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Gregory J. Riely
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.03 - Mobocertinib in NSCLC With EGFR Exon 20 Insertions: Results From EXCLAIM and Pooled Platinum-Pretreated Patient Populations (ID 3186)
11:45 - 12:45 | Author(s): Gregory J. Riely
- Abstract
- Presentation
Introduction
Mobocertinib is a potent first-in-class tyrosine kinase inhibitor (TKI) designed to target EGFR exon 20 insertion (EGFRex20ins) mutations. We report first results from the EXCLAIM extension cohort of a phase 1/2 study (NCT02716116) and results in patients with EGFRex20ins-mutant NSCLC who received prior platinum-based therapy from the dose-escalation/expansion parts of the study and the EXCLAIM extension cohort.
Methods
This 3-part, open-label, multicenter study included dose-escalation/expansion cohorts and the EXCLAIM extension cohort. Data are presented for all patients treated in EXCLAIM (N=96) and for platinum-pretreated patients from the dose-escalation/expansion cohorts (n=28) and from EXCLAIM (n=86); all received mobocertinib 160 mg orally QD. Enrolled patients had locally advanced/metastatic EGFRex20ins NSCLC, ECOG performance status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease. The primary endpoint is confirmed ORR assessed by IRC per RECIST v1.1.
Results
In EXCLAIM, 96 patients were enrolled and treated; median age, 59 years [range: 27–80]; female, 65%; Asian, 69%; ≥2 prior systemic anticancer lines, 49% (range: 1–4). Median time on treatment was 6.5 months (range: 0–14). Confirmed ORR was 23% (22/96; 95% CI: 15%–33%) per IRC and 32% (95% CI: 23%–43%) per investigator; median DoR (Kaplan-Meier estimates) was not mature; median PFS was 7.3 months. See Table. In the analysis of platinum-pretreated patients (n=114), median age, 60 years [range: 27–84]; female, 66%; Asian, 60%; ≥2 prior systemic anticancer lines, 59% (range: 1–7). Median time on treatment was 7 months (range: 0–31); 38 patients (33%) remained on treatment as of 29-May-2020. Confirmed ORR was 26% (30/114; 95% CI: 19%–35%) per IRC and 35% (40/114; 26%–45%) per investigator. Median PFS was 7.3 months: 12-month PFS rate was 33% (95% CI: 21%–47%). Responses were observed among all prespecified subgroups, including Asian/non-Asian patients and those with/without baseline stable brain metastases. The most common treatment-related adverse events (TRAEs; ≥30%): diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30%), and vomiting (30%); grade ≥3 TRAEs (≥5%): diarrhea (22%), anemia (5%), and dyspnea (5%). Nineteen patients (17%) discontinued due to AEs, most commonly diarrhea (4%) and nausea (4%). The safety profile observed in EXCLAIM was largely consistent with that observed in the platinum-pretreated population.
Conclusion
Mobocertinib demonstrated clinically meaningful benefit in previously treated patients with NSCLC and EGFRex20ins mutations, with a manageable safety profile.
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P09 - Health Services Research/Health Economics - Real World Outcomes (ID 121)
- Event: WCLC 2020
- Type: Posters
- Track: Health Services Research/Health Economics
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P09.58 - Replication of Overall Survival in Chemotherapy Arms of 1L NSCLC Trials using Real-World Data External Controls (ID 3008)
00:00 - 00:00 | Author(s): Gregory J. Riely
- Abstract
Introduction
Previous work suggests that replication of overall survival (OS) in control arms of non-small cell lung cancer (NSCLC) trials is possible using real-world data (RWD) external controls (EC). This study expands the previous work by using more recent NSCLC trials.
Methods
Data from four IMpower trials (150-wildtype [WT], 130-WT, 131, 132) were used. Patients with advanced NSCLC who met eligibility criteria were identified from the Flatiron Health EHR-derived de-identified database. Covariates were balanced using propensity scores via standardized mortality ratio weighting and assessed with standardized mean difference (SMD). OS was defined from time from treatment initiation (EC) or randomization (trial) to death, last contact (EC), or end of follow-up (trial). Cox regression was used to estimate hazard ratios (HRs) comparing RWD ECs to trial controls and to experimental arms. After exploring within IMpower150-WT, the final methodology was pre-specified for remaining trials.
Results
The sample size was smallest for nab-paclitaxel (130-WT), which is less common in routine clinical settings. Balance was achieved (SMD<0.1) for all covariates in all trials except for time from diagnosis to 1L initiation for 130-WT. RWD ECs were not statistically different from trial controls, although point estimates suggest worse OS for some RWD ECs (Figure 1). HRs for treatment efficacy were similar to original trial HRs, except for 130-WT and 131 (Figure 2). Percent of patients treated with checkpoint inhibitors (CPIs) in any subsequent line ranged from 54.5% to 57.5% in RWD ECs and 19.3% to 46.4% in trial controls versus 2.8% to 10.3% in experimental arms. Sensitivity analyses using different trimming and weighting methods did not substantially change these results.
Conclusion
RWD ECs replicated OS well in two trials (150-WT, 132). Small sample size, use of CPIs in subsequent lines, and other unmeasured clinical characteristics may contribute to observed differences.
