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Jamie Chaft
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FP04 - Locoregional and Oligometastatic Disease (ID 126)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP04.01 - Heart Dose is a Dosimetric Predictor of Overall Survival in Patients with NSCLC Undergoing Post-Operative Radiation Therapy (ID 1369)
00:00 - 00:00 | Author(s): Jamie Chaft
- Abstract
- Presentation
Introduction
Patients undergoing PORT for locally-advanced NSCLC may be at risk for increased cardiac toxicity. There is an association between radiation dose to the heart and OS in NSCLC patients undergoing definitive radiation therapy (RT). The purpose of this analysis was to evaluate heart dose as a predictor of OS in patients with NSCLC undergoing PORT.
Methods
We reviewed 284 patients with NSCLC treated with PORT at our institution from 5/2004 to 1/2017. Complete dosimetric data and clinical records were reviewed, and OS was assessed. Patients were a median of 67 years old (range 28-87), and most had pathologic stage III NSCLC (91%) and received trimodality therapy (90%). Forty-six (16.2%) patients had pre-existing cardiac disease. Patients underwent lobectomy (81%), sublobar resection (12%) or pneumonectomy (7%). The rates of R0, R1 and R2 resections were 81%, 19%, and 0%, respectively. The median RT dose was 54 Gy (range: 45-70 Gy). Patients were treated with IMRT (71%) or 3DCRT (29%). Major adverse cardiac events (MACE, defined as myocardial infarction, coronary revascularization, cerebrovascular accident or heart failure) and all cardiac toxicities (including arrythmia, valvular or pericardial events) were identified. A systematic univariate Cox proportional hazards model analysis of OS and heart dose variables was performed, using the minimum dose to the hottest x% (Dx) and the volume receiving at least xGy (Vx) with x in increments of 5% and 2Gy respectively, together with mean, min, and max doses. Clinical variables that were univariately significant (p < 0.05), together with the most significant dosimetric variable, were entered in a step-up multivariate analysis.
Results
The median, 2-year and 5-year OS were 41.5 months, 68% and 37%, respectively. Dosimetric variables across a large range of doses to the heart were highly significant for OS, including mean (MHD), minimum and maximum heart doses. The median MHD for the population was 11.2Gy. The median OS for patients with MHD above vs. below 11.2Gy was 31.7 vs. 57.5 months (p<0.001), respectively. The volume of the heart receiving 8Gy (HV8) was the most significant dosimetric variable (p <0.0001), and the median HV8 was 35.5%. The median OS was 33.2 vs. 53.6 months (p<0.005), for patients with HV8 above or below 35.5%. On multivariable analysis, HV8 (HR:1.015/%, p<0.001), increasing age (HR:1.036/yr, p<0.001), use of anticoagulant therapy (HR:2.24, p=0.007), more extensive surgery (HR:1.49, p=0.012), and pre-operative chemotherapy (HR:1.53, p=0.019) were significant for OS. The rates of MACE and all cardiac toxicities were 7.4% and 14.8%, respectively. No heart dosimetric variables predicted for MACE or all cardiac toxicity.
Conclusion
Heart dose, as well as age, use of anticoagulants, presurgical chemotherapy, and the extent of surgery are predictive of worse OS in patients with NSCLC undergoing PORT. Heart V8 is the most significant dosimetric factor associated with OS. Despite the strong correlation between heart dose and OS, heart dose did not predict for cardiac events. This may indicate that the association between OS and heart dose cannot be explained fully by radiation-induced cardiac toxicities in NSCLC patients undergoing PORT.
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P03 - Early Stage/Localized Disease - Clinical Trials in Progress (ID 112)
- Event: WCLC 2020
- Type: Posters
- Track: Early Stage/Localized Disease
- Presentations: 3
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P03.02 - Neoadjuvant Osimertinib with/without Chemotherapy vs Chemotherapy for EGFR Mutated Resectable NSCLC: NeoADAURA (ID 3386)
00:00 - 00:00 | Author(s): Jamie Chaft
- Abstract
Introduction
Background
Approximately 30% of patients with NSCLC present with resectable disease. Primary treatment for resectable NSCLC is curative surgery; patient prognosis following surgery alone remains poor. Neoadjuvant chemotherapy is recommended in resectable stage-III NSCLC, regardless of EGFR mutation status, and has demonstrated clinical benefit. However, improved treatment options for stage II/III are needed. Recent studies indicate that EGFR-TKI therapy could potentially achieve tumour size reduction and clearance of micrometastases in the neoadjuvant setting; treatment effect can be assessed in resected specimens. Osimertinib is a third-generation, CNS-active EGFR-TKI, with superior efficacy to comparator EGFR-TKI in treatment-naïve EGFR mutation-positive (EGFRm) advanced NSCLC. In the Phase III ADAURA study (NCT02511106), osimertinib showed statistically significant DFS improvement (hazard ratio: 0.20 [99.12% confidence interval 0.14, 0.30; p<0.001) in resected stage IBꟷIIIA EGFRm NSCLC following adjuvant chemotherapy, when indicated. A recent study (NCT03433469) found neoadjuvant osimertinib was well tolerated in patients with Stage IꟷIIIA NSCLC. Efficacy and tolerability of osimertinib in advanced and adjuvant settings support its investigation as neoadjuvant treatment in resectable disease. NeoADAURA (NCT04351555) is a Phase III, controlled, randomised study assessing efficacy and safety of osimertinib (with/without chemotherapy) versus chemotherapy plus placebo as neoadjuvant treatment in resectable stage IIꟷIIIB EGFRm NSCLC.
