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Carlo Genova

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-02 - Interim Survival Analysis of Gefitinib Plus Vinorelbine in Advanced EGFR-Mutant Non-Small Cell Lung Cancer (Genoa Trial) (ID 2578)

      10:15 - 18:15  |  Presenting Author(s): Carlo Genova

      • Abstract


      Patients affected by advanced non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR) are eventually destined to experience disease progression in spite of initial benefit from EGFR Tyrosine kinase inhibitors (TKIs). Preclinical studies have suggested that combining cytotoxic agents with EGFR TKIs to treat EGFR-mutant tumors may increase their inhibitory effect; in a preclinical study conducted within our Institution, the administration of vinorelbine followed by gefitinib resulted in increased activity due to synergistic effect of the combined drugs. Here we present the interim analysis of GEfitinib plus viNorelbine in Advanced EGFR mutated NSCLC (GENOA TRIAL), which was designed to investigate the role of oral vinorelbine followed by gefitinib for the management of treatment-naïve patients affected by EGFR-mutant NSCLC ( NCT02319577).


      This was a multi-centric, open-label, randomized phase II trial designed to explore activity and tolerability of vinorelbine followed by gefitinib compared to gefitinib alone in patients affected by EGFR-mutant NSCLC. The estimated enrolment was equal to 80 patients; enrolled patients were randomized (1:1) to receive oral vinorelbine (60 mg/m2) on days 1,8 followed by gefitinib (250 mg) on days 9-21 (Arm A) or gefitinib alone (250 mg) on days 1-21 (Arm B) in three-weekly cycles. The primary end-point of the study was to determine the increase in terms of 6-month progression free survival (PFS) rate with Arm A compared to Arm B, while median PFS and median overall survival (OS) were secondary end-points; PFS data were defined according to response evaluation criteria in solid tumors (RECIST) v.1.1. Safety was assessed according to common terminology criteria for adverse events (CTCAE) v. 4.0.


      Data from 44 patients (Arm A= 23; Arm B= 21) are available for this interim analysis, with a median follow up of 19.1 months. All the patients had advanced lung adenocarcinoma with EGFR mutation (exon 18=2; exon 19= 16; exon 21= 21; multiple exons= 5). The 6-month PFS rate was 48% for Arm A compared to 66% for Arm B (Fisher p= 0.24). Median PFS was 6.2 months for Arm A vs. 9.5 months for Arm B (Log Rank p= 0.17), while median overall survival (OS) was 18.2 months for Arm A and not reached for Arm B (Log Rank p= 0.12). Response rate was 47% for Arm A vs. 55% for Arm B (Fisher p= 0.76). Severe adverse events (AEs) were similarly uncommon in both arms; more specifically, two patients in Arm A experienced grade 3 white blood cells reductions, and two patients in Arm B experienced grade 3 increase of liver alanine aminotransferase. No treatment-related deaths were reported.


      At the interim analysis of GENOA Trial, the combination of oral vinorelbine plus gefitinib was not associated with increased 6-month PFS rate over gefitinib alone; similarly, no advantages in terms of response, PFS or OS were observed in the experimental arm. With regards to safety, no significant difference in terms of AEs was reported, nor unexpected toxicity was observed. The study was interrupted on the basis of this interim analysis.

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    PC05 - Immune Chekpoint Inhibitors in Real World - How Do We Treat NSCLC ''Special Populations'' (ID 87)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      PC05.02 - Are ICIs Effective for Poor Performance Status Patients with Advanced NSCLC? (Now Available) (ID 3575)

