Solomon et al (2020) performed plasma ctDNA analyses from patients enrolled in the LIBRETTO-001 trial (NCT03157128) who experienced disease progression after selpercatinib response.1

Compared to their detectable circulating tumor DNA (ctDNA) samples at baseline, solvent front RET G810 mutations were identified in

• 2 of 3 patients with medullary thyroid cancer (MTC), and
• 1 of 6 patients with non-small cell lung cancer (NSCLC).1

The authors noted that the actual number of acquired front solvent RET mutations is not represented due to the small number of patients with acquired resistance studied and that analysis of other biopsy samples will likely uncover additional mechanisms of resistance to selective RET TKIs.1

Rosen et al (2022) analyzed pretreatment and postprogression tumor samples of 72 patients in the LIBRETTO-001 trial (NCT03157128) in an effort to identify characteristics that may facilitate response and resistance to RET inhibitor therapy.2

The study population included 52 patients with RET fusion-positive tumors and 20 patients with RET-mutant tumors.2 Mitogen-activated protein kinase (MAPK)-activating alterations were not found in the lung cancer specimens based on pretreatment genomic profiling.2

Of the 72 patients, 27 progressed on selpercatinib, and of those patients, 18 had adequate tumor specimens for pre-treatment and postprogression genomic sequencing.2

Overall, 11 of the 18 patients developed the following genetically-driven resistance mechanisms including

• KRAS (n=5)
• RET (n=3)
• MET amplification (n=2), and
• BRAF, FGFR1 amplification, NRAS and PIK3CA (n=1 each).2

The authors noted that nongenetically driven resistance mechanisms could not be ruled out by the analysis.2

A 61-year-old man with KIF5B RET fusion-positive NSCLC showed rapid improvement that included a confirmed a partial response after starting compassionate use of selpercatinib.1

Three months after starting treatment, ctDNA identified a RET G810S solvent front mutation with an ongoing radiographic response. After 4 months, additional RET solvent front mutations were seen (G810R/G810C/G810V). Repeat imaging after 6 months of treatment reported progressive disease. Despite an increased dose of selpercatinib to 240 twice daily, his disease progressed further and he died from his cancer. Postmortem biopsy confirmed the presence of these mutations in several disease sites.1

A patient with CCDC6-RET fusion-positive NSCLC, developed disease progression in the pleural cavity after an initial systemic and intracranial tumor response to selpercatinib. An acquired RET G810S mutation was identified in malignant pleural cells, which was absent from pleural fluid collected immediately before selpercatinib treatment.1

A 49-year-old man with sporadic MTC harboring RET M918T mutation and an acquired RET V804M gatekeeper mutation, was started on single-patient protocol selpercatinib with rapid dose escalation to 160 mg twice daily. He improved and had a confirmed partial response for 24 months. At 25 months of therapy, he remained clinically stable. At around 30 months of therapy, he experienced rapid clinical decline, and developed hyperbilirubinemia and transaminitis. Plasma cfDNA analyses identified resistant mutations RET^Y806C/N and RET^G810C/S.4

A 66-year-old man with no smoking history, and a diagnosis of stage IV metastatic thyroid transcriptions factor-1 lung adenocarcinoma entered the selpercatinib LIBRETTO-001 clinical trial. He improved over a few weeks of receiving selpercatinib, and showed confirmed partial response with an increased performance status, improvement of symptoms, and his tumors showed a 64% reduction. After 18 cycles of treatment, the patient experienced a decreased performance status and new bilobular liver metastasis. Plasma cfDNA analysis identified resistant mutant CDC6-RET^G810C kinase, and BaF3/CCDC6-RET^G810C cells that were resistant to apoptosis initiated by selpercatinib.4