Methods
Trial Design
Eligible patients: ≥18 years (≥20 years, Japan), ECOG PS 0/1, primary non-squamous stage IIꟷIIIB (IASLC Cancer Staging Manual v8) NSCLC and confirmed EGFRm (Ex19del/L858R), deemed completely resectable. Prior treatment with systemic anti-cancer therapy for NSCLC is not allowed. Approximately 351 patients will be randomised 1:1:1 (Figure) to receive platinum-based chemotherapy (pemetrexed 500 mg/m2 plus carboplatin AUC5 or cisplatin 75 mg/m2) plus placebo (Arm 1; double-blind), platinum-based chemotherapy plus osimertinib 80 mg once-daily (Arm 2; double-blind) or osimertinib 80 mg once-daily alone (Arm 3; open-label). Patients will be stratified by disease stage (II/III), race (non-Asian/Chinese/other Asian) and EGFR mutation (Ex19del/L858R).
Following three cycles of chemotherapy (Arms 1 and 2) or nine weeks of osimertinib (Arm 3), patients will undergo complete surgical resection of primary NSCLC. Treatment with osimertinib or placebo may continue until surgery, unless unacceptable toxicity/withdrawn consent/other discontinuation criterion. Post-surgery, patients will receive optimal care (investigator-defined); this may include adjuvant osimertinib treatment for three years (maximum)/until disease recurrence or unmanageable toxicity.
The primary endpoint is MPR, (≤10% residual cancer cells in surgical specimen post-surgery) centrally assessed. Secondary endpoints include pCR, EFS, downstaging, DFS, OS and safety. MPR and EFS will be tested using hierarchal testing procedure at MPR primary analysis.
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P03.03 - MERMAID-1: A Phase III Study of Adjuvant Durvalumab plus Chemotherapy in Resected NSCLC Patients with MRD+ Post-Surgery (ID 3322)
00:00 - 00:00 | Author(s): Jamie Chaft
- Abstract
Introduction
30% of non-small-cell lung cancer (NSCLC) patients present with surgically resectable disease at diagnosis. To reduce disease recurrence, adjuvant chemotherapy is standard of care (SoC) for patients with completely (R0) resected stage II/III NSCLC. However, 5-year disease-free survival (DFS) rates remain low (~40%), with a 5-year absolute benefit of only 5.4% derived from chemotherapy (Pignon et al. JCO 2008;26:3552-9). Determining who will benefit from adjuvant chemotherapy remains challenging. Identifying minimal residual disease (MRD) through detection of circulating tumour (ct) DNA post-surgery could predict early disease recurrence. Durvalumab is a selective, high‑affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. In the phase III PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression following radical platinum-based concurrent chemoradiotherapy, durvalumab improved progression-free survival (PFS) and overall survival (OS), demonstrating its efficacy in situations of residual disease. Further, initial data from POSEIDON showed durvalumab plus chemotherapy prolongs PFS versus chemotherapy in first line treatment of metastatic NSCLC. In the adjuvant setting (i.e. following complete tumour resection), this regimen could provide additional DFS benefit versus chemotherapy alone. MRD assessment could facilitate earlier, more selective adjuvant therapy for MRD+ patients, allowing for treatment intensification for this potentially biologically distinct disease, while minimising overtreatment of MRD– patients. MERMAID‑1 will investigate the efficacy and safety of adjuvant durvalumab + SoC chemotherapy versus placebo + SoC chemotherapy in patients with completely resected stage II/III NSCLC, to assess the benefits of adjuvant therapy in patients with MRD+ status.
