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Benjamin Besse



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    FP05 - Mesothelioma, Thymoma and Other Thoracic Malignancies (ID 135)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP05.04 - Outcomes of Resected Thymic Epithelial Tumors (TET), insights from RYTHMIC (ID 3693)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      TET are rare malignancies, with an annual incidence of 350 cases in France. The main prognostic factors are Masaoka-koga stage and quality of the resection. However, no large cohorts have been published concerning resection outcomes. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network mandated to systematically discuss every case of TET. We aimed to describe the resected tumor outcomes in a large French population.

      Methods

      RYTHMIC database, hosted by IFCT (Intergroupe Francophone de Cancérologie Thoracique), prospectively includes all consecutive pts with a diagnosis of TET discussed in French national or regional tumor boards. We analyzed epidemiologic, clinical and pathological characteristics of 1045 pts operated of a TET.

      Results

      From January 2012 to December 2019, 2909 pts were included in the database. Overall, the median age at diagnosis of TET was 60 (range 9-90) and 52% (n=1513) were male. Of them, 1082 (37,2%) pts were operated. 304/1045 (29%) pts reported autoimmune disorders and Myasthenia Gravis was the most common (250 pts, 82,2%). Masaoka-Koga stages (MK) were well balanced with 23% (n=240) stage I, 17.2% (n=180) stage IIa, 18.2% (n=190) stage IIb, 19.6% (n=205) stage III with lung as a main invaded organ (37%), 8% (n=85) stage IVa and 4.9% (n=51) stage IVb. Among resected tumors, B2 and AB were the most common subtypes (n=247, 23.6% and n=237, 22.7% respectively).

      Sternotomy was the most used approach for resection (n=735, 70.3%). In addition to TET, surgery was extended to lung (35%), pericardium (24%), pleura (13%), recurrent nerve or great vessels (10%) and lymph nodes (46%). Complete resection was assessed in 71% of procedures with a median tumor size of 55mm (1-260) and a range of 0-28 resected pleural metastasis. Intrapleural chemotherapy was used as an associated technique during the first-line surgery (6/17 pts) or after recurrence (9/17 pts, 53%) shrinking the hazard for progression (PD) (OR= 0.5 95%CI [0.29 to 0.84], p<0.00). Induction chemotherapy and adjuvant radiotherapy was administered in 119/182 (65,3%) and 357/1045 (34.2%) pts, respectively. Principal location for progression was the pleura (119/223 pts, 53%) with surgery as the main treatment (31%).

      Median-OS was 263 months (95%CI[NotR-NotR]) and median-PFS was 111 months (95%CI[97,4-124,5]). The Cox proportional Hazard’s model showed a statistically significant greater risk for PD of MK III comparing with other localized tumors (HR=10,618 95%CI[1,172-96,224], p=0,036). Patients presenting thymoma B3 and epidermoid thymic carcinoma assessed risk for PD (HR=1,357 95%[0,531-3,462]; p=0,524 and HR= 1,982 95%CI[0,774-5,073]; p=0,154, respectively). Patients who needed lung or phrenic nerve resection showed higher risk for PD (HR=1,643 95%CI[1,181-2,286]; p=0,003 and HR=1,829 95%CI[1,217-2,748]; p=0,003, respectively). Bigger tumors and those with no complete resection (R1) were more likely to progress (HR=1,009 95%CI[1,004-1,013]; p<0,00 and HR=1,821 95%CI[1,058-3,133]; p=0,03, respectively).

      Conclusion

      Up to 37% of RYTHMIC cohort were resected. MK I and III were the most common resected tumors with 71% of complete resection with impact on survival. Thymic carcinoma and thymoma B3 were more likely to progress. Pleura was the main site for recurrence and surgery the most used treatment, in addition with intrapleural chemotherapy in some cases.

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    FP07 - Pathology (ID 109)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP07.06 - Lung Immune Prognostic Index (LIPI) in Advanced NSCLC Patients Treated with Immunotherapy, Chemotherapy and both Combined Upfront. (ID 823)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      The Lung Immune Prognostic Index (LIPI) that combines the neutrophils/[leucocytes minus neutrophils] ratio (dNLR) and lactate dehydrogenase (LDH), is associated with outcomes in pretreated advanced NSCLC patients receiving single agent immune checkpoint inhibitors (ICI). However, its role in first line treatment of advanced NSCLC patients has not been explored yet. We assessed the value of baseline LIPI in the first line setting, for ICI-monotherapy, ICI-combination or platinum-based chemotherapy alone (CT).

      Methods

      We retrospectively collected data of patients treated with first-line ICI between 2016 and 2019 as single agent if PD-L1 ≥50% (ICI-cohort), or in combination with a CTLA4-inhibitor (ICI+ICI cohort), or with chemotherapy (ICI+CT cohort), from 18 centers worldwide. A control cohort of patients treated with platinum-based CT (CT-cohort) was also collected between 2011 and 2019 from 2 centers. Baseline LIPI was calculated as previously reported and correlated with overall survival (OS) and progression-free survival (PFS) in each treatment cohort.

      Results

      Overall, 930 patients were enrolled, 561 in the ICI-cohort, 186 in the combo ICI+CT, 55 in the ICI+ICI and 128 in the CT-cohort. Median (m) follow-up was 12.5 months. In the whole cohort, median age was 66 years, 70% male, 80% had non-squamous histology, and 84% had PS ≤1. Based on LIPI (available for 792 patients): 305 (38%) were considered good, 331 (42%) intermediate and 156 (20%) poor group.

      Treatment outcomes according to LIPI scores are depicted in Table 1. The LIPI poor population had significantly worse OS compared with other LIPI groups, in the whole cohort (P<0.001) as well as in the ICI monotherapy and combo ICI+CT cohorts (both P<0.0001); and in the CT cohort (P=0.004). In term of PFS, we observed correlation between LIPI groups and outcomes in the whole cohort (P<0.001) and in the ICI- monotherapy cohort (P=0.008); however, no differences were observed in the cohorts of patients receiving chemotherapy regimens, alone (P=0.08) or combined with ICI (P=0.08). The analysis by PD-L1 expression in 756 patients with available data will be presented in the Congress.

      Table 1: Median OS and PFS according to LIPI subgroups. NR = non reached.

      Outcomes

      LIPI

      subgroups

      Overall cohort

      N= 925

      ICI-cohort

      N=558

      ICI + CT-cohort

      N= 185

      ICI + ICI cohort

      N= 55

      CT-cohort

      N=127

      Median OS

      (95% CI)

      All

      16.3 (14.7-18.8)

      21.0 (17.1-NR)

      24.7 (16.9-27.1)

      20.5 (14.1-NR)

      9.79 (8.3-14.4)

      LIPI good, 38.5%

      19.8 (17.2-25.7)

      NR (NR-NR)

      25.7 (25.6-NR)

      33.6 (14.7-NR)

      14.42 (8.9-17.9)

      LIPI interm, 41.8%

      15.8 (14.3-20.3)

      21.2 (17.1-NR)

      20.3 (12.8-NR)

      14.6 (5.5-NR)

      9.30 (7.0-14.5)

      LIPI poor, 19.7%

      6.96 (5.6-12.5)

      8.5 (3.4-13.7)

      6.1 (4.9-NR)

      14.1 (10.3-NR)

      6.1 (5.0-NR)

      Global LogRank P value

      <0.0001

      <0.0001

      <0.0001

      0.4

      0.004

      Overall cohort

      N= 909

      ICI-cohort

      N=543

      ICI + CT-cohort

      N= 185

      ICI + ICI cohort

      N= 54

      CT-cohort

      N=127

      Median PFS

      (95% CI)