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P09.60 - Using Patient-Level Data from Electronic Health Records to Replicate PFS Outcomes for Four 1L NSCLC Trials (ID 3009)
00:00 - 00:00 | Author(s): Gregory J. Riely
- Abstract
Introduction
While previous reports have demonstrated that external controls (EC) derived from electronic health record (EHR) data replicate overall survival (OS) of randomized clinical trial (RCT) controls, there is a need to evaluate non-OS endpoints. This study evaluates consistency of outcomes between progression-free survival (PFS) in external real-world controls (rwPFS) and RECIST-based investigator-assessed PFS from RCTs.
Methods
Data from four IMpower trials (150, 130, 131, 132) were used. Patients meeting trial criteria and receiving the respective comparator treatment were selected as ECs from the US-based Flatiron Health EHR-derived de-identified database. Confounders (age, sex, race, stage, smoking history, time since metastatic diagnosis) were adjusted for using standardized mortality ratio (SMR) weighting. The rwPFS endpoint definition included all progression events (including those without radiographic confirmation and events shortly after baseline), follow-up for progression beyond change of treatment, and deaths <30 days after end of progression follow-up. Methodology was pre-specified, allowing for modifications after exploration of IMpower150 (particularly of rwPFS variants) and subsequent application to the remaining trials. Cox regression was used to estimate hazard ratios (HRs) comparing real-world data ECs to RCT controls and to RCT experimental arms.
Results
Baseline demographics and clinical characteristics were balanced between RCT and real-world control arms except for time from diagnosis to 1L start date in IMpower130. When individual trial control arms were replaced with real-world data, rwPFS had similar results to RCT PFS results (Figure 1). Direct comparison of ECs vs RCT control arms resulted in HR’s close to unity (HR range: 0.88-1.07; Figure 2).
Conclusion
rwPFS outcomes using real-world controls were similar to RCT PFS results, supporting rwPFS as a potential endpoint for use with real-world-derived ECs. Limitations include insufficiently known patient or clinic level factors such as irregular timing of assessments, lack of health insurance, other physician involvement or not using RECIST criteria.
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P90 - Targeted Therapy - Clinically Focused - Misc. Topics (ID 267)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P90.03 - A Phase 2 Trial of MRTX849 in Combination with Pembrolizumab in Patients with Advanced Non-Small Cell Lung Cancer with KRAS G12C Mutation (ID 2968)
00:00 - 00:00 | Author(s): Gregory J. Riely
- Abstract
Introduction
KRAS is the most frequently mutated oncogene in cancer and a key mediator of the signaling cascade that promotes cellular growth and proliferation. Activating KRAS mutations drive increased cell growth, proliferation, and survival, and also decreased apoptosis in animal models. KRAS G12C tumor mutations occur in approximately 14% of patients with non-squamous non–small cell lung cancer (NSCLC).
MRTX849 is a selective small-molecule inhibitor of KRAS G12C that covalently and irreversibly binds to and locks mutant KRAS in its inactive form. MRTX849 was optimized for a long half-life and extensive tissue distribution to enable inhibition of KRAS G12C throughout the entire dosing interval. Preliminary results from a Phase 1/2 study of MRTX849 monotherapy demonstrated antitumor activity and tolerability across multiple KRAS G12C tumor types, including patients with NSCLC previously treated with both platinum-doublet chemotherapy and immune checkpoint inhibitors.
MRTX849 demonstrated reconditioning of the tumor microenvironment and enhanced potential to present antigens resulting in an enhanced immune response in KRAS G12C tumor models— both of which are predicted to augment susceptibility to immune checkpoint inhibition. MRTX849 has also resulted in durable complete responses in a KRAS G12C syngeneic tumor model in combination with a PD-1 antagonist whereas both monotherapy treatments in this study resulted in progression. These data support the rationale to evaluate MRTX849 in combination with immune checkpoint inhibitors in patients with first-line (1L) advanced/metastatic NSCLC.
Methods
Study 849-007 is a global, open-label Phase 2 study being conducted in the US, EU and Canada at approximately 40 sites to evaluate the clinical activity of MRTX849 administered in combination with pembrolizumab as 1L treatment for patients with advanced NSCLC harboring a KRAS G12C mutation. The primary endpoint is Objective Response Rate (ORR) as defined by RECIST 1.1. Secondary and exploratory objectives include evaluation of safety, additional efficacy endpoints, pharmacokinetics (PK), pharmacodynamics (PD), and correlative biomarkers. This study utilizes Simon's optimal two-stage design to derive the sample size.
Subjects will be enrolled in two cohorts based on PD-L1 Tumor Proportion Score (TPS): TPS < 1% (Cohort A; n=56) and TPS ≥ 1% (Cohort B; n=57). The planned regimen for MRTX849 is 600 mg twice daily (BID), administered orally on a continuous basis. Pembrolizumab will be administered by IV infusion, 200 mg every three weeks (Q3W). Subjects will receive study treatment until disease progression, unacceptable adverse events, or receipt of maximal number of cycles per local standard-of-care or investigator decision. This study is expected to initiate before the end of 2020.
