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Marina Chiara Garassino
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ES02 - Pro-Con: Do We Need Biomarkers to Guide the Choice of Immunotherapy Treatment? (ID 157)
- Event: WCLC 2020
- Type: Educational Session
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 10:30 - 11:30, Scientific Program Auditorium
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ES02.04 - We Should Use Combination of IO and Chemotherapy as Maintenance (ID 3973)
10:30 - 11:30 | Presenting Author(s): Marina Chiara Garassino
- Abstract
- Presentation
Abstract not provided
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OA11 - A Symphony of Progress (ID 229)
- Event: WCLC 2020
- Type: Oral
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 15:30 - 16:30, Scientific Program Auditorium
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OA11.06 - IMpower133: Exploratory Analysis of Maintenance Therapy in Patients With Extensive-Stage Small-Cell Lung Cancer (ID 3127)
15:30 - 16:30 | Author(s): Marina Chiara Garassino
- Abstract
- Presentation
Introduction
Several immunotherapies are under investigation across treatment settings in extensive-stage small-cell lung cancer (ES-SCLC). However, studies of maintenance immunotherapy have not shown improved survival outcomes in patients with ES-SCLC. In the Phase I/III IMpower133 study (NCT02763579), adding atezolizumab (anti–PD-L1) to carboplatin+etoposide (CP/ET) followed by atezolizumab maintenance for the first-line treatment of ES-SCLC led to significant overall survival (OS) and progression-free survival (PFS) improvement vs placebo+CP/ET. In this analysis, we explored the benefit of atezolizumab vs placebo in the patients who reached the maintenance phase of IMpower133.
Methods
403 patients with untreated ES-SCLC were randomised (1:1) to four 21-day cycles of carboplatin (AUC 5 mg per mL/min IV) + etoposide (100 mg/m2 IV) with atezolizumab (1200 mg IV) or placebo, followed by maintenance atezolizumab or placebo until unacceptable toxicity, disease progression or loss of clinical benefit. The two primary endpoints were OS and investigator-assessed PFS (RECIST v1.1). Patients who received at least the first dose of maintenance atezolizumab/placebo were included in this exploratory analysis. To account for potential lead-time bias, a multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect. A generalised linear model (GLM) was used to identify characteristics that could be predictive of reaching the maintenance phase. Baseline characteristics tested in the models included ECOG PS, sex, age, presence of brain metastases, LDH level, SLD and number of metastatic sites.
Results
At data cutoff (24 April 2018), the median duration of follow-up was 13.9 mo. A similar proportion of patients received maintenance treatment in the atezolizumab+CP/ET (n=154/201 [76.6%]; 95% CI: 70.2-82.3) and placebo+CP/ET arms (n=164/202 [81.2%]; 95% CI: 75.1-86.3). Baseline characteristics in the maintenance population were well balanced between arms. Median OS in maintenance patients in the atezolizumab+CP/ET and placebo+CP/ET arms was 15.7 and 11.3 mo, respectively (HR, 0.67 [95% CI: 0.49-0.90]; P=0.008); median PFS was 5.5 and 4.5 mo, respectively (HR, 0.73 [95% CI: 0.57-0.92]; P=0.008). The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics (multivariate Cox regression; OS HR, 0.59 [95% CI: 0.43-0.81]; P=0.001; PFS HR, 0.64 [95% CI: 0.50-0.82]; P<0.001). The GLM identified 3 prognostics factors for reaching the maintenance phase: ECOG PS (odds ratio [OR], 0.44; P=0.004), LDH (OR, 0.59; P=0.053) and age (OR, 0.93; P=0.001). Age also appeared to have a significant treatment interaction (P=0.006). Adverse events (AEs) related to treatment with atezolizumab or placebo, respectively, occurred in 64.5% and 52.8% of safety-evaluable maintenance patients. Immune-related AEs in the atezolizumab+CP/ET and placebo+CP/ET arms occurred in 41.3% and 28.2%, respectively. No Grade 5 immune-related AEs were reported.
Conclusion
In this exploratory analysis of IMpower133, OS and PFS benefit in patients receiving atezolizumab vs placebo during maintenance treatment was observed. The positive treatment effect persisted after adjusting for baseline characteristics via multivariate Cox regression models. No new or unexpected safety signals were identified. Induction treatment with atezolizumab in combination with CP/ET together with continuation of maintenance therapy with atezolizumab appeared to contribute to the OS benefit observed in IMpower133.
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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): Marina Chiara Garassino
- 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.
