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Melissa L Johnson



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    ES14 - Novel Immunotherapy Strategies in NSCLC (ID 184)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
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      ES14.02 - Cellular Therapies in NSCLC (ID 4015)

      11:45 - 12:45  |  Presenting Author(s): Melissa L Johnson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immune Effector Cellular Therapies (IECT) are a promising approach to triggering anti-cancer immunity in which autologous T-cells are harvested from a patient, modified ex vivo to express either a CAR (chimeric antigenic receptor) or TCR (T-cell receptor) construct, enabling the modified T-cells to efficiently identify cancer cells once reintroduced into the lymphodepleted patient. CAR T-cell therapies recognize extra-cellular antigens, while TCR therapies can recognize a wider variety of intra-cellular targets, provided they are expressed via permissive HLA molecules. CAR T-cell therapies have received FDA approval for diffuse large B-cell and mantle cell lymphoma as well as pediatric B-cell acute lymphoblastic leukemia. However, development of analogous therapies for patients with solid tumors has been more challenging for a number of reasons including identification of appropriate tumor-associated antigens, enabling the CAR T-cells to traverse from the blood stream into the tumor, as well as surviving in the highly acidic and immunosuppressive tumor microenvironment. As a result, hundreds of prospective CAR and TCR therapies for solid tumors are being developed, many of which are now reaching the clinical development stage.1 While the first generation of solid tumor CAR and TCR trials were largely limited by severe “on-target, off-tumor” toxicities, the current generation of IECT agents appear more tolerable, although associated with expected consequences of cytokine release syndrome and neurotoxicity,2 or challenged by limited persistence after infusion. Mesothelin-targeted CAR T cells have been safely delivered into the pleural space, alone and in combination with pembrolizumab for patients with malignancy mesothelioma with impressive preliminary disease responses.3 Both ADP-A2M4 SPEAR T-cells and next-generation ADP-A2M4CD8 SPEARMAGE-A4-directed TCRs have demonstrated safety and preliminary efficacy when administered in HLA-A*02 positive solid tumor patients whose tumors express MAGE-A4. 4-5 Practical considerations, including efficient screening for tumor antigens and identification of appropriate HLA phenotypes, not to mention appropriate management of the unique adverse events associated with IECT, are also important factors for the on-going development, and ultimate approval of cellular therapies for solid tumor patients.

      Xin Yu J, Hubbard-Lucey VM, Tang J. The Global Pipeline of Cellular Therapies For Cancer. Nature Reviews Drug Discovery 18(11) 2019.

      Wagner J, Wickman E, DeRenzo C et al. CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality? Molecular Therapy 2020 28:11, 2320-2339

      Adusumilli PS, Zauderer MG, Rusch VW, et al. Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent. Journal of Clinical Oncology 2019 37:15_suppl, 2511-2511.

      Hong DS, Van Tine BA, Olszanski AJ, et al. Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors.
      J Clin Oncol 38: 2020 (suppl; abstr 102).

      Hong DS, Clarke J, Johanns T, et al. : Initial safety, efficacy, and product attributes from the SURPASS trial with ADPA2M4CD8, a SPEAR T-cell therapy incorporating an affinity optimized TCR targeting MAGE-A4 and a CD8α co-receptor

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    OA03 - Promising Antibody-Drug Conjugate and Cytotoxic Therapy in NSCLC (ID 100)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 2
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      OA03.03 - Datopotamab Deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in Patients With Advanced NSCLC: Updated Results of TROPION-PanTumor01 Phase 1 Study (ID 3407)

      10:30 - 11:30  |  Author(s): Melissa L Johnson

      • Abstract
      • Presentation
      • Slides

      Introduction

      Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein that is overexpressed in NSCLC and other solid tumors. DS-1062 is a TROP2 directed ADC comprising a novel topoisomerase 1 inhibitor (exatecan derivative, DXd), a tetrapeptide-based linker, and a TROP2 directed monoclonal antibody. DS-1062 has demonstrated promising safety and antitumor efficacy in an ongoing phase 1 study in patients with advanced/metastatic NSCLC (NCT03401385); the MTD was declared as 8.0 mg/kg. The study was expanded to include 80 patients at 8 mg/kg and 50 patients each at 4 mg/kg and 6 mg/kg. Updated interim results for 133 patients treated at these doses are reported here.

