Virtual Library

Start Your Search

Guiseppe Giaccone



Author of

  • +

    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • +

      MA09.01 - A Phase I/II Trial of Dasatinib and Osimertinib in TKI Naïve Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2710)

      15:15 - 16:45  |  Author(s): Guiseppe Giaccone

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy is the standard of care in patients with EGFR-mutant NSCLC. However, a fraction of patients do not respond to EGFR-TKI therapy or have short duration of response. In addition, virtually all patients develop resistance. In a preclinical study, we have shown that overexpression of Cripto-1, a member of the EGF–CFC family, contributes to the development of resistance to EGFR-TKI therapy through the Src pathway and that the combination of EGFR-TKI therapy and Src inhibition works synergistically.

      Method

      This is an open-label, single-arm phase I/II trial of osimertinib and dasatinib, a Src inhibitor, in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02954523). Patients with pleural or pericardial effusions were excluded. The primary endpoint of the phase I portion was to establish a safe and tolerable phase II dose of osimertinib and dasatinib. Dose escalation includes 2 dose levels (DLs) (DL1: osimertinib 80 mg QD, dasatinib 50 mg BID, DL2: osimertinib 80 mg QD, dasatinib 70 mg BID). 2 DLs below the starting dose level (DL-1: osimertinib 80 mg QD, dasatinib 70 mg QD; DL-2: osimertinib 80 mg QD, dasatinib 50 mg QD) could be explored if necessary. Adverse events (AEs) were assessed per CTCAE 4.03.

      Result

      10 patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. None of the patients enrolled at DL2 had dose limiting toxicities (DLTs) but given the frequent dose reductions required and toxicities beyond the DLT period, DL1 was further assessed. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches and body pain, grade 3 neutropenia, grade 3 rash, one each). One patient was enrolled at DL -1 and did not have a DLT. The most common treatment-related adverse events (TRAEs) included pleural effusion (n=9), diarrhea (n=8), rash (n=7), AST elevation (n=6), ALT elevation (n=6), most of which were grade 1 or 2. 4/4/1 patients had grade 1/2/3 pleural effusion, respectively. 7 (70%) patients had grade 3 TRAEs. No grade 4 or 5 toxicities were observed. Eight (80%) patients had a partial response (including 1 unconfirmed partial response) and 2 had stable disease. Median PFS was 27.2 months; median OS was not reached. The recommended phase II dose was determined as osimertinib 80 mg QD and dasatinib 70 mg QD. Pharmacokinetics (PK) analysis is being performed and will be presented. Due to slow accrual after approval of osimertinib in first-line, the trial was closed to enrollment.

      Conclusion

      The combination of dasatinib and osimertinib demonstrated encouraging anticancer activity. Median PFS is longer than what is historically reported with osimertinib alone in first-line setting, although definitive conclusions cannot be drawn given the small sample size. The tolerability of the combination was limited by TRAEs, but they were generally manageable with dasatinib dose reductions and supportive measures.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
    • +

      MA20.05 - Follow-Up Update of 2 Phase II Studies of Pembrolizumab in Thymic Carcinoma (Now Available) (ID 1120)

      11:30 - 13:00  |  Presenting Author(s): Guiseppe Giaccone

      • Abstract
      • Presentation
      • Slides

      Background

      Two phase II studies of pembrolizumab 200 mg every 3 weeks in advanced thymic carcinoma have recently been published (Giaccone et al. Lancet Oncol. 2018, study #1; Cho et al. JCO 2018, study #2). Both studies reported a response rate in about 20% of patients and a rate of autoimmune disorders that is higher than in other tumor types.

      Method

      This report provides a follow-up update of these 2 studies, with particular emphasis on duration of response, and occurrence of autoimmune disorders. Both studies included patients with thymic carcinoma who had progressed after at least one line of chemotherapy.

