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Jose M Pacheco



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    FP03 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) (ID 151)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP03.05 - TLR9 Agonist CMP-001 Plus Atezolizumab +/- Radiation Therapy in Patients With PD-1 Blockade Resistant Advanced NSCLC (ID 3571)

      00:00 - 00:00  |  Author(s): Jose M Pacheco

      • Abstract
      • Presentation
      • Slides

      Introduction

      Patients with non–small cell lung cancer (NSCLC) and progressive disease (PD) following programmed death 1 (PD-1) blockade therapy have a poor prognosis. CMP-001 is a CpG-A Toll-like receptor 9 (TLR9) agonist packaged within a virus-like particle. The multicenter, open-label, 2-part, Phase 1b CMP-001-003 study (NCT03438318) evaluated the safety and preliminary antitumor activity of CMP-001 plus atezolizumab with or without radiation in patients with advanced NSCLC.

      Methods

      Eligible patients with PD following anti–PD-1/programmed death ligand 1 (PD-L1) therapy and ≥1 extra-central nervous system, non-bone metastasis amenable for intratumoral injection received CMP-001 and atezolizumab (Part A) or CMP-001, atezolizumab, and radiation (Part B). CMP-001 was administered at 5 mg subcutaneously once weekly during weeks 1 and 2, followed by 5 mg or 10 mg intratumorally once weekly during weeks 3-5 and every 3 weeks thereafter. Atezolizumab 1200 mg was administered intravenously once every 3 weeks starting on week 2. Radiation therapy in Part B consisted of 20 Gy delivered in 5 fractions starting ≥2 days prior to CMP-001 treatment. Following a safety run-in period (n=5), each Part enrolled additional patients in Stage 1; ≥2 of 12 patients were required to have a RECIST v1.1 response to proceed with Stage 2 enrollment. The primary objective was to evaluate the safety of CMP-001 and atezolizumab with or without radiation. A key secondary endpoint was best objective response per RECIST v1.1 as assessed by the investigator.

      Results

      Twenty-nine patients were enrolled in Stage 1 (Part A, n=13; Part B, n=16). The median number of prior lines of therapy received was 3 (range, 1-6); 31.0% of patients had ≥4 prior lines of therapy. Only 5 patients (17.2%) had response to any prior systemic therapy. The median number of CMP-001 intratumoral injections was 3 (Part A range, 1-12; Part B range, 1-6); 12 patients had a total of 65 injections into visceral lesions, including kidney, liver, lung, and pleura, which were safely performed. The most common treatment-related adverse events (TRAEs; ≥30%) overall were flu-like symptoms (ie, chills and pyrexia) and hypotension. Six patients (46.2%) in Part A and 8 patients (50.0%) in Part B had grade ≥3 TRAEs. Only 1 patient discontinued treatment due to TRAEs (Part A, grade 3 pneumonitis). As of April 15, 2020 (Part A median follow-up, 1.9 months [range, 1-19]; Part B median follow-up, 1.7 months [range, 1-4]), no objective responses were observed. Two patients (15.4%) and 4 patients (25.0%) had tumor shrinkage (<30% decrease in tumor size) in Parts A and B, respectively. Three patients (23.1%) and 8 patients (50.0%) had stable disease as best response in Parts A and B, respectively. Study enrollment was stopped after completion of Stage 1 due to lack of objective response. The cytokine response to CMP-001 treatment and tissue biopsy analyses will be presented.

      Conclusion

      CMP-001 plus atezolizumab with and without radiation therapy had a manageable safety profile. Intratumoral injection of CMP-001 into visceral lesions was safely achieved, and stable disease was observed in heavily pretreated patients with PD-1/PD-L1 refractory NSCLC.

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    MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      MA11.03 - Trastuzumab Deruxtecan in HER2-Mutated Metastatic Non-Small Cell Lung Cancer (NSCLC): Interim Results of DESTINY-Lung01 (ID 1587)

      14:15 - 15:15  |  Author(s): Jose M Pacheco

      • Abstract
      • Slides

      Introduction

      Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a phase 1 trial, patients with HER2-mutated non-small cell lung cancer (NSCLC) who received T-DXd had a confirmed objective response rate (ORR) of 72.7% (8/11) (Tsurutani et al, Cancer Discov 2020). DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase 2 study of T-DXd in patients with non-squamous NSCLC overexpressing HER2 or containing a HER2-activating mutation. We report data for the cohort with HER2-activating mutations after a median follow-up of 8.0 mo (range, 1.4-14.2 mo). This abstract was previously presented at ASCO 2020.

      Methods

      Patients were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR (complete response [CR] + partial response [PR]) by independent central review (ICR). Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety.

