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Lucio Crino



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    EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.16-04 - Real World Clinical Outcomes for Metastatic Non-Small Cell Lung Cancer (mNSCLC) at IRST Italy (Now Available) (ID 2307)

      08:00 - 18:00  |  Author(s): Lucio Crino

      • Abstract
      • Slides

      Background

      This study sought to evaluate the real word clinical outcomes concerning overall survival (OS) for patients in first-line treatment for metastatic non-small cell lung cancer (mNSCLC) prior to the availability of immunotherapies in any line.

      Method

      Patients who received systemic anti-cancer treatment for mNSCLC at IRST between Jan2014-Jun2017 with a minimum follow-up of six months were included. The clinical dataset was obtained from data registered in electronic health records maintained during clinical practice. OS was defined as the interval from start of first-line therapy until death or follow-up end, whichever occurred first. Death information was detected from mortality register. OS was estimated using the Kaplan-Meier method stratified by type of first-line treatment.

      Result

      Among the 428 first-line patients analyzed, 64.5% were over 65 years old and 62.6% were men (Table 1). A total of 79.0% patients had non-squamous histology whereas 15.0% had squamous histology, with the remaining 6% other histologies. EGFR mutation was detected in 15.7% and ALK translocation in 8.4% of patients. In the first-line the majority (57.0%) of patients received platinum-doublet (mainly platinum+pemetrexed) while single agent chemotherapy was administered in 23.8%, whereas 10.0% received targeted therapy. Conversely overall 9.0% were enrolled in clinical trials, while 0.2% received Immunotherapies. Median OS was 19.9 months (95%CI:9.2-21.7) with targeted therapy, 8.5 months (95%CI:4.8-13.6) for patients enrolled in clinical trials, 6.4 months (95%CI:5.8-7.6) with platinum-doublet and 4.4 months (95%CI:3.7-5.7) with single agent chemotherapy. A total of 34.5% of first-line patients continued to receive second-line treatment.

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      Conclusion

      In this analysis prior to the introduction of immunotherapies for NSCLC, OS was similar to real world OS in the published literature. The survival was worse in the single agent chemotherapy group while it is superior in platinum doublets group. Overall survival was longest in patients treated with targeted therapy.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Lucio Crino

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-03 - Molecular Determinants for Lorlatinib Activity in ROS1 Positive NSCLC: Results of the Prospective PFROST Trial (ID 1566)

      09:45 - 18:00  |  Author(s): Lucio Crino

      • Abstract

      Background

      Lorlatinib, an ALK/ROS1 inhibitor, demonstrated activity in ROS1+ NSCLC pretreated with crizotinib. However, molecular events predictive for tumor response during lorlatinib treatment are largely unknown.

      Method

      PFROST was a prospective phase II trial designed to include ROS1+ NSCLC refractory to crizotinib. Eligible patients were treated with lorlatinib at the daily dose of 100 mg until disease progression. Primary end point was response rate (RR). For all included patients pre-lorlatinib tumor tissue or blood sample collection was mandatory. At the time of lorlatinib failure liquid biopsy was recommended. The samples were then run with the NEOliquid assay, specifically designed for liquid biopsies, or NEOselect, a panel optimized for formalin-fixed paraffin-embedded (FFPE) tumor tissue, covering 39 cancer related genes.

      Result

      From June 2017 to April 2019, 22 ROS1+ crizotinib refractory lung adenocarcinoma patients were included in 10 Institutions. Median age was 56 years (range 39-82); male/female: 8/14; ECOG PS 0 (N=8; 36.4%), PS1 (N=14; 63,6%); The majority had brain metastases at baseline (N=15; 68.1%), were never smokers (N=13; 59.1%) and received lorlatinib as third line therapy (N=16; 72.7%). In all cases crizotinib was the last therapy line before lorlatinib. At the time of the present analysis, trial completed its accrual and 13 patients are still receiving therapy. A total of 18 patients were evaluable for response and 7 had confirmed complete (N=1) or partial (N=6) responses for an overall RR of 38.8%. In 4 patients, response to therapy was not yet evaluated. A total of 10 tissue biopsies and 20 blood samples obtained after crizotinib and before lorlatinib therapy were collected. For 7 samples analyses are ongoing. Among responders, no patient harbored a secondary ROS1 mutation. Conversely, no response was observed among patients with secondary ROS1 mutations (N= 1 ROS1S1861I, N=1 ROS1 V2054A, N=3 ROS1G2032R). All patients harboring the ROS1G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of radiological evidence of lorlatinib failure.

      Conclusion

      In our study lorlatinib confirmed its efficacy in crizotinib resistant ROS1+ NSCLC. Molecular profile of refractory patients suggests reduced efficacy in individuals developing secondary ROS1 mutations after crizotinib failure.

