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Jonathan Wesley Riess
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MA02 - Miscellaneous Topics in the Management of Early Stage Lung Cancer (ID 116)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Mireia Serra-Mitjans, Thomas A. D'Amico
- Coordinates: 9/08/2019, 10:30 - 12:00, Interlaken (1988)
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MA02.07 - A Phase I Trial of an Immune Checkpoint Inhibitor Plus Stereotactic Ablative Radiotherapy in Patients with Early Stage Non-Small Cell Lung Cancer (Now Available) (ID 1967)
10:30 - 12:00 | Author(s): Jonathan Wesley Riess
- Abstract
- Presentation
Background
Stereotactic ablative radiation therapy (SABR) is the standard-of-care for medically inoperable, early stage non-small cell lung cancer (NSCLC), but regional and distant failures remain problematic. Based on in vivo preclinical data showing synergy between radiation and immune checkpoint inhibitors (ICI) and the known efficacy and mild toxicity profile of ICI in Stage III and IV NSCLC, we conducted a phase I study to determine the safety, tolerability and maximum tolerated dose of neoadjuvant, concurrent, and adjuvant atezolizumab with SABR for high risk early stage NSCLC (NCT02599454).
Method
Eligible patients had histologically confirmed T1-3 NSCLC with one or more features predictive of increased recurrence risk: diameter ≥1 cm, SUV ≥6.2 on FDG PET, or moderately/poorly differentiated histology. Patients were medically inoperable or refused surgery, and had a Zubrod PS ≤2. Patients received 6 cycles of atezolizumab IV in 21 day cycles. A 3+3 dose finding design was employed with three dose levels: 3 mg/kg, 10 mg/kg, and 1200 mg flat dosing. SABR was delivered starting cycle 3 to 50 Gy over 4-5 fractions. Patients were restaged after cycle 2, prior to SABR. Dose limiting toxicity (DLT) was assessed during the first 9 weeks of treatment.
Result
From April 2016-June 2018, a total of 15 patients enrolled, with 12 evaluable for DLT assessment. Three patients chose to discontinue treatment due to travel issues (1 pt), a COPD exacerbation (1 pt) and grade 2 liver function tests (LFTs) (1 pt). One patient on dose level 2 developed DLT, a grade 3 rash requiring discontinuation of protocol therapy. No other DLTs occurred, resulting in a recommended dose of 1200 mg for future studies. Eleven patients completed protocol treatment. Other grade 3 toxicities include transient lymphopenia in 4 patients. One patient each developed grade 2 pneumonitis, grade 2 hypothyroidism, and grade 2 hyperthryoidism. Three patients had a radiographic partial response and 1 patient had a minor response following 2 cycles. No patient had progressive disease prior to SABR. Results of correlative blood and tissue studies will also be reported.
Conclusion
Neoadjuvant, concurrent, and adjuvant atezolizumab in combination with SABR for early stage NSCLC is well-tolerated, with radiographic PR prior to SABR in 25% of our cohort. Overall efficacy data is premature. Enrollment to an expansion cohort is ongoing, and this combination will be tested in an upcoming randomized phase III trial SWOG/NRG S1914.
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Lung Cancer Research Program under Award no. W81XWH-15-2-0063.
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MA09 - EGFR & MET (ID 128)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Jordi Remon, Juergen Wolf
- Coordinates: 9/08/2019, 15:15 - 16:45, Melbourne (1991)
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MA09.02 - In Vivo, Ex Vivo and Early Clinical Activity of EGFR Monoclonal Antibody and Osimertinib in EGFR Exon 20 Insertion NSCLC (Now Available) (ID 968)
15:15 - 16:45 | Presenting Author(s): Jonathan Wesley Riess
- Abstract
- Presentation
Background
EGFR Exon 20 insertions (Ex20Ins) are the 3rd most common class of EGFR activating mutation, but patients with NSCLC harboring EGFR Ex20Ins lack effective approved EGFR-TKIs. Newer-generation TKIs and combination strategies with EGFR-monoclonal antibodies (moAbs) may enhance activity against EGFR Ex20Ins.
