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Claudio Dazzi



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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.02 - Upfront or Sequential Strategy for New Generation Anaplastic Lymphoma Kinase (ALK) Inhibitors: An Italian Retrospective Study.  (ID 12790)

      13:35 - 13:40  |  Author(s): Claudio Dazzi

      • Abstract
      • Presentation
      • Slides

      Background

      Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected 242 ALK-positive advanced NSCLC diagnosed between 2010 and 2018 in 23 Italian institutions (expanded data collection from Gobbini et al. Lung Cancer 2017). 138 patients received exclusively crizotinib as ALKi (not considered for this analysis). 78 patients received crizotinib and a new (second or third) generation ALKis as further treatments (group A). 26 patients performed a new generation ALKi as upfront agent (group B). These groups are larger than those considered in a previous analysis (15 and 8 patients, respectively).

      4c3880bb027f159e801041b1021e88e8 Result

      Study population clinical features and treatments received are summarized in Table 1.

      Group A

      Crizotinib followed by new generation ALKis

      N= 78

      Group B

      Upfront new generation ALKis

      N=26

      Treatments per line n(%)

      Crizotinib

      28(36)

      50(64)

      -

      -

      -

      -

      2(8)

      -

      Alectinib

      -

      11(14)

      18(23)

      5(17)

      7(27)

      -

      -

      -

      Ceritinib

      -

      9(12)

      23(30)

      3(4)

      8(31)

      8(31)

      1(4)

      -

      Brigatinib

      -

      6(8)

      6(8)

      2(3)

      -

      2(8)

      -

      2(8)

      Lorlatinib

      -

      -

      4(5)

      5(6)

      -

      -

      1(4)

      -

      Chemotherapy

      50(64)

      2(3)

      10(13)

      na

      11(42)

      6(23)

      1(4)

      Na

      Clinical features n(%)

      Age (range)

      58 (27-83)

      55 (24-82)

      Male

      37(47)

      10(38)

      p= 0.42

      Female

      41(53)

      16(62)

      Current smoker

      8(10)

      5(19)

      p= 0.23

      Never/former smoker

      70(90)

      21(81)

      ALKi beyond PD

      27(34)

      4(15)

      p= 0.06

      With a median follow-up of 22.6 months (CI 95% 20.09-25.10), 33 patients had died (32%). In group B, the median progression free survival (PFS) for new generation ALKis administered as first (14.0 months, CI 95% 9.52-18.471), second (12.7 months, CI95% 7.22-18.17) or third-line (12.8 months, CI95% 6.24-19.35) was not statistically different (p= 0.522). The median time from the start of crizotinib to the disease progression after the new generation ALKi sequentially performed (group A) was longer than that one detected in group B for the upfront new generation ALKis (29 vs 14 months, HR 2.47 [CI95% 1.35-4.50], p=0.003). This result was confirmed even considering the time lost between the two treatments in group A. The median overall survival (OS) was not reached. The 12-months OS rate was 97% in group A and 84% in group B.

      8eea62084ca7e541d918e823422bd82e Conclusion

      New generation ALKis maintain their efficacy regardless of the treatment setting considered. The sequential strategy seems to provide a substantial benefit, but a longer follow-up and larger samples are needed to clarify the survival impact.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-53 - Bone Metastases and Efficacy of Immunotherapy in Patients with Pretreated Advanced Non-Small-Cell Lung Cancer (NSCLC) (ID 11980)

      16:45 - 18:00  |  Author(s): Claudio Dazzi

      • Abstract

      Background

      Approximately 40% of NSCLC patients develop bone metastases (BoM). Bone has active functions in regulating immune system. To date, no trial evaluated the role of BoM in modulating response to immunotherapy. Aim of the present study was to investigate whether presence of BoM impact on immunotherapy efficacy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Two different cohorts of pretreated NSCLC patients (cohort A: Non-squamous; cohort B: Squamous) were evaluated for nivolumab efficacy in terms of objective response rate (ORR), progression free survival (PFS), and overall survival (OS) according to presence or absence of BoM. All patients received nivolumab at standard dose of 3 mg/kg every 2 weeks within the Italian Expanded Access Program.

      4c3880bb027f159e801041b1021e88e8 Result

      Cohort A accounted for 1588 patients with non-squamous NSCLC: 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 370 patients with squamous histology: 102 BoM+ (32%) and 251 BoM- (68%). In Cohort A, BoM+ had a significantly lower ORR (12% versus 34%; p < 0.0001), shorter PFS (2.0 versus 4.0 months, p < 0.0001) and shorter OS (7.4 versus 15.3 months, p <0.0001). In cohort B, BoM+ had significantly lower ORR (15% versus 22%; p < 0.04), shorter PFS (2.7 versus 5.4 months, p <0.0001) and shorter OS (5.0 versus 10.9 months, p <0.0001). Presence of BoM negatively affected outcome irrespective of PS (OS cohort A: PS-0 BoM+ 12.0 versus 20.9 months in PS-0 BoM-, p<0.0001; OS cohort B: PS-0 BoM+ 5.8 versus 16.4 months in PS-0 BoM-, p<0.0001). Multivariate analysis confirmed that presence of BoM independently associated with higher risk of death with HR 1.64 and HR 1.78, for Cohort A and B, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results, the first assessing BoM in patients treated with immunotherapy, suggested that BoM predict lower efficacy of immunotherapy. BoM should be included as stratification factor in clinical trials.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-23 - TP53 Mutations as Mechanisms of Primary and Acquired Resistance to Tyrosine Kinase Inhibitors in Patients With EGFR-Mutated NSCLC  (ID 13954)

