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Erika Rijavec
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OA04 - Immuno Combinations and the Role of TMB (ID 126)
- Event: WCLC 2019
- Type: Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Solange Peters, Martin Reck
- Coordinates: 9/08/2019, 15:15 - 16:45, Copenhagen (1980)
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OA04.02 - CheckMate 817: First-Line Nivolumab + Ipilimumab in Patients with ECOG PS 2 and Other Special Populations with Advanced NSCLC (Now Available) (ID 1876)
15:15 - 16:45 | Author(s): Erika Rijavec
- Abstract
- Presentation
Background
Data are limited for immunotherapy in patients with advanced NSCLC and poor performance status or other comorbidities. CheckMate 817 is a multi-cohort, open-label phase 3b/4 study investigating safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in advanced NSCLC. Here we evaluate this regimen as first-line treatment in special populations (cohort A1) and a reference population (cohort A; previously reported).
Method
Patients had previously untreated advanced NSCLC. Cohort A1 (n=198) had ECOG PS 2 or ECOG PS 0–1 with 1 of: asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV. Cohort A (n=391) had ECOG PS 0–1. Patients with known EGFR mutations or ALK translocations sensitive to available targeted therapy were excluded from both cohorts. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W was administered for two years or until disease progression/unacceptable toxicity. Safety and efficacy endpoints were assessed; cohort A1 analyses were exploratory.
Result
Cohort A1 patients were grouped as: ECOG PS 2 (n=139) and all other special populations (AOSP; n=59). Baseline characteristics were generally balanced between cohorts. Rates of grade 3–4 treatment-related adverse events (TRAEs) were similar between cohorts; within cohort A1, grade 3–4 TRAEs were numerically higher in AOSP versus the ECOG PS 2 subgroup; TRAEs leading to discontinuation were similar across populations (Table). ORR was 25% in cohort A1 (patients with ECOG PS 2, 20%; AOSP, 37%) and 35% in cohort A. PFS was numerically shorter in cohort A1 than cohort A; high TMB (≥10 mut/Mb) and higher PD-L1 expression (≥1% or ≥50%) were associated with numerically longer PFS in both cohorts (Table).
Conclusion
First-line flat-dose nivolumab plus weight-based ipilimumab showed a consistent safety profile in special populations with advanced NSCLC, including those with ECOG PS 2. Patients with either high TMB or higher tumor PD-L1 expression appeared to exhibit improved efficacy.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-59 - Expanding Access to Large-Scale Genomic Mutational Analyses for Patients with Advanced NSCLC in Italy (ID 2410)
09:45 - 18:00 | Author(s): Erika Rijavec
- Abstract
Background
In NSCLC, large-scale mutational analysis facilitates access to targeted treatments but is still not routinely employed due to significant technological barriers. The Alleanza Contro il Cancro (ACC) network of Italian Cancer Centers developed an affordable targeted sequencing panel for the identification of multiple genetic alterations with potential clinical utility, and designed a prospective multicentric trial to recruit 1000 newly diagnosed advanced NSCLC patients, aiming to i) compare panel performance against a set of externally validated biomarkers, including alterations in standard-of-care (EGFR, ROS1 and ALK) and non-standard-of-care (KRAS, BRAF, MET) biomarkers; ii) identify alterations in a large dataset of driver and potentially actionable genes; iii) correlate genotypes to survival outcomes and toxicity; iv) carry out ancillary studies on additional biomarkers and/or on specific patient groups (e.g. mutational burden, cfDNA, extensive characterization of immunotherapy-treated patients); v) build a centralized data repository for mutation interpretation and clinical recommendation.
Method
Through systematic literature mining and ad-hoc developed bioinformatic pipelines we identified: i) a set of 164 potentially actionable genes in solid tumors; ii) additional 18 genes with predicted driver function in NSCLC; iii) 70 actionable fusion transcripts; iii) 141 SNPs associated with pharmacogenomics markers. We designed a custom enrichment panel (~800 kb target) and compared PCR- and hybridization-based enrichment on semiconductor or by-synthesis sequencing to be subsequently deployed in a large observational trial. Sequencing is decentralized, to allow rapid turnaround time, but raw and processed data are collected in a single informatic infrastructure for centralized quality control and continuous bioinformatic pipeline improvement.
