Virtual Library

Start Your Search

Stephen V. Liu



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): Stephen V. Liu

      • 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.

  • +

    MS09 - Immunotherapy in Small Cell Lung Cancer (ID 72)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • +

      MS09.03 - Small Cell Lung Cancer: The Immune Microenvironment (Now Available) (ID 3490)

      14:00 - 15:30  |  Presenting Author(s): Stephen V. Liu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Based in part on the relatively high tumor mutational burden (TMB) and the strong link to tobacco use, there was a relative optimism regarding the prospects of success with immunotherapy in small cell lung cancer (SCLC). Over the past few years, while we have seen promising activity with checkpoint inhibitors in SCLC, the gains have been somewhat modest. As in other immune-responsive tumors, durable responses and long-term survival are possible. Nivolumab and pembrolizumab monotherapy have both demonstrated impressive durations of response, circling 18 months in the third line setting (Ready, JTO 2018; Chung, AACR 2019). Landmark survival rates far exceed historic controls in this setting. Meaningful benefit, though, is limited to a subset of patients, with response rates of only 12-19%. Both agents received accelerated approval by the FDA as third-line therapy for SCLC, but given the high attrition rate in SCLC, the impact of these approvals will be limited. Second-line and maintenance trials have failed to improve upon historic standards (Reck, ESMO 2018; Owonikoko, ELCC 2019). Fortunately, the addition of the PD-L1 inhibitor atezolizumab to first line carboplatin and etoposide improved both progression-free survival and overall survival (Horn, NEJM 2018). While the long-overdue improvement in survival was important and led to the FDA approval of atezolizumab in March 2019, there is significant room for improvement.

      The current use of checkpoint inhibitors in SCLC is empiric, though it is glaringly obvious that the true, durable benefit is limited to a subset of patients. Biomarkers are needed to identify those patients – to ensure they receive the appropriate therapy but also to help direct other patients to novel strategies. Predictive biomarkers can also provide valuable insight into the underlying biology of immune responses. Biomarker studies are challenging in SCLC; tissue samples are often scant, and the aggressive nature of the disease often precludes in depth study. Early data, though, speak to particular importance of the immune microenvironment in SCLC.

      Expression of PD-L1 by immunohistochemistry holds predictive value in non-small cell lung cancer (NSCLC). Its role in SCLC is evolving. In the CheckMate-032 study, nivolumab alone or in combination with the anti-CTLA-4 antibody ipilimumab, was explored in patients with previously treated SCLC (Hellmann, ASCO 2017). Using the 28-8 PD-L1 clone and a cutoff of 1%, only 18% of evaluable samples expressed PD-L1. Surprisingly, responses were more frequent in the PD-L1 negative tumors. With nivolumab alone, the response rate was 9% in PD-L1 positive tumors compared to 14% in PD-L1 negative tumors. With the combination of nivolumab and ipilimumab, the difference was even greater with a 10% response rate in PD-L1 positive tumors compared to 32% in PD-L1 negative. Some parallels are seen with pembrolizumab, but our understanding of PD-L1 as a biomarker is evolving. In a single arm study of maintenance pembrolizumab for SCLC (Gadgeel, JTO 2018), only 3 out of 30 patients had tumors with PD-L1 expression using the 22C3 clone (tumor proportion score, TPS). While the median PFS for the entire population was only 1.4 months, the 3 patients with TPS PD-L1 positive tumors all had a PFS over 10 months. Expression of PD-L1 at the stromal interface was also explored (combined proportion score, CPS). More patients had PD-L1 positive tumors using the CPS approach (8/20, 40%) and outcomes were superior in the CPS PD-L1 positive population: response rate was 37.5% vs. 8.3%, median PFS was 6.5 months vs. 1.3 months, and median overall survival was 12.8 months compared to 7.6 months. Similar results were seen in the salvage setting. In KEYNOTE-158, patients with previously treated SCLC received pembrolizumab monotherapy (Chung, ASCO 2018). Using the CPS approach, 39% of patients were PD-L1 positive, 47% were negative and 14% were non-evaluable. Again, outcomes favored the CPS PD-L1 positive subset including response rate (35.7% vs. 6%) and overall survival (14.9 months vs. 5.9 months). A separate retrospective analysis of a 95-sample cohort noted tumor expression of PD-L1 in 18% of samples but PD-L1 expression on tumor infiltrating lymphocytes (TILs) was seen in 67% of samples (Rivalland, ASCO 2017). There was no difference in survival based on tumoral expression of PD-L1, but median survival was longer in patients with PD-L1 positive TILs compared to PD-L1 negative TILs (17.2 months vs. 7.9 months, HR 0.36; 95% CI 0.22-0.60). The importance of the immune microenvironment in facilitating an immune response is becoming increasingly clear but it extends beyond expression of PD-L1. The presence and the specific location of tumor-infiltrating T-cells also holds value. Specific immunophenotypes are present and have been described as immune-desert (with few or no CD8+ T cells), immune-excluded (with CD8+ T cells present but limited to the adjacent stroma), and immune-inflamed (with CD8+ T cells in contact with tumor cells). A study of olaparib and durvalumab examined these phenotypes in patients with advanced SCLC (Thomas, JTO 2019) and found 14% with an immune-desert phenotype, 64% of samples with an immune-excluded phenotype and 21% with an immune-inflamed phenotype. PD-L1 expression was noted in all patients who achieved a response but was also noted in non-responders. In contrast, all of the patients with an immune-inflamed phenotype achieved a response.