      All

      6.5 (5.9-7.1)

      6.3 (5.0-7.6)

      8.9 (6.80-10.9)

      7.2 (5.7-30.6)

      5.7 (5.3-6.4)

      LIPI good, 38.7%

      7.0 (5.9-8.5)

      6.4 (4.5-10.8)

      9.8 (7.8-13.0)

      9.2 (5.7-NR)

      6.0 (5.3-7.8)

      LIPI interm, 41.6%

      6.6 (6.1-7.6)

      6.6 (5.6-8.1)

      10.4 (6.4-12.4)

      5.5 (2.5-NR)

      6.1 (4.3-7.6)

      LIPI poor, 19.7%

      3.6 (3.1-5.6)

      3.3 (1.9-6.7)

      4.5 (2.8-8.2)

      7.1 (2.56- NR)

      3.7 (3.4-NR)

      Global LogRank P value

      <0.0001

      0.008

      0.08

      0.4

      0.08

      Conclusion

      Pretreatment LIPI was prognostic in untreated advanced NSCLC patients regardless of the type of therapy. However, LIPI was associated with PFS only in patients receiving ICI-monotherapy, with no statistically significant differences in CT-containing cohorts (alone or combined with ICI). This value of LIPI to guide treatment selection should be further explored in prospective studies.

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      FP07.11 - Circulating Tumor DNA (ctDNA) Clearance as a Biomarker in Patients With Locally Advanced NSCLC Following Chemoradiation (ID 1432)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      Circulating tumor DNA (ctDNA) testing has the potential to identify patients at high risk for recurrence following completion of concurrent chemoradiation (CRT) for locally advanced non-small cell lung cancer (LANSCLC). The objective of this analysis is to examine the feasibility of ctDNA testing on a commercially available focused gene panel to predict outcomes in patients with LANSCLC.

      Methods

      A total of 43 patients were prospectively enrolled between 09/2017 and 10/2019. Plasma for ctDNA testing was collected at the time of CRT initiation (D1), CRT completion (V1), quarterly follow up appointments for 12 months (FU1, 2, 3 and 4 respectively) after CRT completion, and at the time of relapse (R). ctDNA analysis was performed using InVisionFirst®-Lung, to detect the presence of SNVs, indels and CNAs in 37 cancer-related genes. ctDNA clearance was defined as the absence of D1 variants at V1. Patients without detectable D1 variants or in whom V1 samples were not collected were excluded from this analysis.

      Results

      Nineteen of 43 patients (44%) had detectable variants at D1. In this cohort of 19 patients, the median age at diagnosis was 65 years (range 43 - 82), with the majority of patients being smokers (16/19, 84%). The stage distribution was as follows: IIA (5%), IIIA (37%), IIIB (52%) and IIIC (5%). Nine patients (47%) had squamous cell carcinoma, 7 (37%) had adenocarcinoma, and 3 (16%) had poorly differentiated or NSCLC NOS. A median of 2 mutations per sample (range 1 - 5) were detected with a median of mean allelic frequency (AF) of 0.53 (range 0.05 - 16.28) at D1. Mutations in TP53 were the most commonly detected (17/19, 89%) at D1, followed by mutations in PIK3CA (5/19, 26%), CDKN2A (4/19, 21%), and EGFR (3/19, 16%). Two patients died from non-cancer related causes before FU1 and were excluded from further analysis (1 cleared ctDNA, another did not). All (3/3) patients who did not clear ctDNA had tumor relapse with a median time to relapse of 74 days (30-238), while 50% (7/14) of those who cleared ctDNA have not relapsed after a median follow-up of 469 days (range 130-710). Median time to relapse in patients who cleared ctDNA was 217 days (range 53-587 days).

      Conclusion

      Our results demonstrate that it is feasible to employ ctDNA testing to identify LANSCLC patients who are at high risk for disease recurrence following CRT. This finding requires validation in future studies.

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    FP09 - Screening and Early Detection (ID 175)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP09.05 - Driver Oncogenic Alterations and Indoor Radon in NSCLC Patients From the IFCT Biomarker Cohort: Bioradon France Study (ID 1176)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      Radon is a radioactive gas, considered as the leading cause of lung cancer in non-smokers. In a previous work, we studied the correlation between the estimation of radon concentration from the French Indoor Radon Map (Institut de Radioprotection et de Sûreté Nucléaire, IRSN) and the regional prevalence of driver alterations in a cohort of 116.424 NSCLC patients in France (Mezquita et al, WCLC 2018). The prevalence of driver oncogene alterations was significantly higher in high-radon areas but clinical data were not available. We aim to confirm this hypothesis in an annotated database of NSCLC patients with matched molecular data available for adjustment (Barlesi et al, Lancet 2016).

      Methods

      Retrospective assessment of patients with NSCLC tested for EGFR/BRAF/HER2/KRAS mutations (m) and ALK fusion from the 28 Platform led by the National Cancer Institute between Apr.2012 and Apr.2013, and included in the Biomarkers France dataset. We studied the association between the prevalence of driver oncogenic alterations (EGFR/ALK/BRAF/HER2/KRAS) and the radon mean concentration in the area where the patient was born according to the IRSN Map. Adjustment on age, gender and smoking was performed.

      Results

      Out of 17664 patients, we analyzed 3994 with birthplace available: 63% males, 82% smokers, with a median age of 64 years [18-94]. Lung cancer tumors were mostly adenocarcinoma (76%), followed by other histologies (18%) and squamous (6%). By molecular alterations: 468 tumors harbor EGFRm (12%), 129 ALK (3%), 89 BRAFm (2%), 32 HER2m (1%), 985 KRASm (25%); 2273 wildtype or harbor other non-driver alterations (control; 57%). Adenocarcinoma histology (83.7% vs. 80.2%, p=0.0034), and non-smoker habit (19.5% vs. 16.5%, p=0.0251) were more common in radon high-risk group (comparatively at the low risk group). The mean radon concentration by birthplace was 74.36 Bq/m3 ±53.28SD [range 16.6-622.3], and by molecular groups: EGFRm 72.49 Bq/m3 ± 47.98 SD [16.6-461.4], ALK 80.24 Bq/m3 ±55.22SD [19.3-384.7], BRAFm 73.22 Bq/m3 ±47.86SD [19.3-319.3], HER2m 72.74 Bq/m3 ±39.51SD Bq/m3 [27.8-231.3], KRASm 71.79 Bq/m3 ±53.32SD [16.6-576.8] and control group 75.67 Bq/m3 ± 54.5SD [16.6-622.3] (p=0.20). The prevalence of driver alterations was higher in high-radon areas (table 1; p=0.0472); but no significant difference was observed after adjustment on age, gender and smoking.

      Low radon
      <50 Bq/m3

      High radon
      50 Bq/m3

      P value

      P value adjusted*

      EGFR

      Mutation

      N (%)

      155 (11.4%)

      313 (13.2%)

      0.1218

      0.3024

      Control (1)

      N (%)

      1199 (88.6)

      2059 (86.8)

      ALK

      Fusion

      N (%)

      42 (3.4%)

      87 (4.1%)

      0.3272

      0.4708

      Control (1)

      N (%)

      1199 (96.6)

      2059 (95.9)

      BRAF

      Mutation

      N (%)

      32 (2.6%)

      57 (2.7%)

      0.8708

      0.9865

      Control (1)

      N (%)

      1199 (97.4)

      2059 (97.3)

      HER2

      Mutation

      N (%)

      7 (0.6%)

      25 (1.2%)

      0.0880

      0.1781

      Control (1)

      N (%)

      1199 (99.4)

      2059 (98.8)

      KRAS

      Mutation

      N (%)

      375 (31.3%)

      610 (29.6%)

      0.3227

      0.3478

      Control (2)

      N (%)

      824 (68.7)

      1449 (70.4)

      DRIVER

      Positive

      N (%)

      236 (16.4%)

      482 (19%)

      0.0472

      0.2128

      Control (1)

      N (%)

      1199 (83.6)

      2059 (81)

      (1) population no EGFRm, noBRAFm, no HER2m and no ALKr
      (2) population no EGFRm, noBRAFm, no HER2m, no ALKr and no KRASm

      *adjustment on age, gender and smoking

      Conclusion

      We observed a higher prevalence of driver oncogenic alterations in NSCLC patients born in high radon areas; but no significant difference was observed after adjustment on age, gender and smoker. This study warrants further research on radon gas and driver oncogenes.

