 2.2%. Discontinuations due to AE (brigatinib/crizotinib): 11.8%/8.8%.

      Brigatinib showed a statistically and clinically significant improvement in PFS compared with crizotinib in ALK inhibitor–naive ALK+ NSCLC.

      BIRC-Assessed Endpoint, %

      Brigatinib

      (n=137)

      Crizotinib

      (n=138)

      P-Value
      All patients
      ORRa 76 (68–83b) 73 (65–80b)
      Confirmed ORR 71 (62–78b) 60 (51–68b) 0.0678
      With any intracranial CNS metastases
      (n=43) (n=47)
      iORRa 79 (64–90b) 23 (12–38b)
      Confirmed iORR 67 (51–81b) 17 (8–31b) <0.0001
      Median iPFS, months NR (11–NRb) 6 (4–9b)
      1-year iPFS 67 (47–80b) 21 (6–42b)
      HR 0.27 (0.13–0.54) <0.0001c
      With measurable intracranial CNS metastases
      (n=18) (n=21)
      iORRa 83 (59–96b) 33 (15–57b)
      Confirmed iORR 78 (52–94b) 29 (11–52b) 0.0028
      aResponse, ≥1 assessment; b95% CI; cLog-rank.

      a9ded1e5ce5d75814730bb4caaf49419

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