      Methods

      Eligible patients were aged ≥18 (US) or ≥20 (Japan) years with advanced/metastatic NSCLC refractory to/relapsed from standard treatment, had measurable disease per RECIST v1.1, and had tumor tissue available for retrospective TROP2 analysis (eligible regardless of TROP2 expression level). Primary objectives are identification of the maximum tolerated dose, safety, and tolerability. Secondary objectives include efficacy (including response by blinded independent central review [BICR]), pharmacokinetics, and incidence of antidrug antibodies.

      Results

      As of June 15, 2020, 133 patients were treated with ≥1 dose of DS-1062 at 4.0 mg/kg (n = 29), 6.0 mg/kg (n = 24), and 8.0 mg/kg (n = 80). Patients received a median of 4 cycles (range, 1-26) of DS-1062 (1 cycle = 21 days). At study entry, 108 (81%) had received prior immunotherapy and 119 (90%) had received prior platinum-based chemotherapy (preliminary); 126 (95%) had stage IV disease; and 117 (88%) and 15 (11%) had nonsquamous and squamous NSCLC, respectively. In 125 response-evaluable patients (≥1 post baseline tumor assessment or discontinued study treatment), 1 had a confirmed complete response (CR; at 6.0 mg/kg) by BICR, and 32 had partial responses (PRs) by BICR (8 PRs in 29 patients at 4.0 mg/kg, 4 PRs in 20 patients at 6.0 mg/kg, and 20 PRs in 76 patients at 8.0 mg/kg); 29 CRs/PRs were confirmed, and 4 are awaiting confirmation. Among 29 confirmed responders, the probability of having an ongoing response at 6 months was >80% (based on the Kaplan-Meier method). Disease control rate (confirmed CR/PR + stable disease) was 79% (95% confidence interval [CI], 60.3%-92.0%) at 4.0 mg/kg, 75% (95% CI, 50.9%-91.3%) at 6.0 mg/kg, and 79% (95% CI, 68.1%-87.5%) at 8.0 mg/kg. Any-grade treatment-emergent adverse events (TEAEs) were reported in 128 patients (96%); most frequent TEAEs (≥30%) included nausea (50%), stomatitis (44%), alopecia (40%), and fatigue (33%). Sixty-four patients (48%) experienced grade ≥3 TEAEs (most frequently dyspnea [5%]). There were 12 patients (9%) with interstitial lung disease adjudicated by an independent adjudication committee as treatment related (1 [4%] at 6.0 mg/kg [G2] and 11 [14%] at 8.0 mg/kg [7 at G1-2 and 4 at G3-5]). Fourteen patients [11%] discontinued treatment because of TEAEs. At data cutoff, 49 patients (37%) remained on study treatment. Updated results will be presented.

      Conclusion

      DS-1062 demonstrated encouraging antitumor activity across doses in pretreated patients with prior progression on standard treatment, accompanied by a manageable safety profile.

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      OA03.04 - Efficacy and Safety of the Novel HER3 Directed Antibody Drug Conjugate Patritumab Deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC (ID 3562)

      10:30 - 11:30  |  Author(s): Melissa L Johnson

      • Abstract
      • Presentation
      • Slides

      Introduction

      There are few treatment options for patients with advanced EGFR-mutated (EGFRm) NSCLC after failure of EGFR TKIs and platinum-based chemotherapy. Here we report safety and activity in such patients treated in a phase 1 study (NCT03260491) with patritumab deruxtecan, a HER3 directed antibody drug conjugate, at the 5.6 mg/kg recommended dose for expansion. These data were previously presented at ESMO Congress 2020, Helena A. Yu et al., reused with permission.