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    FP14 - Targeted Therapy - Clinically Focused (ID 252)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP14.15 - Neratinib-Based Combination Therapy in HER2-Mutant Lung Adenocarcinomas: Findings from two International Phase 2 Studies. (ID 1894)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      Somatic HER2 mutations are present in 3–5% of lung cancers, which induce constitutive HER2 signaling and oncogenesis. Neratinib, an irreversible pan‑HER tyrosine kinase inhibitor, has demonstrated antitumor activity across a spectrum of HER2-mutated solid cancers and a manageable safety profile [Hyman et al. Nature 2018]. Findings from a HER2-mutant lung cancer model suggest that neratinib activity is enhanced when given in combination with an mTOR inhibitor (temsirolimus) or anti-HER2 antibody (trastuzumab) [Ivanova et al. Clin Cancer Res 2020]. We present data from two international phase 2 studies of neratinib-based therapy in patients with HER2-mutant lung cancer: PUMA-NER-4201 – a randomized study of neratinib ± temsirolimus (NCT01827267); PUMA-NER-5201 (SUMMIT) – a multi‑tumor ‘basket’ trial including patients treated with neratinib ± trastuzumab (NCT01953926).

      Methods

      Patients with histologically confirmed advanced HER2-mutant non-small cell lung cancers (NSCLC) were treated with oral neratinib 240 mg once daily alone (both studies) or in combination with temsirolimus 8 mg once weekly intravenously with optional dose escalation to 15 mg/week if tolerated (PUMA-NER-4201) or trastuzumab 8 mg/kg initially then 6 mg/kg every 3 weeks intravenously (SUMMIT). Protocol-defined endpoints common to both studies were confirmed objective response rate (RECIST v1.1), best overall response, clinical benefit rate, duration of response, progression‑free survival, overall survival, and safety (NCI CTCAE, v4.0).

      Results

      In PUMA-NER-4201, 62 patients with HER2-mutant NSCLC were enrolled (60 evaluable for efficacy). In SUMMIT, as of 17 July 2020, 78 HER2-mutant lung cancer patients were enrolled and received at least one dose of study drug (all evaluable for efficacy). Baseline characteristics across both studies: median age range 62–66 years, female 66%, adenocarcinoma 92–100%. Exon 20 insertion mutations accounted for 95% of tumors in PUMA-NER-4201 and 66% of tumors in SUMMIT. The most common mutant allele across both studies was Y772_A775dup (53% PUMA-NER-4201; 28% SUMMIT). The safety profile of neratinib was consistent with previous reports, with diarrhea being the most common adverse event (81–86% any grade, 12–40% grade ≥3) in both monotherapy and combination arms. Efficacy results are summarized in the table.

      data table 600 dpi submission.jpg

      Conclusion

      Neratinib, as monotherapy, has limited activity in HER2-mutated NSCLC. Neratinib combined with either an mTOR inhibitor (temsirolimus) or anti-HER2 antibody (trastuzumab) produced numerically greater efficacy including durable responses in a subset of pre-treated patients. Genomic analysis from a subset of responders is forthcoming. Additional novel combinations of neratinib with other HER2-directed therapies in HER2-mutant NSCLC are being considered.

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    MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
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      MA08.04 - LIPI and Outcomes of Durvalumab as Consolidation Therapy after ChRT in Patients with Locally-Advanced NSCLC (ID 1969)

      16:45 - 17:45  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      The lung immune prognostic index (LIPI), which combines pretreatment derived neutrophils/[leukocytes minus neutrophils] ratio (dNLR) >3 and lactate dehydrogenase (LDH) > upper limit of normal (ULN), is associated with outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). We aimed to assess whether pretreatment LIPI correlates with durvalumab efficacy after concurrent chemoradiotherapy in the locally advanced setting.

      Methods

      Multicenter retrospective study of locally advanced NSCLC patients treated with durvalumab consolidation in 21 European/US centers from 12/2015 to 5/2020. Clinical and biological data were collected before durvalumab treatment. PD-L1 expression by immunohistochemistry was also collected at diagnosis. LIPI was calculated according to previous reports and three groups were characterized: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3 or LDH>ULN) and poor (dNLR>3+LDH>ULN). The primary endpoint was progression-free survival (PFS). Response was assessed according to the clinical routine of each center.

      Results

      A total of 267 patients were enrolled. One hundred eighty-five (69%) patients were male, 252 (94%) smokers, with median age of 67 [range 59-73] and 223 (98%) with Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1. 260/266 (98%) were stage III, of which 96 were IIIA, 127 stage IIIB and 37 stage IIIC. 163 (63%) had non-squamous histology and 12/131 (27%) harbored driver alterations: 5 EGFR, 4 BRAF, 3 MET, 2 ALK; missing in 136 cases. PD-L1 was ≥1% in 191/233 (82%) patients both from Europe and US, missing in 34 cases. LIPI was evaluable in 143 patients: 90 were considered good (63%), 50 intermediate (35%) and 3 (2%) as poor LIPI group. dNLR >3 was found in 47/218 (22%) and LDH > ULN in 23/143 (16%) cases. Radiotherapy was delivered concurrent in 219 (82%) of cases. No differences in clinical characteristics were found between 3 LIPI groups, including the response to previous chemoradiotherapy.

      With a median follow-up of 13.4 months [95% confidence interval (CI), 12-15], the median PFS was 20 months [95% CI, 12.7-not reached (NR)]. Median PFS was 7.5 months [95% CI, 3.1-NR] for poor group vs. 10.7 months [95% CI, 5.1-NR] for intermediate group vs. 19.1 months [95% CI, 11.6-NR] for good LIPI group (P=0.020). Median overall survival (OS) was NR [95% CI 47-NR] in the entire cohort and therefore considered not mature. The first objective response rate under durvalumab was 44% (111/251), being 36% (18/50) for the intermediate-poor group and 38% (33/87) for the good group with no significant differences (P=0.099). No differences in PFS and OS between groups were found regarding PD-L1 status (P=0.5 and P=0.4, respectively).

      Conclusion

      Pretreatment LIPI is associated with clinical outcomes in locally advanced patients treated with durvalumab as consolidation after chemoradiotherapy. This cohort is still ongoing to confirm our preliminary findings in a larger cohort.

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    OA07 - Immuno-biology and Novel Immunotherapeutics from Bench to Bed (ID 228)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
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      OA07.08 - HUDSON: An Open-Label, Multi-Drug, Biomarker-Directed, Phase II Platform Study in Patients with NSCLC, who Progressed on Anti-PD(L)1 Therapy   (ID 3535)

      10:30 - 11:30  |  Presenting Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      The HUDSON Platform trial (NCT03334617) is a multi-arm clinical trial for patients with non-small cell lung cancer (NSCLC) who had tumour progression on anti-PD(L)1 immunotherapy and received prior platinum-doublet chemotherapy. The study design allows efficacy, safety, and tolerability assessment of multiple tailored durvalumab based combinations. Novel treatment options for this population can be explored based on efficacy signals. Here we present initial results in Modules 1, 2, 3 and 5 and current status in Modules 6 and 7.

