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Primo Lara
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.11 - A Phase I Trial of Erlotinib and Onalespib in EGFR-mutant NSCLC: Focus on EGFR Exon 20 Insertions (ID 9046)
12:10 - 12:15 | Author(s): Primo Lara
- Abstract
- Presentation
Background:
Onalespib (AT13387) is a non-ansamycin small molecule that inhibits heat shock protein-90 (Hsp90). Hsp90 inhibitors (Hsp90i) preferentially degrade overexpressed and mutated oncoproteins including those that mediate resistance to EGFR-TKIs. Previous Hsp90i studies demonstrated activity in EGFR-mutant NSCLC including EGFR Exon 20 insertions (EGFRex20ins) - uncommon EGFR mutations typically refractory to 1[st] and 2[nd] generation EGFR-TKIs. A phase I study of onalespib plus erlotinib was conducted to determine the MTD, DLT, RP2D, pharmacokinetics (PK) and preliminary antitumor activity for a planned phase 2 trial in EGFR-mutant NSCLC including EGFRex20ins.
Method:
Using a 3 + 3, dose escalation design, onalespib was examined at 2 dose levels (DL) from 150 (DL0) to 120 (DL-1) mg/m[2] IV weekly (D1, D8, D15 on a q28 day cycle). Daily erlotinib was given at 150 mg at both DL. Key eligibility: NSCLC with EGFR activating mutation including EGFRex20ins, age ≥ 18, ECOG PS≤2, acceptable organ function, and ≥1 systemic therapy for advanced disease (platinum-based chemotherapy for EGFRex20ins and EGFR-TKI for other EGFR-mutations). Plasma for PK and ctDNA for next-generation sequencing of ~70 cancer related genes was collected at relevant timepoints.
Result:
9 pts have been treated on 2 DL (3 DL0, 6 DL-1). Pt characteristics: median age 65, M/F (2/7), ECOG PS 0-1 (4/5), EGFRex20ins (8), EGFR E19del (1). 7 pts completed ≥1 cycle. Two DLTs (grade (Gr) 3 maculopapular rash and Gr 3 hypophosphatemia) occurred in DL0. Common drug-related adverse events (AE) of any Gr were diarrhea (100%) and rash (44%), fatigue (55%), increased bilirubin (22%), nausea (44%) and vomiting (33%). Drug-related Gr 3 AEs were diarrhea (55%), maculopapular rash (11%) and hypophosphatemia (11%). At the planned 2-month evaluation, 5 pts had SD, 3 PD, and 1 had withdrawn for toxicity. Of the 5 pts continuing, 2 had SD and 1 PD at the 4-month evaluation. Kaplan-Meier estimate on therapy without progression at the second evaluation is 30% (95% CI: 10 to 87%).
Conclusion:
In patients with EGFR-mutant NSCLC, onalespib plus erlotinib is feasible, tolerable and demonstrates disease control in EGFRex20ins, thereby addressing a key unmet need in NSCLC. The RP2D is erlotinib 150 mg PO daily and onalespib 120 mg/m[2] weekly (D1, D8, D15 q28days). Diarrhea was the most common AE, and generally manageable with supportive care and dose reduction to DL-1. Updated results including PK as well as ctDNA for EGFR-mutation and relevant bypass tracts mediating EGFR-TKI resistance will be presented.
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MS 07 - Neuroendocrine Tumors other than SCLC: Pathology to Patient Management (ID 529)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:C. Barrios, Sang-We Kim
- Coordinates: 10/16/2017, 15:45 - 17:30, F203 + F204 (Annex Hall)
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MS 07.03 - Novel Systemic Therapy for Carcinoid of the Lung (ID 7671)
16:15 - 16:30 | Presenting Author(s): Primo Lara
- Abstract
- Presentation
Abstract:
Carcinoid tumors of the lung belong to a broad group of neoplasms called neuroendocrine tumors (NETs). These tumors are highly heterogeneous and represent a broad spectrum of phenotypes and clinical behavior. Often, the clinical behavior of these tumors corresponds with their underlying pathologic features. For example, in those tumors deemed as “typical carcinoid/NETs”, clinical behavior is often very indolent. At the other end of the spectrum, NETs can present as small cell lung cancer (SCLC) which is characterized by virulent and highly metastatic behavior. Those tumors deemed as “atypical carcinoid/NETs” usually have an intermediate clinical phenotype. Lung NETs are rare: the annual incidence rate is estimated to be approximately 1 in 100,000. In those patients whose lung NETs are no longer surgically resectable and/or have metastasized distantly, the treatment goals are principally disease control and symptom palliation. Because of their rarity, there are very limited prospective Level 1 data to guide optimal management of lung NETs. Treatment recommendations are often based on extrapolation from clinical experience in gastrointestinal NETs (specially pancreatic NET), subset analyses from other NET trials, anecdotal reports (case series), and expert opinion (e.g., consensus panels). Thus, the optimal management strategy for Lung NETs is not yet fully defined. Systemic therapy options range from somatostatin analog therapy, mTOR inhibitor therapy, and cytotoxic chemotherapy. Somatostatin analog therapy is offered in selected patient subsets that have slowly progressing disease and whose tumors express somatostatin receptors as detected by nuclear medicine scanning (Octreoscan). Somatostatin analog therapy is only modestly efficacious, with disease stabilization as the expected clinical benefit. Inhibition of the mTOR with everolimus has demonstrated efficacy in randomized trials. In the RADIANT-2 trial of everolimus+octreotide vs. placebo+octreotide in NETs, a small subset of patients with lung NETs (n=44) was analyzed. This showed an improvement in progression free survival with everolimus+octreotide vs. the control arm (median PFS 8.8 months vs 2.8; Hazard Ratio (HR) = 0.62; p=0.1). Subsequently, the phase III RADIANT-4 trial of everolimus vs placebo in non-functional lung and GI NETs was conducted. In this trial, approximately 30% of the 302 randomized patients had lung NETs. RADIANT-4 showed a PFS and overall survival (OS) benefit in favor of everolimus (PFS HR=0.39, p<0.0001; OS HR=0.64, p=0.037). More recently, a randomized phase II trial (LUNA) of pasitreotide alone, everolimus alone, or the combination showed a trend for improved PFS for the combination arm (PFS at 9 months was 39.0% for pasitreotide alone, 33.3% for everolimus alone, and 58.5% for the combination). In patients who are not candidates for somatostatin analog therapy or everolimus, or have failed these therapies, cytotoxic chemotherapy is often considered. The most commonly used regimens include platinum-etoposide (similar to that employed for SCLC) and temozolomide. Response rates to chemotherapy are reportedly much lower in lung NETs (vs SCLC) in retrospective studies; for example, platinum-etoposide is reported to yield response rates of 20-30% in lung NETs compared to rates greater than 50% in SCLC. It is thought that tumor responses are possibly influenced by the degree of tumor de-differentiation. Other agents with anecdotal activity include 5FU, capecitabine, oxaliplatin, and anthracyclines. Prospective trials of systemic therapy in lung NETs are essential to define the optimal standards of care. Selected References: 1. Hendifar, AE et al. J Thor Oncol 2016; 12(3):425-436 2. Yao, J. et al. Lancet 2016; 387: 968-77 3. Fazio N, et al. Chest 2013; 143(4):955-962
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)
12:05 - 12:15 | Author(s): Primo Lara
- Abstract
- Presentation
Background:
Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.
Method:
Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.
Result:
As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study. S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis. S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis. S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis. S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab
Conclusion:
Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.
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