      Methods

      The dose escalation part was presented previously. The dose expansion part enrolled patients with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy. Primary objective is assessment of activity by confirmed ORR (blinded independent central review, BICR); secondary objectives include evaluation of safety. Patritumab deruxtecan was administered IV Q3W.

      Results

      As of 30 April 2020, 57 patients from dose escalation and dose expansion were treated at the 5.6 mg/kg dose, and 56 patients were evaluable for response. Among 28 patients continuing treatment at data cut-off, 6 had only 1 tumor evaluation. Median prior anticancer regimens for metastatic disease was 4 (range, 1-9); 51 patients [90%] received prior platinum-based chemotherapy. Median number of prior EGFR TKIs was 2 (range, 1-4); 49 patients [86%] received prior osimertinib. 27 patients (47%) had history of central nervous system metastases. Median treatment duration was 3.5 months (range, 1-14 months); median follow up was 5.4 months (range, 0.3-15 months). The most common grade ≥3 treatment-emergent adverse events were platelet count decrease (25%) and neutrophil count decrease (16%). Efficacy for the 56 efficacy-evaluable patients is shown in the table below; 3 additional patients had partial response awaiting confirmation. HER3 was expressed in nearly all tumors. Efficacy was observed in patients with various mechanisms of EGFR TKI resistance, including EGFR C797S mutation, MET amplification, HER2 mutation, BRAF fusion, and PIK3CA mutation.

      Conclusion

      Patritumab deruxtecan at 5.6 mg/kg provides promising evidence of preliminary antitumor activity and safety in heavily pre-treated patients with locally advanced or metastatic EGFRm NSCLC.

      Activity According to BICR Evaluation (Efficacy-Evaluable Population)

      Dose escalation + dose expansion cohorts

      EGFR mutated, 5.6 mg/kg patritumab deruxtecan

      (N = 56)a

      Confirmed BOR, n/N (%)

      CR

      1/56 (2)

      PR

      13/56 (23)

      SD

      25/56 (45)

      PD

      9/56 (16)

      NE

      8/56 (14)

      Confirmed ORR, n/N (%)

      95% CI

      14/56 (25)

      (14.4-38.4)

      DCR, n/N (%)

      95% CI

      39/56 (70)

      (55.9-81.2)

      DoR (95% CI) in months, median (range)

      7 (3.0-7.0)

      a22/56 (39%) patients had best percentage decrease in sum of tumor diameters ≥ 30%.

      BOR, best overall response; ORR, objective response rate; CR, complete response; DCR, disease control rate; DoR, duration of response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

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    OA11 - A Symphony of Progress (ID 229)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
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      OA11.03 - A Phase 1 Study of AMG 757, Half-Life Extended Bispecific T-Cell Engager (BiTE®)Immune Therapy Against DLL3, in SCLC (ID 3414)

      15:30 - 16:30  |  Author(s): Melissa L Johnson

      • Abstract
      • Presentation
      • Slides

      Introduction

      Delta-like ligand 3 (DLL3), an inhibitory Notch ligand that is highly expressed in small cell lung cancer (SCLC) compared to normal tissues, is a potential therapeutic target.1 AMG 757, a half-life extended BiTE® immune therapy, binds DLL3 on tumor cells and CD3 on T cells, leading to T cell‑dependent killing of tumors. Emerging data from the ongoing phase 1 study of AMG 757 in SCLC are reported (NCT03319940).

      Methods

      AMG 757 (0.003–10.0 mg) was administered intravenously every two weeks with/without step dose. Eligible patients had SCLC that progressed or recurred following ≥1 platinum-based regimen. Antitumor activity was assessed using modified RECIST 1.1. Tumor DLL3 expression was assessed by immunohistochemistry. T-cell activation and cytokine profiles pre and post AMG 757 treatment were evaluated.

