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Lyudmila Bazhenova



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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA13.12 - Discussant - MA13.09, MA13.10, MA13.11 (Now Available) (ID 3774)

      14:00 - 15:30  |  Presenting Author(s): Lyudmila Bazhenova

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.01 - A Phase III Randomized Study of Nivolumab/Ipilimumab vs Nivolumab for Previously Treated Stage IV Squamous Cell Lung Cancer (Now Available) (ID 872)

      15:15 - 16:45  |  Presenting Author(s): Lyudmila Bazhenova

      • Abstract
      • Presentation
      • Slides

      Background

      Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. (Lung-MAP Sub-Study S1400I, NCT02785952)

      Method

      S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity.

      Result

      From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). Median follow up for patients still alive was 17.4 months. The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. The response rate was 18% (12-25) in N+I and 17 % (11, 24) in N. Outcomes were similar across TMB subgroups and PD-L1 expression levels. Most AE were low grade. There were 5 grade 5 AE in N+I arm and 1 in N arm. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% of pts on N+I and 16% of pts on N.

      OS and PFS based on TMB and PD-L1

      N+I

      Median in months

      N

      Median in months
      HR p
      OS PD-L1 ≥5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86
      OS PD-L1 <5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97
      OS TMB ≥10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48
      OS TMB <10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74
      PFS PD-L1 ≥ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10
      PFS PD-L1 <5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06
      PFS TMB ≥ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15
      PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

      Conclusion

      S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Molecular correlates will be presented at the meeting.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-127 - Antitumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 in NSCLC with EGFR Exon 20 Insertions (ID 1302)

      09:45 - 18:00  |  Author(s): Lyudmila Bazhenova

      • Abstract
      • Slides

      Background

      We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor.

      Method

      Patients with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for patients with EGFR exon 20 insertions who received TAK-788 160 mg QD. Safety is reported for all patients across all doses and at 160 mg. To improve gastrointestinal tolerability, food intake instructions in this ongoing study were amended to allow for administration with or without a low-fat meal based on emerging clinical pharmacokinetic data in a healthy volunteer study (data on file).

      Result

      As of 14 Sep 2018, 101 patients (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg QD. RP2D was determined to be 160 mg QD. 28 patients with EGFR exon 20 insertions were treated with 160 mg QD during dose escalation or in expansion cohort 1 (3.6 months on treatment; 3.8 treatment cycles [medians]); 24 patients remain on treatment. At data cutoff, best response (RECIST v1.1) among 26 patients with ≥1 disease assessment was PR, n=14; SD, n=9; and PD, n=1 (objective response rate, 54%; 95% CI: 33.4%–73.4%); 2 patients were unevaluable. 7/14 objective responses (all PR) were confirmed (6 awaiting confirmation; 1 unconfirmed PR at 160 mg QD); median time to response in these 14 patients was 56 days. 23/26 patients (89%; 95% CI: 69.9%–97.6%) achieved disease control. 23/24 evaluable patients with EGFR exon 20 insertions treated at 160 mg QD had decreased target lesion measurements (median best percent change, -32.6% [-79.1%–3.8%]). Most common TEAEs (≥20%) in patients treated with 160 mg QD: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), stomatitis (22%); grade ≥3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, stomatitis (7% each). Among patients treated with 160 mg QD, median dose intensity was 93%, rate of dose reduction due to AEs was 21.7%, and rate of treatment discontinuation due to AEs was 10.9%. There was no clear trend that response to TAK-788 was enriched in any single EGFR exon 20 insertion variant.

      Conclusion

      In NSCLC patients with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and a safety profile consistent with other EGFR TKIs.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-57 - Post-Ensartinib Outcomes in Refractory Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID 2800)

      09:45 - 18:00  |  Author(s): Lyudmila Bazhenova

      • Abstract
      • Slides

      Background

      The effectiveness of the next-generation ALK inhibitor, ensartinib, in refractory ALK-rearranged, advanced NSCLC patients represents a promising therapeutic option. With the advent of novel ALK inhibitors utilized in sequence, the survival of patients with ALK-rearranged tumors has improved dramatically. This case series serves to compare tumor response rates and long-term survival outcomes among four patients treated with ensartinib over the course of four years at our institution.

      Method

      We conducted an open-label, first-in-human, IRB approved phase 2 clinical trial using single-agent ensartinib at a dose of 225 mg once daily. Patients were selected from UC San Diego Moores Cancer Center with ALK-rearranged NSCLC who had previously progressed on crizotinib. Other prior therapies included platinum/pemetrexed chemotherapy (n=3) and pembrolizumab (n=1). Objective response was determined every eight weeks according to RECIST 1.1. Patients were treated until disease progression or unacceptable toxicity. Circulating tumor DNA (ctDNA) sequencing was obtained in 3 patients at baseline and 2 patients at the time of progression.