Method
Xenografts derived from CRISPR-modified H2073 cells with Ex20Ins (A763_Y764InsFQEA, D770_N771InsSVD or V769_D770InsASV) and Ex20Ins patient-derived xenografts (PDXs) (D770_N771InsSVD, A797_V769dupASV, D770_N771_InsG, H773_V774_InsNPH) were treated with vehicle, osimertinib , cetuximab, and osimertinib+cetuximab. Ex20Ins spheroid models (D770_N771InsSVD and M766_A767InsASV) were treated with cetuximab at fixed dose and increasing concentrations of osimertinib. Ex20Ins PDX (A763_Y764InsFQEA) was also treated with afatinib and erlotinib; Ex20Ins PDX (D770_N771InsSVD) was treated with these combinations plus afatinib+cetuximab. Immunoblotting for pharmacodynamic studies of on-target and downstream proteins, phospho-proteins and apoptosis markers were performed at relevant timepoints for D770_N771InsSVD PDX and CRISPR model. A phase 1 clinical trial with a dose expansion cohort in Stage IV EGFR Ex20Ins NSCLC is currently open to accrual at osimertinib 80 mg qd and the EGFR-moAb necitumumab 800 mg IV D1 and D8 of 21D cycle with response assessment by RECIST 1.1 (NCT02496663).
Result
The combination of osimertinib and cetuximab achieved significant tumor growth inhibition compared to osimertinib alone across PDX and CRISPR cell line xenograft models (p=0.05), except for the A763_Y764InsFQEA PDX model where osimertinib alone and osimertinib+cetuximab were equivalently effective (both p<0.001 compared to control). Spheroid models for D770_N771InsSVD and M766_A767InsASV showed significantly increased cytotoxicity from the addition of cetuximab across multiple doses of osimertinib. Osimertinib+cetuximab was superior to erlotinib, cetuximab, afatinib and afatinib+cetuximab in a D770_N771InsSVD PDX model (p<0.001). In this model, inhibition of p-EGFR, p-ERK, p-HER2 and increased caspase 3 cleavage were noted, consistent with significant tumor growth inhibition. In the phase 1 EGFR Ex20Ins expansion cohort of necitumumab in combination with osimertinib, 6/18 patients enrolled with 4 patients evaluable for response; 2 patients achieved a partial response and median PFS was 5.3 months.
Conclusion
In vivo and ex vivo modeling in CRISPR cell line xenografts, PDXs and organoids demonstrated preclinical activity of dual EGFR blockade with osimertinib and EGFR monoclonal antibody in the 5 most common EGFR Ex20Ins representing a frequency of ~60% of detectable EGFR Ex20Ins in clinical practice. Osimertinib alone was as active as osimertinib plus cetuximab in A763_Y764InsFQEA, consistent with known sensitivity of this proximal insertion to single-agent EGFR-TKI. In a phase 1 study, osimertinib and the EGFR moAb necitumumab demonstrates preliminary clinically activity in EGFR Ex20Ins NSCLC.
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MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Lecia Sequist
- Coordinates: 9/09/2019, 14:00 - 15:30, Hilton Head (1978)
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MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)
14:00 - 15:30 | Author(s): Jonathan Wesley Riess
- Abstract
- Presentation
Background
Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.
Method
620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.
Result
Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.
Conclusion
In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
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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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P1.01-86 - Occurrence of de Novo Dual HER2/HER3 or HER2/EGFR TMD Mutations: Extending the Spectrum of Targetable Mono-HER2 TMD in NSCLC? (ID 956)
09:45 - 18:00 | Author(s): Jonathan Wesley Riess
- Abstract
Background
HER2 (ERBB2) TMD mutations have recently been described as novel solo actionable drivers in NSCLC responsive to afatinib in small series. However, dual occurrence of de novo EGFR or HER3 (ERBB3) TMD mutations together with HER2 TMD mutations, which may have implications for dimerization patterns and treatment, has not been described.
Method
Hybrid-capture based comprehensive genomic profiling was performed on blood-based circulating tumor DNA (n=5,200) or FFPE tissue (n= 45,780) samples collected during clinical care from 50,980 unique NSCLC patients.