      Methods

      Patients are enrolled into cohorts defined according to a biomarker matched profile (Part A) or non-matched (Part B). Acquired resistance (ACQ) was defined as progression after >24 weeks of prior immunotherapy and primary resistance (PRI) defined as progression ≤24 weeks from onset of prior immunotherapy. Patients received durvalumab in combination with: olaparib (PARPi; Module 1), danvatirsen (STAT3i; Module 2), ceralasertib (ATRi; Module 3), oleclumab (anti-CD73 antibody; Module 5), trastuzumab deruxtecan (HER2 ADC; Module 6), and cediranib (VEGFRi; Module 7). A composite endpoint of overall response rate (ORR), progression-free survival (PFS; 6, 9 and 12 months) and overall survival (OS; 6, 9 and 12 months) was used to decide whether or not to expand the initial module size from 20 patients to 40. Safety, a secondary endpoint, was continuously monitored.

      Results

      Enrolment started in December 2017. As of 25th July 2020, 261 patients have been enrolled from 31 study sites in 6 countries. Enrolment into Modules 1, 2, and 5 is complete, ongoing in Modules 3, 6, and 7, and Module 4 was discontinued with one patient enrolled, when development of vistusertib was stopped. As of Q1 2020, efficacy (ORR), PFS and OS) results were available as per Table 1. Further efficacy updates for Modules 1, 2, 3 and 5 are scheduled in Q3 2020. The safety profile of combination therapy in each module was in line with the safety profile of the individual compounds.

      Table 1. Enrolment and efficacy outcomes to date per patient cohort

      Cohort

      Enrolment status

      Number
      enrolled

      6-month OS (%)

      6-month PFS (%)

      ORR
      (%)

      Median total

      treatment duration (months)

      Part A – Biomarker matched

      LKB1 (+olaparib)

      Complete

      21

      55.8

      10.7

      4.8

      1.84

      HRR (+olaparib)

      Complete

      21

      57.1

      21.8

      4.8

      3.68

      ATM (+ceralasertib)

      Ongoing

      18

      100

      61.2

      13.3

      4.14

      CD73 (+oleclumab)

      Complete

      23

      79.9

      8.3

      0

      2.79

      HER2 (+trastuzumab deruxtecan)

      Ongoing

      1

      Part B – Biomarker non-matched

      PARPi – ACQ
      (+olaparib)

      Complete

      23

      77.4

      26.1

      4.3

      4.70

      PARPi – PRI (+olaparib)

      Complete

      22

      59.1

      15.1

      0

      3.35

      STAT3i – ACQ

      (+danvatirsen)

      Complete

      22

      75.2

      38.5

      0

      3.15

      STAT3i – PRI (+danvatirsen)

      Complete

      23

      50.2

      5.1

      0

      1.91

      ATRi – ACQ (+ceralasertib)

      Complete

      24

      77.3

      37.0

      8.7

      6.44

      ATRi – PRI (+ceralasertib)

      Complete

      20

      74.8

      53.8

      11.1

      2.78

      CD73 Ab – ACQ
      (+oleclumab)

      Complete

      25

      64.4

      26.1

      0

      2.73

      CD73 Ab – PRI (+oleclumab)

      Complete

      9

      NC

      NC

      0

      1.53

      VEGFi – ACQ
      (+cediranib)

      Ongoing

      9

      NA

      Please note: OS, PFS and ORR are currently available for patients enrolled by January 2020. Number enrolled reflects the total enrolled by 25th July 2020.

      Conclusion

      Preliminary efficacy signals were observed with ATRi, which may be more pronounced in ATM selected patients. The subgroup of LKB1 selected patients appear to have the lowest 6-month OS and PFS of subgroups in Module 1 (durvalumab + olaparib). An update is scheduled for Q3 2020.

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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
    • +

      P01.02 - Trastuzumab Deruxtecan Plus Pembrolizumab in Advanced/Metastatic Breast or Non-Small Cell Lung Cancer: A Phase 1b Study (ID 1829)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and potent topoisomerase I inhibitor. In a phase 2 trial in patients with heavily pretreated, metastatic HER2+ breast cancer, T-DXd had a confirmed objective response rate (cORR) of 60.9% (112/184) and median progression-free survival (PFS) of 16.4 mo (Modi N Engl J Med 2019); these results led to the recent FDA approval for HER2+ unresectable or metastatic breast cancer after ≥ 2 prior anti-HER2 based regimens. For HER2-low breast cancer and HER2-expressing/mutated NSCLC, no HER2-directed therapies have been approved. In a phase 1 trial of T-DXd in patients with HER2-low breast cancer or HER2-expressing/mutated NSCLC, cORR was 44.2% (19/43) (Modi SABCS 2018), and 55.6% (10/18) (Tsurutani Thorac Oncol 2018), respectively. In preclinical models, T-DXd combined with an anti–PD-1 antibody was more effective than monotherapy with either agent (Iwata Mol Cancer Ther 2018). Here we describe a phase 1b study of T-DXd in combination with pembrolizumab in patients with locally advanced/metastatic HER2-expressing breast cancer or HER2-expressing/mutated NSCLC (DS8201-A-U106; NCT04042701). This abstract was previously submitted to ASCO 2020.

      Methods

      This is an open-label, multicenter, nonrandomized, multidose, 2-part study in adult (aged ≥18 y) patients in the United States and Europe. In part 1 (dose escalation), patients received T-DXd 3.2 or 5.4 mg/kg IV q3w and pembrolizumab 200 mg IV q3w to determine the recommended dose for expansion (RDE). The RDE will be given to 4 cohorts (part 2): 2 cohorts with breast cancer (HER2+ [IHC 3+ or IHC 2+/ISH+] with progression on prior T-DM1; and HER2-low [IHC 1+ or IHC2+/ISH-] with progression on prior standard treatments) and 2 cohorts with NSCLC (anti–PD-1, –PD-L1, and -HER2 treatment naive either HER2-expressing [IHC ≥ 1+] or HER2-mutated). Enrollment began in February 2020 with approximately 115 to 133 patients planned to be enrolled at 5 sites for part 1 and expanding to 25 sites for part 2. The primary endpoint in part 1 is dose-limiting toxicities. The part 2 primary efficacy endpoint is cORR by independent central review (ICR) per RECIST 1.1. Additional endpoints include duration of response, disease control rate, and progression-free survival by ICR, overall survival, safety, and pharmacokinetics.

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      P01.21 - ANSELMA: Antiangiogenic Second Line Lung Cancer Meta-Analysis on Individual Patient Data in Non-Small Cell Lung Cancer, Again Relevant in ICI Era (ID 721)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      There is renewed interest in the efficacy of 2nd line treatments (2LT) with anti-angiogenics (AA), now that immunotherapy plus chemotherapy (CT) is one of the standard options in 1st line treatment of advanced non-small cell lung cancer (NSCLC). Antibodies (mAb) against VEGF, VEGFR2, or AA tyrosine kinase inhibitors (TKI) have inconsistently shown benefit in combination with CT or erlotinib (E). We performed an individual patient data (IPD) meta-analysis to validate efficacy of these combinations as 2LT.

      Methods

      Randomized trials of AA plus standard 2LT (CT or TKI) compared to 2LT alone that ended accrual before 2015 were identified from publication databases, abstract proceedings and trial registers. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, primary endpoint), progression-free survival (PFS) and subgroup analyses. Peto method was used to estimate survival benefit.

