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Lorenza Landi



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    IBS01 - My Oligometastatic Oncogene Driven Patient (Ticketed Session) (ID 32)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 07:00 - 08:00, Tokyo (1982)
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      IBS01.02 - Strategies Treatment After Oligoprogression (Now Available) (ID 3316)

      07:00 - 08:00  |  Author(s): Lorenza Landi

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer remains the leading cause of cancer-related mortality with more than 50% of the cases diagnosed at advanced stage. For decades, metastatic Non-Small-Cell Lung Cancer (NSCLC) has been considered as incurable disease with limited therapeutic opportunities. In such context, local ablative therapies (LAT), mainly represented by surgical metastasectomy, was the sole treatment with curative intent for selected patients with single brain or adrenal lesion.

      However, improvements in the knowledge of cancer biology coupled with progresses in systemic therapy positively impacted the duration and quality of life. This is the case of NSCLC carrying epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) rearrangement, where targeted therapies have changed the natural history of the disease, with median survival exceeding 4 years. Beyond EGFRmutations and ALKrearrangement, additional actionable alterations have been identified, includingBRAFmutations or ROS1rearrangements as the latest entered in clinical practice. Specific therapies are now available in clinic for all of these aberrations, with osimertinib, alectinib, crizotinib or the combination of dabrafenib and trametinib as the best first-line option for individuals harboring alterations respectively in the EGFR, ALK, ROS1or BRAF. Unfortunately, after an initial response all patients eventually progress. From a clinical point of view, there are two main patterns of progression including rapid and systemic progression or slow, limited and often indolent progression. In the first scenario, shift to a second line therapy is recommended. In the other case (oligoprogressive disease), LAT plus continuation of front-line inhibitor given beyond progression seems the best option.

      The oligoprogressive state is characterized by a limited number of sites in progression, implying that the other sites remain controlled and therefore sensitive to systemic treatments. The advent of non-invasive techniques such as stereotactic radiotherapy, radiofrequency, and mini-invasive surgery has led to a precise re-evaluation of LATs in this situation. Local treatment of the oligoprogressive lesions may allow modification of the natural history of the disease, maintenance of effective systemic targeted treatment and, ultimately, to improved survival. In addition, some LATs have the advantage that can be repeated over time in difficult-to-treat organs as brain. Data validating an aggressive local therapeutic approach in oligoprogressive NSCLC patients are currently limited and essentially retrospective. Several international trials are ongoing and their results could contributing in better defining the role of radical local treatment in oligoprogressive advanced NSCLC patients.

      Unfortunately, even if the addition of a LAT contributes in disease control, majority of patients finally relapse and die for additional metastatic spread. Therapy options at the time of oligometastatic progression are largely influenced by previous therapies, site of progression and molecular portrait of the disease. Molecular characteristics are of particular relevance for defining the possibility of sequential use of additional target agents. This is the case of T790M EGFR mutation occurring in the vast majority of patients progressing after old generation EGFR TKIs for which osimertinib is superior to standard platinum-doublet chemotherapy. Viceversa, in absence of the acquired mutation (T790M negative), chemotherapy or combinations of chemotherapy and immunotherapy should be the preferred choice.

      In conclusion, molecular target therapies and more recently immunotherapy significantly improved survival of patients presenting with metastatic disease at diagnosis. However, acquired resistance inevitably occurs, limiting patient survival. A subset of patients presenting oligometastic disease represent a unique subgroup of patients who can benefit from LAT followed by continuation of systemic therapy. Randomized clinical trials are needed the role of LAT in this context.

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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  |  Presenting Author(s): Lorenza Landi

      • 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): Lorenza Landi

      • 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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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-15 - Phase II Single Arm Study of CABozantinib in Non-Small Cell Lung Cancer Patients with MET Deregulation (CABinMET) (ID 2637)

      10:15 - 18:15  |  Author(s): Lorenza Landi

      • Abstract

      Background

      Mesenchymal-Epithelial Transition gene (MET) amplification and exon 14 skipping mutations are established oncogenic drivers in non-small cell lung cancer (NSCLC), both occurring in about 4% of cases. In patients with MET amplified or mutated lung cancer, oral MET tyrosine kinase inhibitors (TKI) showed promising activity. The American Food and Drug Administration has recently granted crizotinib a breakthrough therapy designation for MET exon 14 mutation positive NSCLC. Cabozantinib is a novel oral inhibitor of MET and other receptor tyrosine kinases that has shown preliminary activity in MET deregulated NSCLC patients pretreated with crizotinib, although definitive data on its therapeutic role are still missing.