      Result

      Four patients were enrolled (age range, 43-61 years) and all had brain metastases at baseline. All four patients achieved an objective partial response to ensartinib, including one patient with an acquired ALK F1174V crizotinib resistance mutation. Intracranial responses included one partial response, two stable disease, and resolution of a non-target lesion in another patient. The median progression free survival was 12.5 months (range, 8-15 months) and the median decrease in tumor size was 42% (range, 39-48%). Primary sites of disease progression included lung (n=1), brain (n=2), both lung and brain (n=1). No somatic alterations were identified in the two patients who received post-ensartinib ctDNA sequencing. At progression, all patients received brigatinib as subsequent therapy with clinical benefit; one received lorlatinib after brigatinib failure and response is ongoing. Median post-ensartinib survival was 27 months (range, 20-38 months). Two patients remain alive 27 and 95 months after first anti-cancer therapy. The most common adverse events with ensartinib were mild rash, diarrhea, and fatigue that did not require dose reduction.

      Conclusion

      Ensartinib is well tolerated and has clinical activity in advanced ALK-rearranged NSCLC patients with brain metastases, despite previously progressing on crizotinib, with durable post-ensartinib survival on subsequent next-generation ALK inhibitors such as brigatinib and lorlatinib. (Trial funded by Xcovery Holdings, Inc.; ClinicalTrials.gov number: NCT01625234)

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-23 - DUBLIN-3, a Phase (Ph) III Trial Comparing the Plinabulin (P)/Docetaxel(D) Combination with D Alone in Stage IIIb/IV NSCLC (Now Available) (ID 476)

      10:15 - 18:15  |  Author(s): Lyudmila Bazhenova

      • Abstract
      • Slides

      Background

      In 2018, practice patterns changed in untreated metastatic NSCLC, as platinum-based chemotherapy (Chemo) started to be combined with pembrolizumab. Prior to 2018, checkpoint inhibitors (C-I) were given sequentially with Chemo. In C-I refractory metastatic NSCLC, single agent D is standard of care. Although effective, D induces AEs (Neutropenia (N) that may require dose reduction to sub-therapeutic levels. The addition of Plinabulin (P) to D (D+P) reduced D-induced grade 4 (Gr4) N (frequency of 33% vs 5% for D vs D+P; p<0.0003) and thrombocytopenia (P<0.02) vs D alone (Blayney ASH 2018; IASLC 2018) in Ph 2. Importantly, P added to D improved median overall-survival (OS) with 4.6-month, and duration of response (DoR) with 1-year (p<0.05) vs D alone (Mohanlal ASCO-SITC 2017) in pts with a measurable lesion (per RECIST 1.1) located in the lung. P induces Dendritic Cell (DC) maturation and CD40 upregulation and facilitates DC-dependent T-cell proliferation in an antigen (Ag) specific manner (Lloyd AACR 2016). Therefore, P is predicted to be the most effective in a setting that harbors novel Ags, that can stimulate the immune system. Subclonal lung lesions can induce novel Ags (De Bruin Science 2014), but clonal lung lesions can also harbor Ags that can stimulate the immune system, as long as immune tolerance is not yet developed. There is a high concordance in mutation status (thus Ags) between clonal primary and metastatic lesions in NSCLC (Sherwood J Exp & Clin Canc Res 2015), but the distant lesions had more time to induce immune tolerance development. Hence, we required the presence of measurable lesion present in the lung in DUBLIN-3. We combined P with D since D can release Ags which in turn can be presented by P-modulated DCs to cytotoxic CD8 T-cells.

      Method

      DUBLIN-3 (NCT02504489), is an ongoing global PhIII study in EGFR wild-type advanced or metastatic NSCLC pts (target n=554) receiving 2nd- or 3rd-line systemic therapy with D+P or D in a 1:1 ratio. The primary endpoint is OS. Key secondary endpoints are incidence of Gr 4 N on day 8 of Cycle 1, D dose modification due to N, QoL (EORTC QLQ-C30), ORR, PFS, and DoR. The study is single-blinded (for pts) to more reliable allow for QoL assessments. Pts must have at least one measurable lesion located in the lung and must have failed a prior platinum-based regimen. Prior PD1/PD-L1 use is allowed. A pre-specified first Interim Analysis (IA) occurred at reaching ~150 events and a second pre-specified IA is to occur at ~ 300 events.

      Result

      ~400 patients have been enrolled to date with more than 200 events achieved. Based on the data at the 1st IA, the study will continue, unmodified, to the 2nd IA.

      Conclusion

      The D+P combination holds the promise of a novel 2nd or 3rd line treatment option with superior efficacy and safety over D alone. The 2nd IA of DUBLIN-3 is expected to occur later in 2019.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Lyudmila Bazhenova

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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