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YASIR Y Elamin
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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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FP04.04 - EGFR Mutations Predict Superior Survival of NSCLC Patients with Oligometastatic Disease Treated with Local Consolidative Therapy (ID 2994)
00:00 - 00:00 | Author(s): YASIR Y Elamin
- Abstract
Introduction
Local consolidative therapy (LCT) following systemic therapy for selected patients with oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment strategy. We sought to identify predictive genomic markers for overall survival (OS) and progression free survival (PFS) in patients presenting with synchronous oligometastatic NSCLC at diagnosis.
Methods
Patients presenting to a single institution (2000-2017) with stage IV NSCLC and ≤3 synchronous metastatic lesions were identified. Of 194 patients who met our inclusion criteria, 121 received comprehensive local consolidative therapy (LCT) to all sites of disease with either surgery or radiation. Intrathoracic nodal disease was counted as one site. Univariable and multivariable Cox regressions were performed to identify factors associated with OS. A ninety-day landmark analysis was performed to limit survivorship bias. Mutational status was obtained via an institutional database, when available.
Results
Of 194 patients who met our inclusion criteria and had genomic data available, TP53 mutations were identified in 40 of 55 (72%), KRAS in 30 of 65 (46%), EGFR in 22 of 90 (24%), ALK in 4 of 81 (5%), ROS1 in 2 of 63 (3%), and BRAF in 1 of 32 (3%) patients. The median age was 62 years. After a median follow-up of 52.3 months, median OS and PFS for this cohort was 26.5 (CI 23.0-30.0) months and 11.1 (95%, 9.1-13.0) months, respectively. Among all patients, comprehensive LCT to all sites of disease (N=121) was associated with improved OS (HR 0.67, CI 0.47-0.96, p=0.03) consistent with our previous study. Among all patients, on univariable analysis, patients with EGFR mutations had improved median OS (95.5 vs 37.2 months, p=0.03) compared to EGFR WT patients. Conversely, TP53, and KRAS mutations did not predict for OS. Among patients who received comprehensive LCT with known EGFR mutational status (N=57), EGFR mutations continued to predict for improved median OS (97.5 vs 29.8 months, p=0.02) (Figure 1).
Conclusion
Aggressive consolidative therapy to the primary lesion and all metastatic sites was associated with improved OS in a large cohort of oligometastatic patients, supporting results of recent prospective trials. EGFR mutations, but not KRAS or TP53 mutations, predicted for improved OS among oligometastatic patients who are treated with comprehensive LCT in addition to systemic therapy. These data support ongoing prospective trials evaluating the benefit of local therapy in oligometastatic EGFR mutant NSCLC.
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.05 - LIBRETTO-431: Selpercatinib in Treatment-Naïve Patients with RET Fusion-Positive Non-Small Cell Lung Cancer (NSCLC). (ID 807)
00:00 - 00:00 | Author(s): YASIR Y Elamin
- Abstract
Introduction
Selpercatinib (LOXO-292) is a highly selective and potent inhibitor of RET signaling. In the LIBRETTO-001 Phase I/II trial, selpercatinib treatment resulted in a 64% objective response rate (ORR) (95% confidence interval [CI]: 54-73%) in the registration dataset (n=105) of patients with RET+ NSCLC who previously received platinum-based chemotherapy and an 85% ORR (95% CI: 70-94%) in treatment-naïve patients with RET+ NSCLC (n=39). Although the duration of response (DOR) and progression free-survival (PFS) were not yet mature in treatment-naïve patients, in patients who previously received chemotherapy, the median DOR was 18 months (95% CI: 12-not estimable [NE]), median PFS was 17.5 months (95% CI: 12-NE), and CNS ORR per RECIST 1.1 was 91% (95% CI: 59-100%) (n=10/11). The most common adverse reactions included dry mouth (39%), diarrhea (37%), hypertension (35%), and fatigue (35%). The majority of adverse reactions were Grade 1 or Grade 2. The most common lab abnormality was increased alanine aminotransferase (ALT) (51%)/aspartate transaminase (AST) (45%). A total of 5% of patients discontinued due to an adverse reaction.
The LIBRETTO-431 trial, is a global, open-label, randomized, controlled, Phase 3 trial evaluating selpercatinib vs platinum-based and pemetrexed treatment +/- pembrolizumab in treatment-naïve patients with locally advanced or metastatic RET+ non-squamous NSCLC (NCT04194944).