      Results

      IPD were available for 15 out of 17 eligible trials (only via remote access for 9 trials). Out of 8,502 patients (pts) enrolled, 35% were female and 64% had adenocarcinoma. At 3 years, 10.5% were alive. Addition of AA significantly prolonged OS (HR=0.93 [95% confidence interval (CI): 0.89-0.98], p=0.005) and PFS (0.80 [0.77-0.84], p<0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.9% [95% CI: -0.3%;+4.1%] and +3.6% [+2.0%;+5.2%] respectively. According to the 3 types of combinations (mAb AA + CT, TKI AA + CT, AA + E), there was no significant interaction for OS. Interaction was significant for PFS (p=0.004): HR=0.78 [0.72-0.85], 0.86 [0.80-0.91] and 0.70 [0.63-0.77] respectively. There was a significant reduction of AA benefit on OS when age increased: 0.86 [0.75-0.99], 0.89 [0.81-0.97], 0.94 [0.87-1.02] and 1.04 [0.93-1.17] for pts <50, 50-59, 60-69 and ≥70 respectively (interaction p=0.009). Effect of AA was independent of sex (p=0.98) and performance status (0, ≥1; p=0.78) and ethnicity (Asian, non-Asian, p=0.38). Subgroup results were similar for PFS.

      Conclusion

      In the 2LT of advanced NSCLC, adding AA modestly but significantly prolongs OS and PFS. This appears independent of type of AA drugs, but the observed benefit may be higher in younger pts.

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    P16 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Translational) (ID 155)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
    • +

      P16.07 - Immuno-Modulatory Effects of Ceralasertib in Combination with Durvalumab in NSCLC with Progression on Anti-PD(L)1 Treatment (HUDSON)  (ID 3491)

      00:00 - 00:00  |  Presenting Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      The HUDSON platform trial (NCT03334617) is a multi-arm clinical trial for patients with non-small cell lung cancer (NSCLC) who had tumour progression on anti-PD(L)1 immunotherapy and received prior platinum-doublet chemotherapy. We report preliminary translational data, where available, from patients treated with ceralasertib (an ataxia telangiectasia and Rad3-related protein inhibitor, ATRi) and the PDL1 inhibitor durvalumab.

      Methods

      The study protocol included analyses of archival and fresh tumour biopsies, and longitudinal liquid biopsies. Patients were enrolled into biomarker matched (ATM-selected) or unmatched arms after the development of primary or acquired resistance to PD-(L)1 immunotherapy. Primary and acquired resistance were defined as progression before or after 6 months on anti-PD(L)1 therapy respectively. Biomarker status was determined using next generation sequencing (Foundation Medicine) for ATM mutation status or immunohistochemistry (IHC, Ventana) for ATM protein expression. Gene expression from whole blood samples (PAXgene®) was analysed using the PanCancer IO gene panel from Nanostring Technologies.

      Results

      Translational data are currently only available from a subset of patients. Clinical response data will be presented separately. Tumour and liquid biopsy samples were collected from patients treated with ceralasertib and durvalumab. Gene expression data were available from 8 ATM biomarker-positive and 17 biomarker-negative patients. Peripheral gene expression analyses in responding patients showed greater than two-fold higher granzyme levels at baseline, when compared with non-responders. The 19 patients with controlled disease on ceralasertib (partial response or stable disease by RECIST v1.1) and available gene expression data also showed a two-fold reduction in peripheral IL-8 gene expression in paired blood samples when compared with the six patients showing progressive disease with available gene expression data. Samples collected during a ceralasertib-only period prior to durvalumab treatment showed modified biomarkers of peripheral immunity including significant increases in antigen presentation gene signature and significant decreases in both exhausted T cell and NK cell signatures from bulk whole-blood RNA samples. Ceralasertib also decreased 4 macrophage gene expression signatures in on-treatment samples. Similar gene expression profiles were not observed from comparable samples on other HUDSON arms. No correlation between ATM biomarker status and RECIST response was observed. No significant correlations with ceralasertib response were observed between tumour mutation burden or PDL1 status by IHC.

      Conclusion

      Taken together, these data support a role of immune activation by ceralasertib as a feature of response to combination therapy with ceralasertib plus durvalumab in NSCLC following progression on anti-PD(L)1.

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    P33 - Pathology - Immunotherapy Biomarker (ID 101)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
    • +

      P33.10 - Identification of Long-Responders and Fast-Progressors under Immunotherapy Based on Early Monitoring of dNLR in Advanced NSCLC Patients (ID 2519)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      The dNLR score, based on [neutrophil/(leucocytes-neutrophils)] ratio (dNLR) at baseline (B) and before 2nd cycle (C2), has been correlated with immune checkpoint inhibitors (ICI) outcomes in NSCLC patients. We aimed to assess whether dNLR score can identify the different response phenotypes to ICI in NSCLC, particularly the fast-progressors (FP) and long-responders (LR) under ICI.

      Methods

      Advanced NSCLC patients receiving ICI between Nov.12 and Jan.19, were enrolled in Gustave Roussy. dNLR was retrospectively collected at B and C2. Patients were categorized as low vs. high-dNLR at each time-point (defined as ≤3 or >3), and the change between B and C2 (good = low at both time-points, poor = high at both time-points, mixed = different at each time-point). Response types were evaluated: a) “responder” (objective response (ORR) and progression-free survival (PFS) >6 months (mo.)), b) “LR” (ORR + PFS >12 mo. and median overall survival (OS) >24 mo.), c) “standard-progressor" (PD) (progressive disease as best response; not including FP) and d) “FP” (defined as early death within the 1st 12 weeks).

      Results

      469 patients were included: 65% males, 90% smokers, median age of 63, 75% performance status ≤1; adenocarcinoma histology in 66% and 12% harboring driver alterations. PD-L1 was ≥1% in 143/259 (55%), missing in 210 patients. The ORR was 19% (80/431); 15% were LR, 35% standard-PD and 13% FP. Overall, the median OS was 10.0 mo. [95% CI, 8.2-12.2]; 45.2 mo. [95% CI, 31.9-not reached] in LR, 4.2 mo. [95% CI, 3.2-5.7] in PD and 0.7 mo. [95% CI, 0.6-0.9] in FP population. dNLR (B) was high in 41% of FP vs. 44% of standard-PD vs. 27% of LR (P<0.001). dNLR (C2) was high in 81% of FP vs. 45% of PD vs. 14% of LR (P<0.001). Response phenotypes were strongly correlated with the dNLR score subgroups (table 1).

      Overall

      N=291

      Long-responder

      N=48

      Responder

      N=108

      Standard progressor

      N=116

      Fast-progressor

      N=16

      P value
      Good 151 (52%) 32 (67%) 65 (60%) 52 (45%) 2 (13%) <0.001
      Intermediate 71 (24%) 13 (27%) 24 (22%) 30 (26%) 3 (19%) <0.001
      Poor 69 (24%) 3 (6%) 19 (18%) 34 (29%) 11 (69%) <0.001

      Conclusion

      The dNLR score, especially at C2, is an accessible and simple tool that can add information to radiological examination discriminating the different phenotypes of response under ICI, particularly aggressive patterns such as FP.

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    P34 - Pathology - Liquid Biopsy (ID 104)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
    • +

      P34.06 - The Clinical Utility of Liquid Biopsy by Digital Droplet PCR in Patients with Advanced NSCLC (ID 3190)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      EGFR mutations occur in 15% of Caucasian and up to 50% of Asian patients with advanced NSCLC. Tissue genomic profiling is the gold standard but the liquid biopsy is a good surrogate of the tissue for molecular diagnosis. The digital droplet PCR (ddPCR) is a rapid and low-cost liquid biopsy technique for genomic analyses. We aimed to evaluate the clinical utility of the ddPCR for genomic profiling of advanced NSCLC with EGFR mutations.