Methods
MERMAID-1 (NCT04385368) is a phase III, parallel-arm, placebo-controlled, double‑blind, multicentre study, conducted across 16 countries. Patients aged ≥18 years with histologically confirmed EGFR-/ALK- Wild-type, stage II/III NSCLC will enter the first screening period; a personalised MRD panel will be created. Before randomisation, and following assessment of MRD status post-surgery, patients will be further screened for full eligibility (no evidence of disease recurrence, WHO/ECOG performance status 0/1). Patients who have received prior adjuvant therapy or durvalumab, and those with mixed small cell and NSCLC histology or evidence of post-operative disease recurrence are ineligible. MRD status will be determined via ctDNA analysis of plasma samples, collected 3–4 weeks post-surgery, and based on personalised panels (comprised of ≤50 tumour-specific DNA variants) created by whole exome sequencing analysis of the patient’s resected tumour tissue. Approximately 332 patients will be randomised 1:1 (stratified by disease stage, MRD status, and PD-L1 expression) to durvalumab (1500 mg, intravenously) or placebo, plus concurrent SoC chemotherapy, once every three weeks (Q3W) for 12 weeks. Patients will continue with durvalumab monotherapy/placebo Q4W thereafter, until Week 48 or disease recurrence, whichever occurs first. Following a baseline radiological scan prior to randomisation, patients will be assessed Q12W until disease recurrence (per RECIST v1.1). The primary endpoint is DFS in the MRD+ analysis set (investigator-assessed). Secondary endpoints include DFS in the full analysis set (FAS; investigator-assessed); DFS in the MRD+ analysis set and FAS (blinded independent central review); OS in the MRD+ analysis set and FAS; and safety and tolerability, and patient-reported outcomes.
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P03.04 - Phase II Study of TKIs as Neo(adjuvant) Therapy in Stage II–III Resectable NSCLC with ALK, ROS1, NTRK or BRAFV600 Alterations (ID 1802)
00:00 - 00:00 | Author(s): Jamie Chaft
- Abstract
Introduction
Despite complete surgical resection, cure rates remain unacceptable in early-stage NSCLC. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated a 5-year overall survival benefit of 5% for patients with resectable disease. Developing new treatment strategies to increase cures following resection is critical in this patient population. There are numerous immunotherapy trials ongoing in the neoadjuvant and adjuvant setting for patients with early-stage NSCLC. While there are a few targeted therapy trials in the adjuvant setting for patients with genetic alterations, neoadjuvant targeted therapies have remained incompletely explored in patients with potentially resectable NSCLC. Neoadjuvant trials allow for early trial read outs and in vivo efficacy assessment, which can guide adjuvant therapy options. The use of targeted therapies in patients with early-stage lung cancers with driver mutations has the potential to improve outcomes and provide an alternative treatment modality beyond immunotherapy and chemotherapy. Tyrosine kinase inhibitors (TKIs) are hypothesized to provide greater clinical benefit with a more favorable safety profile than the current standard of care platinum-based chemotherapy in the neoadjuvant setting. This ongoing Phase II umbrella study (ML41591) is designed to determine the efficacy and safety of targeted therapies for patients with stage II–III NSCLC with ALK, ROS1, NTRK or BRAFV600 alterations.
Methods
ML41591 is a Phase II, multicenter, non-randomized, open-label, umbrella study in patients with resectable stage II, IIIA, or selected IIIB NSCLC tumors that harbor fusions in ALK, ROS1, NTRK or BRAFV600 missense mutation. The study is designed to determine the efficacy and safety of targeted therapies, and to investigate potential surrogate biomarkers of response. Patients will be enrolled and assigned to treatment within the appropriate cohort:
- ALK cohort: ALK gene rearrangements - alectinib
- ROS1 cohort: ROS1 gene rearrangements - entrectinib
- NTRK cohort: NTRK1/2/3 gene rearrangements - entrectinib
- BRAF cohort: BRAFV600 mutation - vemurafenib plus cobimetinib.
Each cohort will enroll approximately 25 patients. The study will be conducted in two parts: pre-surgery neoadjuvant treatment will evaluate pathologic response to neoadjuvant TKIs in each cohort. Patients who undergo surgery and whose tumors lack radiographic progression will enter the post-surgery surveillance phase, which includes adjuvant treatment and follow-up for survival. This portion of the trial is exploratory. Patients will receive 4 cycles of chemotherapy followed by TKIs as adjuvant therapy for up to 24 months. The primary efficacy objective for this study is to evaluate the major pathological response rate for each treatment, defined as ≤10% residual viable tumor cells in the surgical resection specimens. Secondary efficacy objectives include investigator-assessed radiographic response, pathologic complete response, disease-free survival, event-free survival, overall survival and circulating-tumor DNA clearance rate. This trial will also evaluate exploratory biomarkers pre- and post-treatment in tissue and blood and their correlation with clinical outcomes.