      Much more work is needed to fully understand how the immune microenvironment facilitates (or precludes) immune responses. It is not yet clear whether these characteristics can be used as a predictive marker for use of checkpoint inhibitors. It is also not clear whether strategies to alter the microenvironment (with radiation therapy or other immune modulators) will induce effective immune responses. What is clear is that empiric therapy can only take us so far in the management of this exceptionally lethal disease. The path forward will require insight into the complexities orchestrating immune responses and a personalization of therapy for specific subsets of SCLC, subsets that certainly exist but, to date, evade proper detection. We have made tremendous strides in recent years to improve outcomes in SCLC but there remains much work to do.

      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): Stephen V. Liu

      • 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.

  • +

    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.14-25 - Targeting NRG1-Fusions in Lung Adenocarcinoma: Afatinib as a Novel Potential Treatment Strategy (ID 1805)

      09:45 - 18:00  |  Author(s): Stephen V. Liu

      • Abstract
      • Slides

      Background

      Neuregulin 1 (NRG1) gene fusions result in activation of ErbB2-/ErbB3-mediated signaling pathways, and may function as oncogenic drivers. NRG1 fusions have emerged as a potential therapeutic target across multiple tumor types, including non-small-cell lung cancer (NSCLC). Afatinib, a pan-ErbB-family blocker, may be a treatment option for patients with NRG1+ NSCLC, as supported by preclinical evidence and seven published case reports (Table).

      Method

      Here, we report clinico-pathological and molecular characteristics of four new cases of NRG1 fusion-positive lung adenocarcinoma treated with afatinib. Afatinib activity is reported.

      Result

      Case 1 is a 70-year-old, female, never-smoker, diagnosed with pan-wildtype, non-mucinous, adenocarcinoma. She received afatinib in the fifteenth-line setting and experienced a partial response (PR) for 24 months. Following further progression on chemotherapy, NRG1-fusion was identified using NanoString analysis (re-biopsy was performed to find an explanation for afatinib efficacy). The patient was re-challenged with afatinib (best response: PR [3 months]), before switching to atezolizumab (best response: progressive disease).

      Case 2 is a 66-year-old female, never-smoker, diagnosed with metastatic, non-mucinous adenocarcinoma. A CD74-NRG1 fusion was identified by Oncomine™ Comprehensive Assay, and fifth-line afatinib treatment was initiated. She experienced a PR, ongoing after 14 months of treatment.

      Case 3 is a 68-year-old male diagnosed with lung adenocarcinoma. A SDC4-NRG1 fusion was subsequently identified using Next Generation Sequencing and the patient initiated second-line afatinib treatment. He achieved stable disease as best response, lasting for four months.

      Case 4 is a 43-year-old, female, non-smoker, diagnosed with advanced invasive mucinous adenocarcinoma. A CD74-NRG1 fusion was subsequently identified by RNA sequencing and the patient initiated third-line afatinib treatment; PR is ongoing.

      Conclusion

      These findings add to a growing body of evidence suggesting afatinib activity in NRG1-fusion positive NSCLC. Prospective study of a larger cohort of patients with NRG1-fusion positive NSCLC treated with afatinib is warranted to better evaluate this potential activity.

      Patient

      Tumor type

      NRG1 fusion partner

      Best response

      Duration of response (months)

      Reference

      i

      Non-mucinous lung adenocarcinoma

      SLC3A2

      PR

      12

      Gay, et al. J Thoracic Oncol 2017

      ii

      IMA

      CD74

      PR

      10

      Gay, et al. J Thoracic Oncol 2017

      iii

      Non-mucinous lung adenocarcinoma

      SDC4

      PR

      12

      Jones, et al. Ann Oncol 2017

      iv

      IMA

      CD74

      PR

      6.5

      Cheema, et al. J Thoracic Oncol 2017

      v

      IMA

      CD74

      SD

      3

      Drilon, et al. Cancer Discov 2018

      vi

      IMA

      SDC4

      PD

      -

      Drilon, et al. Cancer Discov 2018

      vii

      IMA

      CD74

      PD

      -

      Drilon, et al. Cancer Discov 2018

      IMA, invasive mucinous lung adenocarcinoma; PD, progressive disease; SD, stable disease

      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.