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

Abstract

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.

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer

“…The combination arm demonstrated statistically significant improved PFS and objective response over erlotinib monotherapy, thus supporting the hypothesis of synergism with dual inhibition of EGFR and VEGF pathways. The combination of osimertinib with bevacizumab is being investigated and the first phase I results were reported in 2017, showing that the combination is tolerable (45). Three phase II studies with this drug combination in various lines of treatment are currently ongoing (NCT02803203, NCT03133546, NCT02971501, see Table 2).…”

Improving therapy for patients with epidermal growth factor receptor‐mutant lung cancer

“…However, the combination with vascular endothelial growth factor inhibition is in early stages of investigation. 21 Another more general combinatorial approach currently in exploration is the use of immunotherapy in combination with EGFR TKIs for patients with EGFR-mutant NSCLC. Although single-agent immunotherapy with programmed cell death protein 1/ programmed death-ligand 1 inhibitors has shown limited in efficacy in patients with EGFR-mutant lung cancers, 22 combining EGFR TKIs with immune checkpoint inhibitors is an approach that currently is being explored in numerous clinical trials.…”

“…Whether we can observe similar improvement in outcomes with newer EGFR TKIs, such as osimertinib, is a yet unanswered question. However, the combination with vascular endothelial growth factor inhibition is in early stages of investigation . Another more general combinatorial approach currently in exploration is the use of immunotherapy in combination with EGFR TKIs for patients with EGFR‐mutant NSCLC.…”

Rationale and Design of a Phase II Trial of Osimertinib Combined With Bevacizumab in Patients With Untreated Epidermal Growth Factor Receptor-mutated Non–small-cell Lung Cancer and Malignant Pleural and/or Pericardial Effusion (SPIRAL II Study)

“…These findings indicate that the PFS of patients with pleural or pericardial effusion is expected to be prolonged with combination use of an EGFR-TKI plus bevacizumab compared with that with an EGFR-TKI alone. However, although phase I clinical trial data have been reported for the combination of osimertinib plus bevacizumab and demonstrated their safety, the efficacy remains unclear, 14 particularly in patients with pleural or pericardial effusion.…”