      Methods

      The ddPCR technique was prospectively applied in a cohort of advanced EGFR mutant (EGFRmut) NSCLC patients either at baseline or at the time of at failure to tyrosine kinase inhibitor (TKI). Ten ml of blood sample were collected and centrally analyzed. Blood samples were centrally analyzed by ddPCR. Clinical and molecular data were also recorded. We assessed the liquid biopsy sensitivity at baseline for activating EGFR mutations (EGFRmut) and at progression for activating and T790M resistance EGFR mutations.

      Results

      A total of 70 samples (15 collected at baseline and 55 at disease progression) were collected in 41 patients included (27 (66%) with EGFR exon 19 [Del19], 14 (34%) with EGFR exon 21 mutations [L858R], median age of 62 years, 27 (66%) were females, 27 (66%) never-smokers and 37 (90%) had adenocarcinoma). At the moment of sample collection, patients had a median number of 3 metastatic sites [range: 1-6].

      At baseline, ddPCR detected 87% of cases (13/15) with an EGFRmut; 90% (9/10) and 80% (4/5) for Del19 and L858R, respectively. The 2 negative cases had single sites of progression in bone and pleura, respectively.

      At disease progression, EGFRmut by ddPCR was detected in 55% (30/55); 58% (22/38) for Del19, and 47% (8/17) for L858R. Of note, brain was the most common site of progression (42%). Among the cases with activating EGFRmut detected in blood at progression after first and second generation TKI, the EGFR T790M mutation was found in 35% (6/17) samples. The median number of metastatic sites was 4 [2-4] in T790M-positive vs. 2 [1-5] in T790M-negative.

      In patients with isolated central nervous system progression (iCNS), EGFRmut was detected in 33% (5/15), and 2 cases had EGFR T790M. In patients with isolated thoracic progression, 60% (9/15) had positive EGFRmut, among who one case had the EGFR T790M mutation.

      Conclusion

      Liquid biopsy by digital PCR is a high sensitive tool for EGFR detection at diagnosis. At progression, liquid biopsy positivity for activating and resistance mutations was more likely observed in case of systemic progression and a high tumor burden. ddPCR could be used to provide a rapid molecular result to guide treatment selection in NSCLC.

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    P53 - Tumor Biology and Systems Biology - Basic and Translational Science - Misc. Topics (ID 213)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
    • +

      P53.02 - Integrated Profiling of Advanced Non-Small-Cell Lung Cancer: The EORTC IMMUcan Project - Lung Cohort (ID 953)

      00:00 - 00:00  |  Presenting Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      Immune checkpoint inhibitors (ICIs) and targeted agents dramatically changed the therapeutic landscape for advanced Non-Small-Cell lung cancer (NSCLC) patients at the first-line setting. While cancers harbouring a specific molecular alteration usually get some clinical benefit from targeted therapeutics, our knowledge regarding predictive biomarkers of response to ICIs is limited. The PD-L1 expression and the Tumor Mutational Burden (TMB) level alone showed disappointing predictive values in phase III trials, highlighting the urgent need for a better understanding on how to select patients. Moreover, the increase of combination therapy trials to maximize patient benefit makes the issue even more complex. Indeed, each of these therapies may have a different impact on tumor microenvironment possibly modifying the tumor-immune system interplay. A better understanding of the tumor and its microenvironment as well as the impact of current therapeutic interventions is therefore needed. The combination of molecular, cellular, and clinical information, including patient’s response to ICPis would help in the comprehension of tumor-immune system interaction complexity and future clinical trials development.

      Methods

      IMMUcan is a European, prospective, translational research study, enrolling several cohorts of cancer patients, treated according to standard of care and to their own physicians. The Lung Cohort aims to include 700 patients having a diagnosis of a locally advanced/metastatic NSCLC, treatment-naïve and supposed to receive a first-line treatment by a target agent or ICI (alone or combined with chemotherapy) as per standard of care. Tissue and blood samples are collected along with clinical data at baseline and, when available, at first progression. Biological material is analyzed by tumor RNA-seq and Whole Exome Sequencing (WES) but also by multiplex immunofluorescence and Imaging Mass Cytometry focusing on the tumor microenvironment (IMMUcan workflow in Figure 1). All biological characteristics and clinical data are analyzed together with the goal of understanding the tumor microenvironment and the effect of current therapeutic interventions and to discover new biomarkers or therapeutic targets. To note a clinical report based on RNA-seq and WES data along with the advice from the EORTC Mutational Tumor Board is returned to physicians with a median turnaround of 6 weeks for treatment decision. The study is open with 45 patients registered at time of submission.

      immucan image.jpg

      Figure 1: IMMUcan workflow

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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
    • +

      P77.04 - PROPEL: A Phase 1/2 Trial of Bempegaldesleukin (NKTR-214) Plus Pembrolizumab in Lung Cancer and other Advanced Solid Tumors (ID 1548)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      Checkpoint inhibitors (CPIs), are now part of standard treatment in many advanced solid tumors, including metastatic non-small cell lung cancer (NSCLC). However, novel, more effective CPI combinations are needed to broaden, deepen, and prolong responses, especially for patients with poor prognostic features or negative predictive clinical factors for CPI benefit, including programmed death-ligand 1-negative (PD-L1[-]) status. Bempegaldesleukin (BEMPEG; NKTR-214) is a first-in-class CD122-preferential interleukin-2 pathway agonist that directly activates and expands effector T cells and natural killer cells over immunosuppressive regulatory T cells. BEMPEG plus CPI combination has demonstrated promising efficacy and can convert PD-L1(-) tumors to PD-L1(+) in patients with various solid tumors.(1,2) Given the early efficacy data and favorable safety profile of BEMPEG plus nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of BEMPEG combined with another CPI, pembrolizumab (PEMBRO). Here, we present the updated methodology and protocol for the enrolling PROPEL study.(3)

      Methods

      This phase 1/2 multinational trial evaluates BEMPEG plus PEMBRO in patients with locally advanced or metastatic solid tumors. During dose escalation (US only), ~40 patients with various advanced solid tumors (first- and second-line melanoma, NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, and hepatocellular carcinoma; regardless of PD-L1 status) will be treated with escalating doses of BEMPEG plus PEMBRO according to a 3+3 or step-up design. During dose expansion (global), ~58 patients with previously untreated advanced or metastatic NSCLC will be enrolled, and stratified based on PD-L1 status (<1%, 1-49%, and >50% staining on tumor cells by immunohistochemistry [for France only, patients with PD-L1 ≤49% will be excluded]). The primary objectives of the dose escalation are to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase 2 dose for BEMPEG in combination with PEMBRO. The primary objective of the dose expansion is objective response rate (by RECIST 1.1) in first-line metastatic NSCLC. Enrollment is ongoing (NCT03138889).

      References: 1. Diab A, et al. J Immunotherapy Canc 2019;7(1 suppl):3006; 2. Siefker-Radtke A, et al. J Clin Oncol 2019;37(7 suppl):388; 3. Reck M, et al. Poster presented at ESMO 2019; Poster 127TiP.

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    P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
    • +

      P84.01 - The ARIA Study: Activity of Next-Generation ALK TKIs Based on ALK Resistance Mutations Detected by Liquid Biopsy in ALK Positive NSCLC Patients. (ID 3092)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      Detection of resistance mechanisms to tyrosine kinase inhibitors (TKI), in particular ALK mutations (ALKm), could help to select the subsequent treatment in ALK-positive NSCLC patients. Liquid biopsy can identify these ALKm from ctDNA in up to 29% of patients after 2nd-generation TKI-failure. We assessed the activity of next-gen TKIs based on the presence of ctDNA ALKm.

