Evolution and clinical impact of genetic epistasis within EGFR-mutant lung cancers

9039 Background: Clarke (Neurooncol 2010) reported responses with intermittent high pulse doses of erlotinib (leading to higher concentrations in CSF) given to patients with EGFR-mutant central nervous system metastases developing on standard erlotinib doses. In a phase 1 study of pulse-continuous dose erlotinib, no patient developed progression in existing or new brain or leptomeningeal metastases (Yu Ann Oncol 2016). This phase 2 trial tested pulse-continuous dose erlotinib in patients with lung cancers with EGFRmutations with brain metastases. Methods: Patients had no prior EGFR TKI or radiation to the brain and at least 1 target brain metastasis. All received initial daily "pulse" doses of erlotinib 1200 mg days 1&2 and "continuous" 50 mg doses days 3-7 (doses and schedule from the Yu Phase 1 study), weekly until progression. The co-primary endpoints were overall and brain metastasis response by RECIST 1.1. Results: We enrolled 19 patients with EGFR-mutant lung cancers: median age 61yrs (range 45-80), 74% women, 95% Karnofsky PS ≥80%, 1 leptomeningeal disease, 33% prior pemetrexed-based chemotherapy. The median size of target brain metastases was 13 mm (range 10-19 mm). 32% were on dexamethasone for cerebral edema. The partial response rate overall was 74% (95% CI 51-89%) and also 74% in brain metastases. Of 10 patients with progression, 9/10 occurred in non-brain sites (4 EGFRT790M, 1 with progression in brain as well), 1 with leptomeningeal. The median progression free survival was 10 mo (range 7-NR mo). Pulse doses were reduced in 68% (median delivered pulse dose 1050 mg days 1&2, range 600-1200 mg). Incidences of any gradeof rash and diarrhea were 84% and 63% respectively. There were no grade 4 or 5 toxicities. Conclusions: Pulse-continuous dose erlotinib alone controlled brain and leptomeningeal metastases in 89% (95% CI 67-98%) of patients with EGFR-mutant lung cancers with central nervous system spread pretreatment, with an overall response rate of 74% and progression free survival and rates of rash and diarrhea comparable to series with erlotinib 150 mg daily. Supported by Astellas, CA 129243, CA 008748. NCT01967095 Clinical trial information: NCT01967095.

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A phase 1 study of osimertinib and bevacizumab as initial treatment for patients with EGFR-mutant lung cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9033 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9033-9033 ◽

Cited By ~ 5

Author(s):

Helena Alexandra Yu ◽

Sara A. Hayes ◽

Robert J. Young ◽

Ai Ni ◽

Christopher Rodriguez ◽

...

Keyword(s):

Initial Treatment ◽

Phase 1 ◽

Line Treatment ◽

First Line ◽

Lung Cancers ◽

Grade 3 ◽

Egfr Mutant ◽

Egfr Tki ◽

Egfr T790m ◽

First Line Treatment

9033 Background: EGFR tyrosine kinase inhibitors (TKI) are the recommended first line treatment for EGFR-mutant lung cancers. Osimertinib, an EGFR TKI that inhibits both sensitizing EGFR mutations and EGFR T790M, is approved for use after progression on an EGFR TKI with evidence of EGFR T790M, and is currently being assessed as initial treatment for EGFR-mutant lung cancers. The addition of bevacizumab to erlotinib resulted in improved progression free survival (PFS) compared to erlotinib alone as initial treatment (16 vs 10 months, HR 0.41). This phase 1/2 study is assessing osimertinib and bevacizumab as initial treatment for patients with EGFR-mutant lung cancers. Methods: We evaluated toxicity and efficacy of osimertinib and bevacizumab as initial treatment for patients with advanced EGFR-mutant lung cancers. Using a 3+3 design, full doses of osimertinib (80mg PO daily) and bevacizumab (15mg/kg IV q3 weeks) were given, with a planned dose de-escalation (osimertinib 40mg PO daily) should grade 3 or greater toxicity be seen. Six patients must be treated without a dose-limiting toxicity (DLT) to determine the MTD. 43 additional patients will be treated at the MTD in the phase 2 study, with a primary endpoint of PFS at 12 months. Response was evaluated by RECIST 1.1. Results: From Sept 2016 to Jan 2017, 15 patients were enrolled. Median age: 63; Women 11; EGFR L858R = 8, Ex19del = 6, G709A/G719S = 1. After median duration of treatment of 2.7 months, no DLTs were seen in any patient. The MTD was determined to be osimertinib 80mg, bevacizumab 15mg/kg q3 weeks. In total, 15 patients are being treated at the MTD to date. Treatment-related adverse events (AE) were all grade 1-2, except for grade 3 hypertension. The most frequent treatment-related AEs (any grade) were rash (53%), diarrhea (40%), hypertension (33%), fatigue (20%), and itching (20%). All 15 patients continue on study. Conclusions: Combination osimertinib and bevacizumab is a tolerable first-line treatment for patients with EGFR-mutant lung cancers and the MTD is osimertinib 80mg and bevacizumab 15mg/kg q3 weeks. Assessment of efficacy with an endpoint of PFS at 12 months is ongoing. Supported by AstraZeneca (NCT02803203). Clinical trial information: NCT02803203.

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Elevated murine HB-EGF confers sensitivity to diphtheria toxin in EGFR-mutant lung adenocarcinoma

Disease Models & Mechanisms ◽

10.1242/dmm.049072 ◽

2021 ◽

Author(s):

Camila Robles-Oteiza ◽

Deborah Ayeni ◽

Stellar Levy ◽

Robert J. Homer ◽

Susan M. Kaech ◽

...

Keyword(s):

Diphtheria Toxin ◽

Tumor Regression ◽

Genetically Engineered ◽

Lung Cancers ◽

Genetically Engineered Mice ◽

Elevated Expression ◽

Murine Tissue ◽

Egfr Mutant ◽

Lung Adenocarcinomas

Conditional ablation of defined cell populations in vivo can be achieved using genetically engineered mice in which the human diphtheria toxin (DT) receptor (DTR) is placed under control of a murine tissue-specific promotor, such that delivery of diphtheria toxin selectively ablates cells expressing the high-affinity human DTR. Cells expressing only the endogenous low-affinity mouse DTR are assumed to be unaffected. Surprisingly, we found that systemic DT administration induced rapid regression of murine EGFR-mutant lung adenocarcinomas in the absence of a transgenic allele containing human DTR. DT enzymatic activity was required for tumor regression, and EGFR-mutant tumor cells were the primary targets of DT toxicity. In FVB mice, EGFR-mutant tumors upregulated expression of HB-EGF, which is the DTR in mice and humans. HB-EGF blockade with CRM197, an enzymatically inactive DT mutant, partially abrogated DT-induced tumor regression. These results suggest that elevated expression of murine HB-EGF (low-affinity DTR) confers sensitivity to DT in EGFR-mutant tumors, demonstrating a biological effect of DT in mice lacking transgenic DTR alleles and highlighting a unique vulnerability of EGFR-mutant lung cancers.

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