      16:45 - 18:00  |  Author(s): Claudio Dazzi

      • Abstract
      • Slides

      Background

      Around 80% of patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations usually respond to tyrosine kinase inhibitors (TKIs). We previously demonstrated that TP53 mutations are associated with primary resistance to TKIs in patients with EGFR-mutated lung adenocarcinoma (ADC) treated with a first-line TKI. In the present study we investigated whether TP53 mutations are modulated by TKIs, evaluating its status before and after TKI treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Thirty-five patients with EGFR-mutated lung ADC treated with a first-line TKI and who subsequently underwent re-biopsy after disease progression were considered. Tumor tissue was available for evaluation before and after TKI treatment for all patients. EGFR and TP53 mutation analyses were performed by Sanger Sequencing or Next Generation Sequencing methods. The different mutations were evaluated in relation to disease control rate (DCR) [complete response (CR), partial response (PR) or stable disease (SD)] and objective response rate (ORR) (CR, PR).

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 35 patients, 14 (40%) showed a TP53 mutation, 12 in exons 5-8 (5 in exon 5, 2 in exon 6, 2 in exon 7 and 3 in exon 8) and 2 in other exons (1 in exon 2 and 1 in exon 4) of the gene. The group was treated with a first-line TKI and data on response and follow-up were available for 30 patients. Of these, 11 were treated with gefitinib, 11 with erlotinib, 6 with afatinib and 2 with dacomitinib. Overall DCR and ORR were 90% and 77%, respectively. With regard to TP53 mutations, DCR and ORR were 94% and 83%, respectively, in TP53 wt patients, and 83% and 66% in TP53 mutated cases. All 30 patients underwent re-biopsy at progression and 20 (67%) showed T790M mutation in tumor tissue. Of the 10 T790M-negative patients, 5 (50%) had a TP53 mutation which was not present at baseline in 2 cases. Among the patients who were TP53 wild type at baseline, 4 (22%) showed a mutation at disease progression. Data on progression free survival and overall survival are currently being evaluated.

      8eea62084ca7e541d918e823422bd82e Conclusion

      TP53 mutations were associated with a lower response to TKIs in EGFR-mutated patients and may have been acquired during TKI treatment, independently of the T790M mutation.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-06 - TP53 Status in Relation to Response to Anti-ALK Agents in Patients with EML4-ALK-Translocated NSCLC (ID 12580)

      16:45 - 18:00  |  Author(s): Claudio Dazzi

      • Abstract
      • Slides

      Background

      Patients with non-small-cell lung cancer (NSCLC) carrying the EML4-ALK translocation are responsive to anti-ALK agents, such as crizotinib. However, about 30%-40% of patients show primary resistance to treatment. We previously demonstrated that TP53 mutations are associated with poorer prognosis in EGFR-mutated patients treated with tyrosine-kinase inhibitors. In the present study we analyzed the impact of TP53 mutations on response to anti-ALK treatment in EML4-ALK-translocated NSCLC

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eighty-three patients with EML4-ALK-translocated NSCLC identified in the Wide Catchment Area of Romagna between 2012 and 2016 were considered. TP53 status was evaluated in 61 patients on the basis of DNA availability. Of these, 28 patients received an anti-ALK agent as second-or-more-line treatment and follow-up data were available. TP53 status was analyzed in relation to disease control rate (DCR): complete response (CR), partial response (PR) or stable disease (SD).

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, TP53 mutations were observed in 14 (23%) patients, 6 (43%) showing a mutation in exon 5, 1 (7%) in exon 6, 3 (21%) in exon 7 and 4 (28%) in exon 8. We found one insertion (7%), one deletion (7%) and 12 point mutations (86%). Of the 28 patients treated with an anti-ALK agent, 5 (20%) showed TP53 mutations, 2 (40%) in exon 5, 1 (20%) in exon 5 and 2 (40%) in exon 8. Clinical response was not evaluable in 3 patients due to rapid disease progression (2 had a stop mutation in exon 5 of TP53). DCR for the remaining 25 patients was 60% in those with TP53-mutated tumors and 92% in those with TP53 wild-type disease.

      8eea62084ca7e541d918e823422bd82e Conclusion

      TP53 mutations were associated with a poorer DCR in EML4-ALK-translocated NSCLC patients treated with an anti-ALK agent. These results highlight the potential role of TP53 in determining primary resistance to anti-ALK agents, and should be confirmed in a wider case series.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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