Result
PCR/semiconductor sequencing was selected for deployment based on cost and feasibility (2-day, highly automated workflow). 182 patients have been enrolled to date (90% stage IV, 10% IIIB). Of 65 patients with treatment information available, 28 (43%) subsequently received immunotherapy and 13 (20%) targeted therapy. For 56 patients with complete sequencing data, EGFR and KRAS status was concordant in 9/10 and 38/41 cases; discordant cases are being validated with orthogonal methods. Clinically significant MET amplifications were called in 2/2 cases. Remaining target regions did not show pathogenic alterations. Multiple alterations in potentially actionable genes were identified.
Conclusion
Large-scale sequencing is reliable, feasible and sustainable across multiple hospitals and provides clinically relevant results. The increased availability of genomic information may result in enhanced access to tailored therapies. Data and sample integration in centralized, shared repositories will allow multiple ancillary studies.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-02 - Interim Survival Analysis of Gefitinib Plus Vinorelbine in Advanced EGFR-Mutant Non-Small Cell Lung Cancer (Genoa Trial) (ID 2578)
10:15 - 18:15 | Author(s): Erika Rijavec
- Abstract
Background
Patients affected by advanced non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR) are eventually destined to experience disease progression in spite of initial benefit from EGFR Tyrosine kinase inhibitors (TKIs). Preclinical studies have suggested that combining cytotoxic agents with EGFR TKIs to treat EGFR-mutant tumors may increase their inhibitory effect; in a preclinical study conducted within our Institution, the administration of vinorelbine followed by gefitinib resulted in increased activity due to synergistic effect of the combined drugs. Here we present the interim analysis of GEfitinib plus viNorelbine in Advanced EGFR mutated NSCLC (GENOA TRIAL), which was designed to investigate the role of oral vinorelbine followed by gefitinib for the management of treatment-naïve patients affected by EGFR-mutant NSCLC (Clinicaltrials.gov: NCT02319577).
Method
This was a multi-centric, open-label, randomized phase II trial designed to explore activity and tolerability of vinorelbine followed by gefitinib compared to gefitinib alone in patients affected by EGFR-mutant NSCLC. The estimated enrolment was equal to 80 patients; enrolled patients were randomized (1:1) to receive oral vinorelbine (60 mg/m2) on days 1,8 followed by gefitinib (250 mg) on days 9-21 (Arm A) or gefitinib alone (250 mg) on days 1-21 (Arm B) in three-weekly cycles. The primary end-point of the study was to determine the increase in terms of 6-month progression free survival (PFS) rate with Arm A compared to Arm B, while median PFS and median overall survival (OS) were secondary end-points; PFS data were defined according to response evaluation criteria in solid tumors (RECIST) v.1.1. Safety was assessed according to common terminology criteria for adverse events (CTCAE) v. 4.0.
Result
Data from 44 patients (Arm A= 23; Arm B= 21) are available for this interim analysis, with a median follow up of 19.1 months. All the patients had advanced lung adenocarcinoma with EGFR mutation (exon 18=2; exon 19= 16; exon 21= 21; multiple exons= 5). The 6-month PFS rate was 48% for Arm A compared to 66% for Arm B (Fisher p= 0.24). Median PFS was 6.2 months for Arm A vs. 9.5 months for Arm B (Log Rank p= 0.17), while median overall survival (OS) was 18.2 months for Arm A and not reached for Arm B (Log Rank p= 0.12). Response rate was 47% for Arm A vs. 55% for Arm B (Fisher p= 0.76). Severe adverse events (AEs) were similarly uncommon in both arms; more specifically, two patients in Arm A experienced grade 3 white blood cells reductions, and two patients in Arm B experienced grade 3 increase of liver alanine aminotransferase. No treatment-related deaths were reported.
Conclusion
At the interim analysis of GENOA Trial, the combination of oral vinorelbine plus gefitinib was not associated with increased 6-month PFS rate over gefitinib alone; similarly, no advantages in terms of response, PFS or OS were observed in the experimental arm. With regards to safety, no significant difference in terms of AEs was reported, nor unexpected toxicity was observed. The study was interrupted on the basis of this interim analysis.