      Method

      CABinMET (NCT03911193) is a phase II, single arm, multicenter study assessing the efficacy of cabozantinib in subject with MET amplification or MET exon 14 skipping mutation pretreated or not with MET inhibitors. The primary endpoint of the trial is overall response rate. Secondary efficacy endpoints are progression free survival, overall survival and disease control rate. Main inclusion criteria include histologically/cytologically confirmed diagnosis of advanced stage NSCLC, presence of MET exon 14 skipping mutation or MET amplification (MET/CEP7 ratio ≥2.2 on FISH analysis) on archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or circulating tumor DNA, measurable disease, ECOG PS 0-1, at least 1 prior line of standard therapy, adequate organ function. Patients with co-existent driver events or with symptomatic brain metastases are excluded from the trial. Cabozantinib is administered orally at 60 mg once daily until disease progression, patient refusal or unacceptable toxicity. Disease is assessed every 8 weeks. Exploratory biomarker analyses are conducted on archival FFPE tumor tissue and on blood samples collected at baseline, at the time of the first disease assessment and at progression.

      Result

      The study is currently running in 9 Italian centers. Recruitment started in September 2018 and 6 of the planned 25 patients have been enrolled.

      Conclusion

      Enrollment will be completed in 24 months.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-49 - Nivolumab Plus Ipilimumab (NI) Versus Chemotherapy Plus Nivolumab (CN) in Squamous Cell Lung Cancer (SqCLC): The SQUINT Trial (ID 1557)

      10:15 - 18:15  |  Presenting Author(s): Lorenza Landi

      • Abstract

      Background

      Treatment landscape for patients with advanced NSCLC is rapidly evolving, with recent randomized phase III trials demonstrating superiority of chemo-immuno combinations versus chemotherapy alone. Role of chemo-free combinations, including NI, is under investigation with limited available data. Aim of the present trial is to investigate outcome of SqCLC patients when treated with NI or CN.

      Method

      SQUINT (NCT03823625) is an open-label, randomized, parallel, non-comparative phase II study designed to assess the efficacy of NI (Arm A) or CN (Arm B) in patients with advanced, metastatic SqCLC. Eligibility requires age ≥ 18 years, histologically confirmed stage IV or recurrent stage IIIB SqCLC, p63+/p40+ and TTF- tumour tissue, availability of PD-L1 status, no prior systemic therapy, ECOG performance status 0-1, adequate organ functions. Key exclusion criteria include concomitant radiotherapy or chemotherapy, prior treatment with immune checkpoint inhibitors, untreated brain metastases, other serious illness or medical condition potentially interfering with the study or with NI administration. Patients are randomly assigned 1:1 to receive N 360 mg Q3W plus I 1 mg/kg Q6W (Arm A) or plus platinum-based chemotherapy up to 6 cycles plus nivolumab 360 mg Q3W (Arm B), and stratified by PD-L1 expression (<1% versus ≥1%), presence of bone metastases (yes/no) and liver metastases (yes/no). In both arms, immunotherapy is given until disease progression, unacceptable toxicity, patient refusal and in any case for up to 24 months. Primary endpoint is 1-year overall survival (OS) rate in Arm A and B. Secondary endpoints include: response rate (RR), duration of response (DoR), median progression free survival (PFS) and median OS in Arm A and B, and according to predefined stratification factors. Sample size has been calculated assuming for each arm a minimum acceptable 1-year OS rate of 40% and an auspicated 1-year OS rate of 60%, a power of 90% and a one side significant level of 0.05. Based on such premises, the total number of patients required for the study is 112.

      Result

      At the time of this analysis a total of 11 Italian Centers are recruiting and 25 subjects have been enrolled.

      Conclusion

      We expect to conclude enrolment by January 2020.