      Results

      As of 7 August 2020, 40 patients (median age [range], 64 years [44–80]; ECOG PS: 0-1, n=39 [97.5%], median prior lines: 2.0 [1–6]; prior PD-1/PD-L1 treatment: n=17 [42.5%]) enrolled at eight dose levels (DL) received ≥1 AMG 757 dose. Median treatment duration was 6.1 weeks (0.1–59.4). Adverse events occurred in 39 (97.5%) patients, resulting in discontinuation in 4 (10.0%); 32 (80.0%) were treatment-related, including 7 (17.5%) grade ≥3 and 1 (2.5%) grade 5 (pneumonitis; DL5 [0.3 mg]). Cytokine release syndrome (CRS) was reported in 18 (45.0%) patients; grade 2 CRS in 5 (12.5%); no grade ≥3 CRS. CRS presented mainly as fever ± hypotension, was reversible, did not lead to treatment interruption or discontinuation, occurred mostly within 24 hours of the first two doses of AMG 757, and was managed with supportive care, corticosteroids, and/or anti-IL-6 treatment. AMG 757 showed dose proportional increase in exposures.

      Confirmed partial response (PR) was reported for 6 (15.8%) patients (1/12 [8.3%] in DL5, 1/8 [12.5%] in DL6, 3/7 [42.9%] in DL7, and 1/7 [14.3%] in DL8 [Figure]). Stable disease was reported for 11 (28.9%). One patient has ongoing unconfirmed PR in DL8. Evaluation of DL8 is ongoing. Patients with confirmed PR had a median of 2 (1–4) prior lines of therapy and duration of response of 1.9+ to 9.4+ months. DLL3 expression at any level was observed in 31/32 (96.9%) patient tumor samples, with overall H-score 40–300. Tumor shrinkage occurred across a wide range of DLL3 expression (H-score, 55–300).

      amg 757 phase1_ figure.jpg

      Conclusion

      AMG 757 has acceptable safety at doses of up to 10 mg and shows anti-tumor activity in patients with SCLC. Dose escalation is ongoing.

      References

      1. Leonetti A, et al. Cell Oncol (Dordr). 2019;42(3):261-273.

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    P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P01.01 - HERTHENA-Lung01: A Randomized Phase 2 Study of Patritumab Deruxtecan (HER3-DXd; U3-1402) in Previously Treated Metastatic EGFR-mutated NSCLC (ID 3412)

      00:00 - 00:00  |  Author(s): Melissa L Johnson

      • Abstract
      • Slides

      Introduction

      Few treatment options have demonstrated meaningful therapeutic benefit for patients with epidermal growth factor receptor- (EGFR-) mutated non-small cell lung cancer (NSCLC) that has progressed after treatment with EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy. HER3, a member of the human epidermal growth factor family, is detectable in the majority of EGFR-mutated NSCLC, and expression has been associated with worse clinical outcomes. Currently, there are no approved HER3 directed therapies for the treatment of NSCLC. Patritumab deruxtecan is a novel, investigational antibody drug conjugate comprising an anti-HER3 monoclonal antibody, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In an ongoing Phase 1 study of patritumab deruxtecan in patients with EGFR-mutated TKI-resistant NSCLC, preliminary evidence of safety and antitumor activity were observed, providing proof of concept of patritumab deruxtecan. This Phase 2 study (HERTHENA-Lung01) is further evaluating patritumab deruxtecan in patients with previously treated metastatic or locally advanced EGFR-mutated NSCLC.