Result
HER2 TMD mutations were identified in 0.12% (60/50,980) of cases and included V659E (n=33), V659D (n=8), G660D (n=15), V659E+G660R, V659_I661>VVEGI, G660E>R, and S653C (1 each). Within this subset, the median age of patients was 61 years (range 33-91) and 62% were female. No co-occurring known NSCLC driver alterations were detected, except one case with EGFR exon 19 deletion and one case with EGFR L858R and lung co-primary tumors noted. However, co-occurring HER3 (I649R) or EGFR (G652R) TMD mutations were found in 18% (11/60) and 5.0% (3/60) of cases, respectively. Notably, these ERBB3 or EGFR TMD mutations only co-occurred with HER2 TMD V>D (8/9 cases) or G>D (7/15 cases), but not with V>E changes (0/34 cases; p=0.0002). HER2 amplification co-occurred with V659E in 15% (5/34) of cases, and G660D mutation was seen with the oncogenic extracellular domain S310F mutation in one case. Importantly, neither EGFR G652R nor ERBB3 I649R was found in the absence of a HER2 TMD mutation. Preliminary modelling studies suggest formation of a salt-bridge which would increase propensity for HER2/HER3 and HER2/EGFR heterodimerization favoring receptor activation. Two patients in this series with V659E were previously reported to have responded to afatinib and 1 patient with G660D+I649R did not respond to afatinib. Updated clinical data for these patients and others treated with HER2-tageted therapies will be presented.
Conclusion
HER2 TMD mutations (V659D/E or G660D/R) are uncommon but targetable driver alterations in NSCLC. In cases with HER2 TMD V>D or G>D, a de novo co-existing EGFR or HER3 TMD mutation was frequently observed (88% and 47%, respectively), which may explain differential dimerization preference and in turn response to ERBB inhibitors. We hypothesize that dual HER2/HER3 or HER2/EGFR TMD mutants may be more aggressive than single HER2 TMD mutants due to the arginine-aspartic acid interaction, and these dual mutants may require combined kinase inhibitor + antibody therapy to block dimerization. Studies utilizing models to further characterization these co-alterations are in progress.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-58 - A Phase II Study to Evaluate Neoadjuvant Osimertinib for Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer (ID 580)
09:45 - 18:00 | Author(s): Jonathan Wesley Riess
- Abstract
Background
The third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is well-tolerated and effective for first-line treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC). The efficacy of osimertinib in the treatment of early stage EGFR-mutant NSCLC, however, is unknown, and cytotoxic chemotherapy is considered the standard of care when systemic therapy is necessary for these patients. Neoadjuvant chemotherapy is an established therapeutic modality in locally-advanced NSCLC, in which a major pathologic response is associated with improved survival. Neoadjuvant use of targeted therapies in oncogene-driven NSCLC may offer the dual advantages of increased response rates and of more favorable toxicity profiles compared to cytotoxic chemotherapy, and also provides the opportunity to identify mechanisms underlying tumor cell persistence despite optimal oncogene-targeted therapy.
Method
This ongoing phase II, multi-institution study aims to enroll 27 patients with surgically resectable stage I-IIIA EGFR-mutant NSCLC. Patients are treated with one to two months of osimertinib 80 mg orally daily followed by surgical resection. The primary endpoint is major pathologic response (mPR) rate, defined as less than 10% residual viable tumor at surgical resection. Secondary endpoints include safety assessment, unanticipated delays to surgery, surgical complication rate, pathological complete response rate (pCR), unconfirmed objective response rate (ORR), rate of lymph node downstaging, disease-free survival, and overall survival. Tumor biopsies are obtained prior to osimertinib treatment in order to permit comparative correlative studies between pre- and post-osimertinib treated tumors. This includes genomic and transcriptomic analyses, evaluation of tumor immune cell infiltrates, and development of patient-derived model systems for functional validation studies.
Result
As of March 2019, five patients with EGFR-mutant NSCLC (2 stage IIIA, 1 stage IB, 2 Stage IA) have been enrolled and treated with osimertinib for an average of 56 days prior to surgical resection. Restaging imaging prior to surgical resection demonstrated an unconfirmed radiographic partial response in three patients (60% ORR) and stable disease in two patients (100% disease control rate). The mPR rate is 20% (1 of 5). No pCR’s were observed. One patient demonstrated lymph node downstaging from N2 to N0. Treatment was well-tolerated without SAEs and all patients proceeded to surgical resection without unscheduled delay or surgical complications. Genomic and immunophenotyping analyses are underway and will be reported.
Conclusion
Preliminary data from this phase II study indicates that neoadjuvant osimertinib treatment in surgically-resectable, EGFR-mutant NSCLC is well-tolerated and can induce pathological responses and downstaging of disease prior to surgery.