      Result

      In study #1 a total of 40 patients with advanced thymic carcinoma were treated, with a median follow up of 40.6 months. The response rate did not change (22.5%) compared to the original publication, however one patient who had developed myositis, myocarditis and myasthenia gravis (MG), continues to be in nearly complete response after only two cycles of pembrolizumab, 36 months from initiation of treatment. One patient who had developed myositis and hepatitis with unclear signs of MG developed overt MG symptoms several months after the interruption of therapy. No other new autoimmune disorders were observed (6/40 = 15%). Five patients completed 2 years of treatment according to protocol and 4 of them elected to continue treatment. Three patients who had been off therapy were rechallenged with pembrolizumab upon progression (one responded). Median duration of response was 38 months (from 22.4 in initial report), median PFS was 4.2 months (identical) and median survival was 25.8 months (24.9 in the initial report).

      At completion of this study, an amendment was introduced to add epacadostat 10 mg BID to pembrolizumab in the same patient population. Four patients were treated before the study was closed after the results of a randomized trial of the combination in melanoma failed to meet its primary endpoint. No patient responded (2 stable and 2 progressions). One patient developed grade 2 myocarditis.

      In study #2 a total of 26 patients with advanced thymic carcinoma were included, with a median follow up of 33.4 months. The response rate (19.2%) did not change, and no other autoimmune disorder appeared since the initial publication (5/26 = 19%). Median duration of response (9.7 months), median PFS (6.1 months) and median survival (14.5 months) did not change compared to the initial publication. No additional autoimmune disorders were documented compared to the original publication. A total of 5 patients received 2 years of pembrolizumab according to protocol; no patient continued beyond 2 years or was retreated upon progression with pembrolizumab.

      Conclusion

      These two studies confirm definite activity of pembrolizumab in advanced thymic carcinoma. Recently pembrolizumab was included in the NCCN guidelines for thymic carcinoma. No additional autoimmune disorders were noted after discontinuation of pembrolizumab. There are significant differences in duration of response and overall survival in the 2 studies and potential factors are being investigated. In study #1 pembrolizumab was continued beyond 2 years in several patients and rechallenge was an available option.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MS08 - Management of Thymic Carcinoma (ID 71)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
    • +

      MS08.03 - Optimal Management of Metastatic Thymic Carcinoma (Now Available) (ID 3483)

      14:00 - 15:30  |  Presenting Author(s): Guiseppe Giaccone

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic carcinoma represents approximately 10-15% of all thymic epithelial tumors, it is more aggressive than thymomas and also somewhat less sensitive to chemotherapy. More often than thymomas, thymic carcinomas are not resectable and therefore the use of systemic therapies and radiation are more often required than in thymomas. In general the sensitivity of thymic carcinomas to chemotherapy is lower than with thymomas, with response rates usually less than 50% in metastatic disease, and somewhat higher in locally advanced disease.

      In presence of borderline operable cases, neoadjuvant chemotherapy is indicated, in order to make the tumor more easily operable. Because thymic carcinomas often infiltrate surrounding tissues, radical resection are sometimes not achievable. The use of postoperative radiation is indicated even if margins are clear. Several chemotherapy regimens have been used, and the more commonly employed remain platinum combinations, with or without an anthracycline (mainly doxorubicin). More recently data the combination carboplatin-paclitaxel has been added to the potential chemotherapy regimens and it is often preferred becasue of its milder toxicity profile. When radiation is planned, the use of doxorubicin is contraindicated, becasue of the enhanced toxicity. The role of debulking surgery, reoperation and metastasectomy is much more controversial in thymic carcinomas than in thymomas, given the more aggressive behaviour. However, the histological diagnosis sometimes is not paralleled by an aggressive phenotype and individual treatment decisions should always be considered.