      Methods

      This is a randomized, open-label, global Phase 2 study that will enroll up to 300 patients at approximately 60 study sites across North America, Europe, and Asia. Eligible patients will have metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R), progression during or after systemic treatment with ≥1 EGFR TKI and ≥1 platinum-based chemotherapy regimen, and at least 1 measurable lesion confirmed by blinded independent central review (BICR) per RECIST v1.1. Patients with an EGFR T790M mutation must have received and progressed on prior osimertinib. Patients will be excluded if they have evidence of previous small cell or combined small cell/non-small cell histology or any history of interstitial lung disease. Tumor tissue will be assessed retrospectively for HER3 expression and molecular mechanisms of TKI resistance. The HER3 expression results will not be used to select patients for enrollment. Two Q3W dose regimens will be independently evaluated: 5.6 mg/kg patritumab deruxtecan in a fixed-dose regimen (Arm 1), or an up-titration dose regimen (Arm 2: Cycle 1, 3.2 mg/kg; Cycle 2, 4.8 mg/kg; Cycle 3 and subsequent cycles, 6.4 mg/kg). Patients will be randomized 1:1 to receive 1 of the 2 regimens. After initial review of ongoing phase 1 study data in an interim analysis, a decision will be made to continue with enrollment into 1 or both study arms. The primary objective of the study is to evaluate the efficacy of patritumab deruxtecan as measured by objective response rate (ORR) according to BICR. Secondary objectives are to evaluate the efficacy and safety/tolerability of patritumab deruxtecan, as well as to assess the relationship between efficacy and HER3 expression. Secondary endpoints include duration of response, progression-free survival, ORR by investigator assessment per RECIST v1.1, disease control rate, time to response, best percentage change in the sum of diameters of measurable lesions, and overall survival. Anticipated total study duration is expected to be 26 months, consisting of approximately 12 months for enrollment and 14 months on treatment. The study is planned to begin in 2020.

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      P01.06 - CX-2029, a Probody Drug Conjugate Targeting CD71 in Patients With Selected Tumor Types: PROCLAIM-CX-2029 Dose Expansion Phase (ID 3264)

      00:00 - 00:00  |  Presenting Author(s): Melissa L Johnson

      • Abstract
      • Slides

      Introduction

      CX-2029 is a Probody® drug conjugate (PDC) of monomethyl auristatin E (MMAE), a potent microtubule inhibitor, directed against transferrin receptor 1, CD71. CD71 mediates iron uptake and is highly expressed on both malignant and normal cells, precluding antibody-drug conjugate (ADC) targeting. PDCs are masked ADCs, unmasked by tumor-associated proteases, thereby restricting target engagement to the tumor. Both the CD71 PDC and ADC had significant activity in multiple xenograft tumor models; however, in toxicology studies, the PDC was tolerable at doses consistent with efficacy in nonclinical tumor models while the ADC was not.

      Methods

      PROCLAIM-CX-2029 is an open-label, phase 1/2 study (NCT03543813) evaluating CX-2029 in patients with advanced solid tumors or diffuse large B-cell lymphoma (DLBCL). Results from the dose escalation component of the trial were previously reported (Johnson 2020). Clinical activity was observed at doses of 2 mg/kg and higher (all confirmed responses were observed in squamous histologies: non-small cell lung; head and neck cancers). The dose expansion in 4 selected tumor types is underway and is planned to enroll up to 25 patients per tumor type (Figure 1). Eligible patients are aged ≥18 years with Eastern Cooperative Oncology Group performance status of 0–1; adequate hematologic, renal, and hepatic function; and 1 of the following advanced malignancies: non–small cell lung cancer (squamous histology only); head and neck squamous cell carcinoma; esophageal cancer; or DLBCL. All patients must have received appropriate prior systemic therapy for their advanced disease. CX-2029 will be administered at 3 mg/kg in 21-day cycles until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary endpoint is overall response rate by Response Evaluation Criteria in Solid Tumors version 1.1 or modified Lugano classification for DLBCL. Secondary endpoints include duration of response, progression-free survival, overall survival, safety, and pharmacokinetics. Tumor specimens are required during screening (optional at 3-5 days following the first infusion) for assessment of CD71 parameters and possible correlation with response.