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      P1.14-05 - TP53 Exon 8 Mutation and Prognosis in EGFR-Mutated NSCLC Patients Treated with First-And-Second-Generation TKIs (ID 457)

      09:45 - 18:00  |  Author(s): Lucio Crino

      • Abstract
      • Slides

      Background

      TP53 mutation seems to be associated with a worse prognosis in epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) treated with first generation tyrosine kinase inhibitors (TKIs). We previously showed that this was mainly significant for exon 8 TP53 mutations (Canale M et al, Clin Cancer Res 2017). However, its role on survival, as well as in relation to response to second generation TKIs is not clearly established.

      Method

      A retrospective cohort of 270 EGFR-mutated NSCLC treated with first- (gefitinib and erlotinib) and second- (afatinib) generation TKIs, in the first line setting, were considered. TP53 status was evaluated by Sanger Sequencing or Next generation Sequencing. The different mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

      Result

      One hundred and forty-four patients (53.3%) received a treatment with gefitinib, 84 (31.1%) with erlotinib and 42 (15.7%) with afatinib. In the overall cohort, ORR and DCR were 61.5% and 86.4%, respectively, with about 50% of patients responsive for more than 10 months. Median PFS and OS were of 11.08 (95% CI 9.3-12.6) and 22.9 (95% CI 20.4-27.5) months, respectively. Overall, 79 (30.7%) patients showed a TP53 mutation. The presence of TP53 exon 8 mutation was associated with a worse outcome with respect to patients wt or with other TP53 mutations. In particular, a lower ORR and DCR were observed for patients with TP53 exon 8 mutation (ORR 94.16% vs 5.84%, p=0.05, and DCR 94.04% vs 5.96%, p<0.001, respectively), together with a worse PFS (HR 1.88 [95% CI 1.20-2.96], p=0.006). These results was even more significant in the subgroup of patients with EGFR exon 19 deletion, where TP53 exon 8 mutation was associated with both worse PFS (HR 4,72 [95% CI 2.31-9.65], p<0,001) and OS (HR 2.60 [95% CI 1.11-6.04], p=0.027).

      At the multivariable analysis, EGFR exon 19 deletion and TP53 exon 8 mutation remained independently associated with PFS (HR 0.56 [95% CI 0.35-0.89], p=0.014 and HR 1.81 [95% CI 1.13-2.88], p=0.013, respectively). Moreover, EGFR exon 19 deletion and age resulted independently associated with OS (HR 0.52 [95% CI 0.26-1.03], p=0.059, and HR 1.02 [95% CI 1.01-1.04], p=0.009, respectively). No other patient and clinical covariate showed an association with PFS and OS in the multivariable models.

      Conclusion

      Our results confirm that TP53 exon 8 mutation confers a worse outcome in patients treated with first and second generation TKIs and that this is particularly evident in patients with EGFR exon 19 deletion.

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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-01 - STELLAR Trial: Radiological Response Patterns of TTFields Plus Chemotherapy in First-Line Treatment of Malignant Pleural Mesothelioma (ID 2533)

      10:15 - 18:15  |  Author(s): Lucio Crino

      • Abstract
      • Slides

      Background

      Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. TTFields have significantly extended survival of glioblastoma patients. In-vitro, human malignant pleural mesothelioma (MPM) cells were highly susceptible to TTFields. In the STELLAR trial [NCT02397928], patients with unresectable MPM treated with first-line chemotherapy in combination with TTFields had a significantly higher median overall survival compared to historical controls (18.2 Vs. 12.1 months). We analyzed radiological data from STELLAR patients whose tumors responded while receiving the combined therapy.

      Method

      The trial accrued 80 patients with unresectable, previously untreated mesothelioma who were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin (at standard dosing). Inclusion criteria: ECOG PS of 0-1, pathologically proven mesothelioma and at least one measurable lesion according to modified RECIST criteria. Patients were followed q3w (CT scan q6w) until disease progression. Radiological assessments were done at each study site. EOCG status and cancer-related pain were assessed until disease progression using a visual analog scale.

      Result

      Partial responses (PRs) were seen in 40.3% of evaluable patients and clinical benefit (PR+SD) was seen in 97.2% of patients. The median time between treatment start and PR was 1.8 (1.4-4.4) months). All patients presenting with PR during the STELLAR study had continuous reduction in the total sum of lesion diameters, suggesting no initial/pseudo-progression. 83% of the patients who responded to the combined therapy finally had disease progression within median response duration of 5.7 (1.4-13) months, per Kaplan-Meier Estimator. One patient did not progress for more than 27 months. Median time to deterioration in performance status was 13.1 months. Average pain score was lower compared to baseline during the first 7 months of treatment and higher later with a median time to a clinical significant 33% increase in pain of 8.4 months. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy. No TTFields-related other than expected dermatitis below the arrays were reported.

      Conclusion

      The STELLAR study showed significant survival extension in previously untreated MPM patients. Response rates were similar to that of current SOC treatment, but lasted longer with the addition of TTFields. TTFields was not associated with a decrease in performance status or an increase in pain. TTFields in combination with chemotherapy are efficacious in MPM vs chemotherapy alone reported in historical data.

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