      Methods

      Patients with ALK-positive advanced NSCLC pretreated with 1st and/or 2nd-generation ALK-TKI were selected in 9 European centers. Liquid biopsy was collected immediately before starting brigatinib or lorlatinib. ALKm were defined by commercial or homemade next-generation sequencing run on ctDNA and covering ALK exon 22/23/25. We correlated the activity of brigatinib or lorlatinib based on three ctDNA molecular groups: presence ALKm (if one: single; if ≥2: complex); other mutations and no detectable mutations. We assessed progression-free survival (PFS), objective response rate (ORR), intracranial ORR according to the clinical routine of each center and overall survival (OS).

      Results

      62 patients were identified, 58 evaluable at cutoff data (Jul-20): 16 before brigatinib and 42 before lorlatinib. Median age was 53 [27-80], 64% were female, 67% nonsmoker; 97% with adenocarcinoma; 7% and 10% with isolated thoracic and brain disease, respectively. The median (m) number of TKIs was 3 [2-7]; 90% received 2nd-generation TKIs. The mFU since liquid biopsy was 24.8 months. ALKm were detected in 28% (3 brigatinib; 13 lorlatinib), 9 single and 7 complex; others were detected in 17% (n=10) and none in 55% (n=32). The most common mutation was G1202R (7 before lorlatinib), followed by G1269A and F1174L in 3 cases each, all pretreated with 2nd-generation TKIs. The TKI outcomes according to the ctDNA molecular groups is summarized in table 1. In the ALKm group, lorlatinib showed an ORR of 46% and 56% of intracranial ORR with mPFS of 6.5 months (7=single/6=complex) while no responses were observed in the 3 cases treated with brigatinib, with mPFS of 3.5 months (2=single/1=complex).Those 7 cases harboring the G1202Rmut (4=complex) had an ORR of only 14% but an intracranial ORR of 50%; mPFS was 3.6 mo. No differences were observed among ctDNA molecular groups.

      Overall

      ALK mutations

      Others

      None

      BRIGATINIB

      N=16

      n= 3

      n=3

      n= 10

      PFS, median (95% CI)

      5.6 months

      (4.27-16.79)

      3.5 months

      (2.63-NR)

      6.2 months

      (4.27-NR)

      8.1 months

      (4.40-NR)

      12 months-PFS rate

      27.3 %

      (11.9-62.6)

      33.3%

      (6.7-100)

      0%

      40%

      (18.7-85.5)

      ORR

      27%

      (4/15)

      0%

      (0/3)

      67%

      (2/3)

      22%

      (2/9)

      ORR CNS

      50%

      (6/12)

      0%

      (0/2)

      100%

      (2/2)

      50%
      (4/8)

      OS*, median (95% CI)

      62.6 months

      (31.7-not reached)

      38.4 months

      (31.7-NR)

      62.6 months

      (21 .4-NR)

      NR

      (24.5-NR)

      LORLATINIB

      N= 42

      n= 13

      n= 7

      n= 22

      PFS, median (95% CI)

      7.6 months

      (5.26- 11.14)

      6.5 months

      (3.61-NR)

      7.6 months

      (5.22-NR)

      7.3 months

      (4.63-NR)

      12 months-PFS rate

      29.5%

      (17.7-49.1)

      30%

      (12.0-74.7)

      28.6%

      (8.9-92.2)

      30%

      (14.6-61.6)

      ORR

      38%

      (16/58)

      46%

      (6/13)

      71%

      (5/7)

      23%

      (5/22)

      ORR CNS

      62%

      (18/29)

      56%

      (5/9)

      60%

      (3/5)

      67%

      (10/15)

      OS*, median (95% CI)

      55.5 months

      (45.0-NR)

      62.6 months

      (54.8-NR)

      45.0 months

      (24.5-NR)

      NR

      (41.9-NR)

      PFS: progression-free survival; ORR: objective response rate; CNS: central nervous system; OS: overall survival; *since systemic therapy start

      Conclusion

      In our study, lorlatinib showed activity in heavily-pretreated patients with ALK-positive NSCLC, regardless the ctDNA molecular groups. Poor outcomes were observed for brigatinib in 3 heavily-pretreated patients with ctDNA ALKm. The recent use of 2nd-gen TKI upfront calls for similar studies to confirm if ctDNA may be a biomarker for guiding the sequential therapy.

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    P87 - Targeted Therapy - Clinically Focused - RET (ID 264)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P87.02 - AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET-Fusion+ Advanced/Metastatic NSCLC (ID 1787)

      00:00 - 00:00  |  Presenting Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). The investigational oral RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multi-kinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), patients with RET-fusion+ NSCLC treated with pralsetinib 400 mg once daily (QD) after platinum-based chemotherapy (n=80) achieved an overall response rate (ORR) of 61% (95% CI 50, 72; two responses pending confirmation) per independent central review. In addition, an ORR of 73% (all centrally confirmed responses) was attained in the systemic treatment naïve cohort (n=26). Most treatment-related adverse events were grade 1–2 across the entire safety population treated with pralsetinib 400 mg QD (N=354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) in first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). This abstract was previously submitted to the American Society of Clinical Oncology 2020 annual meeting, May 29 to June 2, 2020, and to the IASLC 2020 North America Conference on Lung Cancer meeting in Chicago, Illinois, United States of America, October 16 to 17, 2020.

      Methods

      Approximately 250 patients with advanced/metastatic RET-fusion+ NSCLC will be randomized 1:1 to pralsetinib 400 mg QD or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status 0 vs 1. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET-fusion+ tumor by local or central assessment, no additional actionable oncogenic drivers, no prior treatment with a selective RET inhibitor, and measurable disease per RECIST v1.1. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability, and quality of life. Recruitment has begun with sites (active or planned) in North America, Europe, Asia, and Australia.

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    P90 - Targeted Therapy - Clinically Focused - Misc. Topics (ID 267)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P90.04 - RAS Precision Medicine Trans-Atlantic Partnership: Multi-Centre Pooled Analysis of RAS Pathway Mutations in Advanced NSCLC (ID 3663)

      00:00 - 00:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      The most common histological subtype of non-small cell lung cancer (NSCLC) is adenocarcinoma (50-55% of patients), of which the most common oncogenic driver is KRAS mutation (~30% internationally). Genetic data has altered the taxonomy of NSCLC over the past 10 years, highlighting subgroups such as EGFR mutation, which have improved prognosis and are susceptible to targeted therapies. Despite its frequency, targeting RAS has historically been limited by pre-clinical and clinical failures. Emerging preclinical/clinical data suggests there is value looking beyond RAS mutation, analysing subtypes- represented by a limited number of variations in its mutational isoforms, codons and alleles. Through international collaboration our partnership aims to extend existing knowledge of RAS precision medicine in NSCLC, evaluating biological, clinical and treatment effects at subtype level.

      Methods

      For this analysis, the first 309/384 patients with stage IIIb/IV RAS- and/or NF1-mutant NSCLC were identified from the Christie NHS Foundation Trust and the Gustave Roussy Cancer Centre between August 2008 and July 2020. DNA was extracted from archival FFPE samples, plasma or both to identify mutations using targeted next generation sequencing. Molecular, clinical, pathological and outcome data were collected on all patients and Kaplan-Meier survival analysis was performed to test for survival differences between subtypes based on treatment arms. For clinical characteristics, Mann-Whitney and Fisher’s exact tests were used for statistical comparisons in continuous and dichotomous datasets, respectively.