      figure 1.jpg

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    P77 - Immunotherapy (Phase II/III Trials) - Combining Different Immunotherapeutic Approaches (ID 254)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P77.02 - Efficacy of Tiragolumab + Atezolizumab in PD-L1 IHC and TIGIT Subgroups in the Phase II CITYSCAPE Study in First-Line NSCLC (ID 3501)

      00:00 - 00:00  |  Author(s): Melissa L Johnson

      • Abstract
      • Slides

      Introduction

      The immunomodulatory receptor TIGIT (T-cell Immunoreceptor with Ig and ITIM domains) is a novel inhibitory immune checkpoint on activated T cells and natural killer cells in multiple cancers. Tiragolumab (tira) is a humanized IgG1/kappa monoclonal antibody that binds TIGIT to prevent its interaction with its ligand PVR (CD155). Because PD-L1 expression is considered a hallmark of pre-existing immunity and is positively correlated with TIGIT expression, we investigated the combination of tira + atezolizumab (atezo) in patients with newly diagnosed PD-L1-positive metastatic NSCLC in the phase II CITYSCAPE trial. We recently reported an improvement in progression-free survival (PFS) with the tira + atezo combination over atezo monotherapy in patients whose tumors showed high PD-L1 expression (≥50% TPS or tumor proportion score) by the pharmDx immunohistochemistry (IHC) 22C3 assay (PFS hazard ratio [HR] 0.30, 95% confidence interval [CI]: 0.15-0.61) [Rodriguez-Abreu. ASCO 2020]. To determine whether these results were consistent across different PD-L1 IHC assays, we assessed the efficacy of tira + atezo in PD-L1 subgroups defined by the SP263 IHC assay. We also evaluated whether TIGIT expression was associated with tira + atezo efficacy.

      Methods

      PD-L1 expression was assessed prospectively using 22C3 IHC and retrospectively with SP263 IHC, both of which yield a tumor cell (TC) membrane staining score. TIGIT expression on tumor-infiltrating immune cells (IC) was assessed with an exploratory IHC assay.

      Results

      Among the 135 enrolled patients with PD-L1-positive NSCLC (intent-to-treat [ITT] population), 113 had results from the SP263 assay and 105 had results from the TIGIT assay. The biomarker-evaluable populations (BEP) for both of these assays were similar to the ITT population. Comparable PFS improvement with tira + atezo relative to atezo monotherapy was seen in PD-L1–high (≥50% TC) subgroups defined by SP263 (PFS HR 0.23, 95% CI: 0.10–0.53) when compared with PD-L1-high subgroups defined by 22C3. However, for patients whose tumors were defined as TIGIT-high (≥5% IC), no strong association with PFS improvement was observed.

      Biomarker subgroup

      Subgroup, n (BEP, N)

      PFS HR (CI) relative to atezo monotherapy arm

      ITT (PD-L1 IHC 22C3 >1% TPS)

      135 (135)

      0.58 (0.39–0.88)

      PD-L1 IHC 22C3 (≥50% TPS)

      58 (135)

      0.30* (0.15–0.61)

      PD-L1 IHC SP263 (≥50% TC)

      45 (113)

      0.23* (0.10–0.53)

      TIGIT IHC (≥5% IC)

      49 (105)

      0.62* (0.30–1.32)

      *Unstratified HR

      Conclusion

      Prevalence of PD-L1 subgroups in the BEP was comparable with previous reports for both IHC assays. The PFS benefit observed with tira + atezo in patients with tumors defined as PD-L1-high by 22C3 was also observed using the SP263 IHC assay, but not in tumors classified as TIGIT-high using an exploratory TIGIT IHC assay. Our results suggest that PD-L1 expression, assessed by 22C3 or SP263, may be a biomarker for tira + atezo combination therapy in metastatic PD-L1-positive untreated NSCLC.

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