      Unfortunately thymic carcinoma have the tendency to metastatize wildly to virtually all organs, and brain metastases are all but rare. Complete staging procedures, including brain MRI are therefore indicated in patients with thymic carcinoma. In patients with metastatic disease, chemotherapy is indicated as first line therapy, and the CAP regimen (cisplatin, doxorubicin, cyclophosphamide) or carboplatin-paclitaxel, are the preferred regimens, with response rates in the range of 30-50%. Unfortunately, chemotherapy at this stage is not curative and most patients will require further systemic therapies after failure of chemotherapy. There have been a number of studies in recent years, which have established activity of a few agents, such as sunitinib and pembrolizumab in thymic carcinomas. Both of them are now listed in the NCCN guidelines and have a response rate of about 25%. Pembrolizumab however has a much longer duration of response, albeit the frequency of severe autoimmune disorders is higher than in other diseases in which immune checkpoint inhibitors are used. Further chemotherapy also has some activity, such and the combination gemcitabine-capecitabine and other single agents, with responses in the 20-30% range.

      The biology of thymic carcinoma does not appear to provide clues to specific treatments, although mutations in epigenetic genes have been found in a significant number of patients. No easily targetable mutations or genetic abnormalities have so far been found. The most common mutation is in the p53 gene, in about 30% of cases, which is not targetable and is associated with a poorer survival.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P1.12 - Small Cell Lung Cancer/NET (ID 179)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.12-04 - A Phase I Study of the <sup>177</sup>Lu-DOTA<sup>0</sup>-Tyr<sup>3</sup>-Octreotate in Combination with Nivolumab in Patients with Extensive-Stage Small Cell Lung Cancer (ID 2887)

      09:45 - 18:00  |  Author(s): Guiseppe Giaccone

      • Abstract

      Background

      Despite initial sensitivity to systemic treatment, most patients with extensive-stage small cell lung cancer (ES-SCLC) relapse. It has been shown that somatostatin receptors are expressed in SCLC. Lutathera is a 177Lutetium-labeled somatostatin analog approved for treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Nivolumab, an anti-PD-1 antibody, in combination with lutathera may act synergistically to generate anti-tumor immunity. Here we report the final results of the phase I study of this combination in patients with ES-SCLC.

      Method

      This is a phase I/II trial of lutathera and nivolumab in patients with ES-SCLC (NCT03325816). For phase I, patients with either relapsed/refractory ES-SCLC or non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed the standard 3+3 design, assessing two dose levels (dose level 1: Lutathera 3.7 GBq Q8W for 4 doses with nivolumab 240 mg Q2W; dose level 2: Lutathera 7.4 GBq Q8W for 4 doses with nivolumab 240 mg Q2W). The DLT period was defined as first 8 weeks after treatment initiation. Adverse events (AEs) were assessed per CTCAE 4.03.

      Result

      A total of 9 patients were enrolled. Three patients with ES-SCLC (2 relapsed ES-SCLC, 1 non-progressing ES-SCLC after first-line chemotherapy) were enrolled at dose level 1 and no DLTs were observed. At dose level 2, six patients (3 relapsed/refractory ES-SCLC, 2 metastatic atypical carcinoid, and 1 high-grade NET) were enrolled. One patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related AEs (trAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). 5 (55.5%) of 9 patients had grade 3 trAEs, but the most common grade 3 trAE was lymphopenia (n=4). Grade 3 anemia, thrombocytopenia, pneumonitis, and rash occurred in one patient each. No grade 4/5 trAEs were reported. Among 7 patients with measurable disease, 1 patient with non-progressing ES-SCLC had a confirmed partial response and 2 patients with metastatic atypical carcinoid had stable disease lasting 6 months. The RP2D was lutathera 7.4 GBq Q8W for 4 doses with nivolumab 240 mg Q2W.

      Conclusion

      Evidence from this phase I study of lutathera and nivolumab suggests that the combination has a manageable safety profile and showed initial signs of antitumor activity. The safety and efficacy of the combination may be further explored in phase II as maintenance therapy in patients with ES-SCLC.