Methods
Patients will be randomized to receive selpercatinib 160 mg BID in 3-week cycles (Arm A) or pemetrexed (500 mg/m2 IV) in 3-week cycles plus investigator’s choice of carboplatin (AUC 5) or cisplatin (75 mg/m2 IV) for 4 cycles (Arm B). For patients in Arm B, at the investigator’s discretion, pembrolizumab (200 mg IV) may also be given for up to 35 cycles and patients may receive maintenance pemetrexed +/- pembrolizumab. Crossover to selpercatinib is allowed for Arm B patients who have disease progression. Treatment will be discontinued for progressive disease, unacceptable toxicity, decision to withdraw or death. Stratification factors include geography: East Asian versus non-East Asian, brain metastases: presence versus absence, and intended treatment if randomized to Arm B: +/- pembrolizumab. RET status may be determined in tumor (by PCR or NGS) or in blood (by NGS) using a qualified local test or a Lilly-enabled regional test. Key eligibility criteria include age ≥18 years; treatment-naïve; non-squamous Stage IIIB-IIIC not suitable for surgery/radiation therapy or Stage IV NSCLC; measurable disease by RECIST 1.1; ECOG performance status 0-2. Key exclusion criteria include presence of other known oncogenic drivers and symptomatic central nervous system metastases. Tumor assessments will be performed until progressive disease, the start of a new anticancer treatment, death or study completion. The co-primary endpoint, PFS by independent review in intent-to-treat (ITT) patients with pembrolizumab (if assigned to control), will act as a gatekeeper to the co-primary endpoint PFS by independent review in the ITT population. Secondary endpoints include investigator assessed PFS, ORR/DOR, intracranial ORR/DOR, overall survival, time to deterioration in pulmonary symptoms, progression after the next line of therapy, RET fusion status: local versus central, and safety/tolerability. The study was initiated in March 2020 and enrollment is ongoing.
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MA13 - Tumor Biology: Focus on EGFR Mutation, DNA Repair and Tumor Microenvironment (ID 214)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA13.07 - Structural Classification of Atypical EGFR Mutations Identifies 4 Major Subgroups with Distinct Patterns of Drug Sensitivity (ID 3760)
16:45 - 17:45 | Author(s): YASIR Y Elamin
- Abstract
Introduction
While osimertinib has resulted in striking improvements in outcomes for patients with NSCLC harboring classical EGFR mutations (Ex19del, L858R, and/or T790M), patients with atypical EGFR mutations have shown heterogeneous and in some cases inferior responses to EGFR inhibitors. The frequency, structural and clinical implications of atypical EGFR mutations are less understood.
Methods
We characterized the mutational landscape (N=16,715 patients with EGFR mutations), in vitro sensitivity (N=70 Ba/F3 cell lines), and in silico structure of primary and co-occurring acquired EGFR mutations to determine functional groups. Clinical outcomes in patients with atypical EGFR mutations treated with EGFR TKIs were evaluated through a retrospective analysis from the MD Anderson GEMINI database and Moffitt Cancer Center.
Results
Among EGFR mutant NSCLC patients, 67% had classical mutations, 31% had atypical EGFR mutations, and 3% had a tertiary mutation including Ex19del/L858R with T790M plus an atypical mutation. Atypical mutations included exon 20 insertions (9%), other primary atypical mutations (13%), and complex mutations including an atypical mutation (9%). EGFR mutations could be separated into four distinct functional subgroups: 1) classical-like, 2) T790M-like including a subset of tertiary mutations, 3) exon 20 insertions, and 4) ATP-Binding Pocket Volume-Reducing (PVR) mutations. The classical-like were broadly sensitive to 1st, 2nd, and 3rd-generation inhibitors with a drug binding pocket similar to classical mutations. T790M-like mutations were sensitive to 3rd-generation EGFR inhibitors, but resistant to first- and second-generation inhibitors irrespective of co-occurring mutations. Tertiary mutations were generally resistant to EGFR inhibitors, but a drug repurposing screen identified select PKC and ALK inhibitors as having activity. The exon 20 insertion mutations, which cause significant reduction in drug binding pocket volume, were highly resistant to the majority of EGFR inhibitors but sensitive to novel exon 20 specific inhibitors. Lastly, we found a fourth group of mutations, ATP-Binding Pocket Volume Reducing (PVR) mutations that were associated with resistance to 1st- and 3rd-generation inhibitors, but selectively sensitive to quinazoline-based, 2nd-generation inhibitors such as afatinib and poziotinib preclinically. These mutations were primary located in the P-loop (exon 18), the c-terminal loop of the αc-helix (exon 20), and the A-loop (exon 21) of EGFR. Retrospective analysis of patients with PVR mutations revealed that patients had a significantly longer median progression free survival (mPFS) when treated with a 2nd-generation inhibitor (mPFS = 24mo) versus a 1st-generation (mPFS = 9.5mo, p = 0.013, HR = 4.2) or 3rd-generation inhibitor (mPFS = 6.4mo, p <0.0001, HR = 3.4). Three patients with NSCLC, who acquired PVR mutations after first-line osimertinib treatment had clinical benefit after receiving 2nd-generation EGFR inhibitors.
Conclusion
EGFR mutations can be separated into four distinct subgroups based on the structural changes caused by the mutation and differential sensitivity to EGFR inhibitors. The PVR subgroup, largely comprised of exon 18 or 20 point mutations, had greater relative sensitivity to 2nd-generation drugs with a quinazoline core than 3rd-generation drugs such as osimertinib in vitro, and improved outcomes in patients treated with these agents compared with osimertinib. These findings define subgroups of EGFR mutations that may better guide future treatment approaches for atypical EGFR mutations.
