EGFR/RET TKI Combination Active Against EGFR+ NSCLC With Acquired RET Fusion

The combination of osimertinib (Tagrisso) and selpercatinib (Retevmo) was found to be an active regimen in patients with EGFR-positive non–small cell lung cancer (NSCLC) with acquired RET fusions, according to a systematic analysis of patients with EGFR-mutant NSCLC who had acquired RET resistance to osimertinib.¹

Understanding Osimertinib Resistance

Multiple resistance mechanisms to osimertinib have previously been identified, including the presence of EGFR C797X, L718Q, and S768I point mutations and EGFR amplification. More recently, secondary genomic mechanisms of resistance like MET and HER2 amplifications have been found. Patients with EGFR-mutant NSCLC can also develop BRAF V600E secondary mutation and for 40% to 50% of the osimertinib-resistant population, the mechanism of resistance is unknown.

Fusions in the RET and ALK genes have also been identified, and subsequently case reports have shown that treatment with an EGFR tyrosine kinase inhibitor (TKI) in combination with a RET or ALK TKI induced responses in patients with these resistance mechanisms. RET fusions have been seen in approximately 5% of patients with EGFR-mutant NSCLC who had developed osimertinib resistance and the combination of osimertinib and pralsetinib (Gavreto) was specifically able to elicit responses.

Another RET inhibitor designed for RET fusion–positive NSCLC is selpercatinib, which has recently been granted FDA approval for the treatment of this patient group. In the phase 1/2 LIBRETTO-001 study (NCT03157128), which supported the FDA approval, selpercatinib achieved an overall response rate of 85%, patients receiving the drug had a 1-year progression-free survival (PFS) rate of 75%, which caused investigators led by Julie Rotow, MD, of Dana-Farber Cancer Institute, to believe that it may be effective in combination with osimertinib to address resistance.²

Osimertinib Plus Selpercatinib Against Osimertinib Resistance

Patient data in this analysis came from the selpercatinib compassionate access programs, including single patient protocols, named patient protocols, and expanded access programs. Patients were treated according to individual access protocols with osimertinib 80 mg daily in combination with selpercatinib 80 mg twice daily as the recommended dose. It was noted that more the 50% of patients included in the analysis received the FDA-approved monotherapy dose of selpercatinib.¹

All patients had EGFR-mutant NSCLC with acquired RET fusions at the time of osimertinib resistance and were retrospectively evaluated. Rotow et al also completed a review of the patient data to determine clinical outcomes, including, response per RECIST v1.1, duration of treatment, tolerability, and the number of dose adjustments required.

Overall, 12 patients were analyzed, with 11 of the patients evaluable for safety and 10 evaluable for response. At baseline, the patients had a median age of 62 years (range, 33-78), were predominantly female (55%), and were never smokers (73%). In terms of prior treatment, 55% of patients received a prior first- or second-generation EGFR TKI. RET fusions were detected at baseline via tissue biopsy in 64% of patients and via circulating tumor DNA (ctDNA) in 36%. The RET fusion partners found in patients included NCOA4 and CCDC6, each in 36% of patients, as well as KIF5B in 18% of patients, and RUFY2 in 9%.

Treatment with osimertinib in combination with selpercatinib led to an objective response rate of 50% in the patients evaluated. Responses included partial responses in 50% and stable disease in 30% of the responders, which resulted in a disease control rate of 80% in the study. The median depth of response was –43%. Notably, 1 patient with EGFR deletion 19–positive NSCLC and an acquired CCDC6-RET fusion achieved a radiographic response after just 2 months of treatment that lasted for 39 months.

Patients in the study received selpercatinib for a median of 7.4 months (95% CI, 6.1 to not reached [NR]). The median duration of treatment for responders to osimertinib plus selpercatinib was 11 months (95% CI, 7.4-NR).

The safety profile of osimertinib plus selpercatinib was generally well tolerated in the study population. The adverse events (AEs) that occurred were consistent with the profiles of either drug alone. Treatment was discontinued by one patient due to the development of pneumonitis. Dose reductions were observed for both study drugs, which included 1 due to grade 2 hypersensitivity to selpercatinib and 1 due to toxicities of osimertinib, including grade 3 QT prolongation, grade 1 diarrhea, and grade 2 muscle weakness. Serious AEs occurred but were unrelated to the study drug, including grade 5 lung infection, grade 3 vomiting, grade 2 pleural effusion, headache, and dyspnea, as well as grade 1 hepatotoxicity and nausea.

The grade 3 treatment-related AEs that were observed were hypertension, QT prolongation, neutropenia, leukopenia, each in 1 patient.

Despite the activity and safety of the combination in patients with EGFR-mutant NSCLC and acquired RET fusion, the data from this study suggest that this combination may not overcome resistance. One patient from the study underwent assessment for genomic mechanisms of acquired resistance after 11 months of treatment with osimertinib plus selpercatinib. The analysis revealed heterogeneous mechanisms of resistance, which included second-site resistance mutations. Rotow et al noted during a presentation for the 2020 World Conference on Lung Cancer that the second-site mutations observed with combination therapy mirror that observed with monotherapy.

_References:

_{Rotow J, Patel JD, Hanley MP, et al. Combination Osimertinib plus selpercatinib for EGFR-mutant non-small cell lung cancer with acquired RET fusions. Presented at: 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract FP14.07.}

_{Drilon A, Oxnard GR, Tan, DSW, et al. Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2020;383(9):813-824 doi:10.1056/NEJMoa2005653}