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Frank Griesinger



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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  |  Author(s): Frank Griesinger

      • 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.

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      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • 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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      P1.01-82 - Risk of Not Receiving 2nd Line Therapy is High in EGFR mt+ pts: Real World Data of Certified Lung Cancer Centers on Treatment Sequence in EGFR mt+ pts (ID 13238)

      16:45 - 18:00  |  Author(s): Frank Griesinger

      • Abstract
      • Slides

      Background

      Recently FLAURA study demonstrated significant PFS and numeric OS benefit for Osimertinib 1st line vs. 1st generation TKI’s Erlotinib/Gefitinib. The number of patients switching from 1st generation to 3rd gen. TKI (30%) appeared to be low and it is questionable whether these data represent real world sequencing treatment patterns. Therefore, we investigated the sequence pattern, i.e. the percentage of 2nd line therapy in EGFR mt+ patients in 3 certified lung cancer centers in Germany.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data of 912 of 1477 patients tested for EGFR mutations (treated in Oldenburg, Bremen, Hamburg) were analyzed between 2009-2017. 140/144 patients with an activating EGFR mutation (16%) and treated with systemic therapy (4 patients received no therapy) were identified and their treatments were captured as well as their outcome. 36 patients were treated before accessibility to 3rd generation TKI and 104 patients after accessibility to 3rd generation TKI.

      4c3880bb027f159e801041b1021e88e8 Result

      130/140 patients were treated with 1st line TKI and 10 received 1st line chemotherapy. 17 patients are still on 1st line TKI, 8 patients were lost to follow-up, 3 patients died while on 1st line TKI. 112 patients were candidates for 2nd line therapy. 34/112 (30%) of these patients did not receive 2nd line therapy. Causes for not receiving 2nd line therapy were patients refusal (n=2), bad PS (n=26) frequently due to CNS metastases, fast progression and death (n=6). After accessibility of 3rd generation TKI, 20 of 66 (30%) patients did not receive 2nd line therapy. Median OS of the overall cohort was 27 months (n=140), median OS of patients receiving 2nd line (n=78) vs. no 2nd line (n=62) was 36 vs. 14 months (p<0.0001). After accessibility of 3rd generation TKI 30/104 patients (29%) receive a 3rd generation TKI after 1st line or 2nd line therapy. Median OS of patients receiving (n=30) and not receiving 3rd generation TKI (n=110) was 55 months vs. 22 months (p<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In real world, a significant number of patients treated with 1st or 2nd generation TKI do not reach 2nd line therapy even when 3rd generation TKI were accessible. Reasons for not receiving 2nd line therapy are in most cases deterioration of PS and lack of possibility to test for T790M in the minority of cases (n=28/66, 42% were not tested). These data, although favorable for the small and very selected cohort of patients treated with Osimertinib, might argue for the most effective therapy in 1st line for patients with EGFR mt+ tumors.

      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): Frank Griesinger

      • 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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