      Results

      Updated data to be presented at the meeting. At data cutoff (25 Nov 2019), 42 patients (64.3% female) had received T-DXd. Median age was 63.0 years (range, 34-83 years; < 65 y, 59.5%); 45.2% had CNS metastases; ECOG performance status was 0 in 23.8% of patients and 1 in 76.2%. HER2 mutations were predominantly in the kinase domain (90.5%). Most patients (90.5%) had prior platinum-based chemotherapy and 54.8% had anti–PD-1 or –PD-L1 treatment. The median number of prior treatment lines was 2 (range, 1-6). Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of patients remained on treatment.

      Confirmed ORR by ICR among the 42 patients was 61.9% (95% CI, 45.6%-76.4%). At data cutoff, median DOR was not reached, and 16 of 26 responders remained on treatment. DCR was 90.5% (95% CI, 77.4%-97.3%) and estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo).

      All patients (42/42) had treatment-emergent adverse events (TEAEs); 64.3% were grade ≥ 3 (52.4% drug-related), including decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (all grade 2, no grade ≥ 3) and 1 case of grade 1 ILD is pending adjudication. TEAEs led to dose interruption in 25 patients (59.5%), dose reduction in 16 patients (38.1%), and treatment discontinuation in 10 patients (23.8%).

      Conclusion

      T-DXd demonstrated promising clinical activity with high ORR and durable responses in patients with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies.

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    OA04 - New Data from Rare EGFR Alterations (ID 223)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      OA04.05 - Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Interim Results of DESTINY-Lung01 (ID 1419)

      11:45 - 12:45  |  Author(s): Jose M Pacheco

      • Abstract
      • Presentation
      • Slides

      Introduction

      Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase 2 study evaluating T-DXd in 2 separate cohorts of patients with unresectable and/or metastatic nonsquamous non-small cell lung cancer (NSCLC): overexpressing HER2 (centrally confirmed, IHC 2+ or 3+) or containing a HER2-activating mutation. We have previously shown promising activity of T-DXd in patients with HER2-mutated NSCLC (confirmed objective response rate [cORR] by independent central review [ICR], 61.9%; Smit ASCO 2020). Here we report data from an interim analysis of the HER2-overexpressing cohort.

      Methods

      Patients with HER2-overexpressing metastatic NSCLC were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was ORR (CR + PR) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety.

      Results

      At data cutoff (May 31, 2020), 49 patients had received T-DXd. Median age was 63 years (range, 37-85 years); 61.2% were male; 34.7% had CNS metastases at enrollment; 32.7% were never-smokers. 79.6% of patients (n=39) had HER2 IHC 2+ and 20.4% (n = 10) had HER2 IHC 3+. 91.8% of patients had received prior platinum-based chemotherapy and 73.5% had received anti−PD-1/PD-L1 treatment; median number of prior regimens was 3 (range, 1-8). Median treatment duration was 18.0 weeks (range, 3.0-57.1 weeks); 22.4% of patients remained on treatment.

      Confirmed ORR by ICR was 24.5% (95% CI, 13.3%-38.9%), including 1 CR and 11 PRs; IHC 2+, 25.6% (95% CI, 13.0%-42.1%); IHC 3+, 20.0% (95% CI, 2.5%-55.6%). Median DOR was 6.0 months (95% CI, 3.2-NE months); DCR was 69.4% (95% CI, 54.6%-81.8%); estimated median PFS was 5.4 months (95% CI, 2.8-7.0 months).

      All patients had ≥ 1 treatment-emergent adverse event (TEAE); the most common any-grade TEAEs were nausea (59.2%), decreased appetite (38.8%), and fatigue (32.7%). Grade ≥ 3 TEAEs were reported in 73.5% of patients (55.1% drug-related); the most common were decreased neutrophil count (20.4%) and fatigue (10.2%). There were 8 cases (16.3%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (grade 1, n = 2; grade 2, n = 3; grade 5, n = 3). TEAEs were associated with dose interruption in 26 patients (53.1%), dose reduction in 17 patients (34.7%), and treatment discontinuation in 11 patients (22.4%).

      Conclusion

      In this interim analysis, T-DXd demonstrated preliminary evidence of antitumor activity in heavily pretreated patients with HER2-overexpressing NSCLC. The safety profile of T-DXd was generally manageable, but ILD remains a known serious risk that requires proactive monitoring and care. An additional cohort to evaluate T-DXd 5.4 mg/kg in patients with HER2-overexpressing NSCLC has opened and started enrollment to further understand and characterize the safety and efficacy profile of T-DXd in this population.

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