      14:30 - 16:00  |  Author(s): Carlo Genova

      • Abstract
      • Presentation
      • Slides


      The management of non-small cell lung cancer (NSCLC) in patients with poor performance status (PS) has always been a challenging task. Until the last decade, platinum-based chemotherapy has been the main therapeutic approach to NSCLC, and is retaining a major role in patients without actionable oncogenic drivers and low expression of programmed death protein ligand 1 (PD-L1). However, patients with poor PS are generally excluded from combination-based regimens and from enrollment in novel clinical trials [1]. While immunotherapy with immune checkpoint inhibitors (ICIs) has become a cornerstone in the management of advanced NSCLC, data regarding its role in ECOG PS=2 patients are generally limited; indeed, the most relevant phase III randomized controlled trials involving ICIs in advanced NSCLC have excluded ECOG PS=2 patients, resulting in a general lack of recommendations from international guide-lines [2]. The currently available information on this specific population has been collected from a handful of clinical studies, all of them involving patients receiving ICIs in second or further lines. In the phase II CheckMate 171 trial, 98 ECOG PS= 2 previously treated patients with squamous NSCLC received single-agent nivolumab; in the preliminary data, the safety profile of nivolumab and the objective response rate (ORR) in ECOG PS=2 patients were globally similar to the overall population, while median overall survival (mOS) was lower, as expected due to the prognostic effect of PS [3]. The phase III-IV CheckMate 153 trial, designed to assess safety of nivolumab in pre-treated NSCLC patients, showed similar results, but notably, in patients with ECOG PS=2, a significant improvement in symptom burden was observed [4]. An additional source of data for unfit NSCLC patients treated with ICIs is represented by expanded access programs (EAPs), in which real-life patients received nivolumab before its registration. In the largest EAP (Italian nivolumab non-squamous NSCLC cohort), 108 pre-treated ECOG PS=2 patients received nivolumab; the independent negative prognostic role of ECOG PS on survival was confirmed, while no safety issues were observed [5]. In contrast with the previous studies, the PEPS2 trial was specifically designed to assess the role of pembrolizumab in a population of previously treated NSCLC patients with ECOG PS=2. The study is currently ongoing, although the data reported so far encourage the use of pembrolizumab in this population; moreover, PD-L1 tumor proportion score appeared to be associated with survival [6]. In conclusion, while the well-known prognostic effect of poor performance status is observed during administration of ICIs, the safety profile and the activity of these agents make immunotherapy a feasible strategy for treating unfit NSCLC patients, especially when single-agent ICIs are administered, although limited outcomes in terms of survival are to be taken into account when choosing whether to offer active antineoplastic treatment to unfit patients or not; since ECOG PS=2 represents a wide range of patients, this choice needs to be made on an individual basis. Notably, a limit of the aforementioned data is represented by the lack of comparison with chemotherapy in controlled randomized studies; to fill this gap, some ongoing trials are being conducted: more specifically, the IPSOS trial is designed to enroll patients who are unfit for platinum-based chemotherapy and randomize them to atezolizumab vs. single-agent chemotherapy [7], while another trial (NCT02581943) is designed to compare pembrolizumab alone or in combination with low-dose carboplatin-paclitaxel [8]; finally, the eNERGY trial is designed to compare ipilimumab-nivolumab with a carboplatin-based doublet in ECOG PS=2 patients [9]. The availability of data from these and similar studies will provide additional insights on the role of ICI in unfit NSCLC patients.



      ECOG PS=2 patients

      (% of global population)

      Results in ECOG PS=2 (results in global population)

      CheckMate 171 (phase II)


      98 (12%)

      TRAEs= 46% (50%)

      Grade 3-4 TRAEs= 6% (12%)

      mOS= 5.4 months (9.9)

      ORR= 11% (14%)

      CheckMate 153 (phase III-IV)


      128 (9%)

      TRAEs= 48% (62%)

      Grade 3-4 TRAEs= 11% (12%)

      mOS= 4.0 months (9.1)

      Italian non-squmous EAP


      108 (7%)

      Compared to PS=0-1: increased risk of OS < 3 months (odds ratio at multivariate analysis= 0.29 (0.19-0.44)

      PEPS2 (phase II)


      60 (100%)

      Grade 3-4 TRAEs= 12%

      mPFS= 5.4 months

      mOS= 11.7 months

      ORR= 28%

      Table 1. Studies involving ICIs in ECOG PS=2 patients with NSCLC.


      [1] Carmichael JA, Wing-San Mak D, O'Brien M. A Review of Recent Advances in the Treatment of Elderly and Poor Performance NSCLC. Cancers (Basel). 2018;10(7).

      [2] Passaro A, Spitaleri G, Gyawali B, et al. Immunotherapy in Non-Small-Cell Lung Cancer Patients With Performance Status 2: Clinical Decision Making With Scant Evidence. J Clin Oncol. 2019:JCO1802118.

      [3] Popat S, Ardizzoni A, Ciuleanu TE, et al. 1303PD Nivolumab in previously treated patients with metastatic squamous NSCLC: Results of a European single-arm, phase 2 trial (CheckMate 171) including patients aged ≥70 years and with poor performance status. Annals of Oncology, Volume 28, Issue suppl_5, September 2017, mdx380006, https://doiorg/101093/annonc/mdx380006. 2017.

      [4] Spigel DR, McCleod M, Jotte RM, et al. Safety, Efficacy, and Patient-reported Health-related Quality of Life and Symptom Burden with Nivolumab in Patients with Advanced Non-Small Cell Lung Cancer, Including Patients Aged >/=70 Years or with Poor Performance Status (CheckMate 153). J Thorac Oncol. 2019.

      [5] Grossi F, Crino L, Delmonte A, et al. 1156P - Italian nivolumab expanded access programme: real-world results in non-squamous non-small cell lung cancer patients. Annals of Oncology (2017) 28 (suppl_5): v403-v427. 2017.

      [6] Middleton G, Brock K, Summers Y, et al. Pembrolizumab in performance status 2 patients with non-small-cell lung cancer (NSCLC): results of the PePS2 trial. Annals of Oncology (2018) 29 (suppl_8): viii493-viii547. 2018.

      [7] A Study of Atezolizumab Compared With Chemotherapy in Treatment Naïve Participants With Locally Advanced or Recurrent or Metastatic Non-Small Cell Lung Cancer Who Are Deemed Unsuitable For Platinum-Containing Therapy (IPSOS)

      [8] Effect of Pembrolizumab With or Without Carboplatin and Paclitaxel on Immune Response in Patients With Recurrent or Stage IIIB-IV Non-small Cell Lung Cancer

      [9] Randomized Phase III Study Testing Nivolumab and Ipilimumab Versus a Carboplatin Based Doublet in First Line Treatment of PS 2 or Elderly Patients With Advanced Non-small Cell Lung Cancer (eNERGY)

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