      Results

      Of 309 patients analysed, 151 patients were from the Christie NHS Foundation Trust and 158 patients from the Gustave Roussy Cancer Centre. Mean age was 63, range 19-92. 30 patients (10%) had stage IIIb disease with the remainder stage IV, 292 patients (94.5%) demonstrated non-squamous histology vs. 16 (5%) squamous vs 1 (0.5%) adenosquamous. Median PD-L1 status across the cohort was 20%. 209 patients (68%) had a mutation identified by tissue analysis, 38 patients (12%) by plasma and 62 (20%) by both. The most common RAS mutation identified was KRAS in 259 patients (84%), followed by NRAS in 13 patients (4%) and HRAS in 7 patients (2%). Amongst the KRAS mutant population, 111 pts (43%) harboured a mutation in G12C, followed by 52 (20%) G12D and 41 (16%) G12V. Codon 61 was most commonly mutated within this subgroup 16/259 (6%). 40 patients (13%) were identified as carrying a mutation in NF1; 35 non-squamous histology, 4 squamous and 1 adenosquamous. Progression free survival following first line chemotherapy plus immunotherapy or immunotherapy alone was variable across KRAS-, NRAS- and NF1-mutant subgroups (8.3 vs. 14.9 vs. 10.2 months; p=0.86). Median PD-L1 status was found to be 63% vs. 100% vs. 79% respectively. Analysis of RAS codon and allelic subgroups, including their therapeutic vulnerabilities beyond immunotherapy, will be presented following further analysis.

      Conclusion

      The RAS precision medicine Trans-Atlantic partnership is designed to evaluate prognostic/predictive value of RAS and NF1 mutations in advanced NSCLC, focusing specifically on signal seeking for therapeutic vulnerabilities in mutant RAS isoforms, codons, and allelic subtypes. Ongoing analysis is planned to expand the dataset and inform the optimal sequence of therapy for subtypes of RAS- and NF1-mutant patients.

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    PL03 - Bench to Bedside (Immunology) (Japanese, Mandarin, Spanish Translation Available) (ID 142)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 1
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      PL03.02 - Chair (ID 3910)

      18:00 - 20:00  |  Presenting Author(s): Benjamin Besse

      • Abstract

      Abstract not provided

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    PS01 - Presidential Symposium (Japanese, Mandarin, Spanish Translation Available) (ID 143)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 1
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      PS01.07 - CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer (ID 3037)

      07:00 - 09:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction

      Outcome in patients with advanced non-small cell lung cancer (NSCLC) on second- or third-line therapies is poor, with a response rate of <20% and median progression-free survival (PFS) of <4 months. Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutation. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. In the phase 1 cohort of the CodeBreaK 100 trial (NCT03600883), sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response (DoR) of 10.9 months, and a median PFS of 6.3 months in patients with heavily pretreated NSCLC. Here, we present for the first time the primary analysis from the registrational phase 2 portion of the trial.

      Methods

      This international, single-arm, phase 2 study evaluated the efficacy and safety of sotorasib, administered orally once daily at 960 mg, in the cohort of patients with locally advanced or metastatic KRAS p.G12C mutant NSCLC. Key inclusion criteria: centrally confirmed KRAS p.G12C; progression on anti-PD-1/PD-L1 immunotherapy and/or platinum-based combination chemotherapy, and targeted therapy if EGFR, ALK, and ROS1 alterations were identified; and ≤3 prior lines of therapy. Patients with untreated active brain metastases were excluded. Primary endpoint was confirmed objective response rate (ORR), assessed by blinded independent central review per RECIST 1.1. Key secondary endpoints included disease control rate (DCR), PFS, DoR, and safety.

      Results

      Data cutoff was September 1, 2020. A total of 126 patients were enrolled and received at least 1 dose of sotorasib. Median follow-up time on study was 9.3 months (range: 1.1+ to 12.2). Median age was 63.5 years (range: 37 to 80), and 117 (92.9%) were former or current smokers. 72 (57.1%) patients received 2 or 3 prior lines of anticancer therapy. 91.3% received anti-PD-1/PD-L1 immunotherapy, and 81.0% received both platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy. Per central review, 123 patients had at least 1 measurable lesion at baseline and were evaluated for efficacy. 46 patients experienced a confirmed response (2 complete responses and 44 partial responses), resulting in an ORR of 37.4% (95% Cl: 28.8–46.6). At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1). Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients and led to discontinuation in 9 (7.1%) patients. Grade ≥3 TRAEs were reported in 26 (20.6%) patients; those that occurred in >3% of patients were alanine aminotransferase increase (8/126, 6.3%), aspartate aminotransferase increase (7/126, 5.6%), and diarrhea (5/126, 4.0%). No fatal TRAEs were reported.

      Conclusion

      In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C, validating the previous phase 1 results. After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need. Updated data including DoR, PFS, and biomarkers will be presented.

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    PS02 - Presidential Symposium (Re-Broadcast) (Japanese, Mandarin, Spanish Translation Available) (ID 275)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 1
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      PS02.07 - CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer (ID 4290)

      18:00 - 20:00  |  Author(s): Benjamin Besse

      • Abstract
      • Slides

      Introduction
      Outcome in patients with advanced non-small cell lung cancer (NSCLC) on second- or third-line therapies is poor, with a response rate of <20% and median progression-free survival (PFS) of <4 months. Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutation. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. In the phase 1 cohort of the CodeBreaK 100 trial (NCT03600883), sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response (DoR) of 10.9 months, and a median PFS of 6.3 months in patients with heavily pretreated NSCLC. Here, we present for the first time the primary analysis from the registrational phase 2 portion of the trial. Methods
      This international, single-arm, phase 2 study evaluated the efficacy and safety of sotorasib, administered orally once daily at 960 mg, in the cohort of patients with locally advanced or metastatic KRAS p.G12C mutant NSCLC. Key inclusion criteria: centrally confirmed KRAS p.G12C; progression on anti-PD-1/PD-L1 immunotherapy and/or platinum-based combination chemotherapy, and targeted therapy if EGFR, ALK, and ROS1 alterations were identified; and ≤3 prior lines of therapy. Patients with untreated active brain metastases were excluded. Primary endpoint was confirmed objective response rate (ORR), assessed by blinded independent central review per RECIST 1.1. Key secondary endpoints included disease control rate (DCR), PFS, DoR, and safety. Results
      Data cutoff was September 1, 2020. A total of 126 patients were enrolled and received at least 1 dose of sotorasib. Median follow-up time on study was 9.3 months (range: 1.1+ to 12.2). Median age was 63.5 years (range: 37 to 80), and 117 (92.9%) were former or current smokers. 72 (57.1%) patients received 2 or 3 prior lines of anticancer therapy. 91.3% received anti-PD-1/PD-L1 immunotherapy, and 81.0% received both platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy. Per central review, 123 patients had at least 1 measurable lesion at baseline and were evaluated for efficacy. 46 patients experienced a confirmed response (2 complete responses and 44 partial responses), resulting in an ORR of 37.4% (95% Cl: 28.8–46.6). At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1). Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients and led to discontinuation in 9 (7.1%) patients. Grade ≥3 TRAEs were reported in 26 (20.6%) patients; those that occurred in >3% of patients were alanine aminotransferase increase (8/126, 6.3%), aspartate aminotransferase increase (7/126, 5.6%), and diarrhea (5/126, 4.0%). No fatal TRAEs were reported. Conclusion
      In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C, validating the previous phase 1 results. After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need. Updated data including DoR, PFS, and biomarkers will be presented.

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