Hunting Resistance Mechanisms in RET-Fusion Lung Cancer

As detected by circulating tumor DNA (ctDNA), acquired resistance to pralsetinib (Gavreto) in RET fusion-positive lung cancer was relatively uncommon, findings from the ARROW study suggested.

In 42 non-small cell lung cancer (NSCLC) patients who experienced disease progression on pralsetinib, ctDNA identified on-target mutations in four patients and off-target alterations in another four, while no mechanisms of acquired resistance were clearly defined in the remaining cases, reported Justin Gainor, MD, of Massachusetts General Hospital in Boston.

“In most cases, no putative mechanisms of resistance was identified in ctDNA, underscoring the need for additional tissue analysis to understand the full spectrum of resistance,” he said during a presentation at the virtual North America Conference on Lung Cancer.

On-target mutations were seen in the “solvent front” (RET G810) and “roof” (RET L730), which during in vitro screening had been areas predicted as possible mechanisms of resistance, explained Gainor. Off-target alterations included MET amplifications in three patients and mutations in BRAF V600E in one patient, consistent with observations of other tyrosine kinase inhibitors (TKIs) for NSCLC.

Pralsetinib is a potent and selective TKI that targets RET alterations, which drive roughly 1%-2% of NSCLC cases, and was designed to have limited off-target kinase activity and potency against RET V804 gatekeeper mutations. The drug gained FDA approval last month for adults with metastatic RET fusion-positive NSCLC based on results from ARROW.

In an updated analysis of the phase I/II study, Gainor noted that 65% of the 116 evaluable patients achieved an objective response (reaching 73% in the untreated group). Complete responses were seen in 6% of patients (12% in the untreated subset), and nearly all saw some degree of tumor shrinkage. The median duration of response had not been reached, and 75% of patients remained on therapy at the most recent data cutoff.

No RET gatekeeper mutations were observed in the study, noted Gainor.

As part of ARROW, patients underwent plasma sampling at baseline, at each restaging visit, and at the end of treatment. The ctDNA analysis was performed using the Personal Genome Diagnostics PlasmaSELECT 64 assay — a next-generation sequencing panel that analyzes single nucleotide variance and indels in 58 different genes, along with the full coding region of RET. The assay can also detect rearrangements in 17 genes and amplification in 18 genes.

One patient highlighted by Gainor had a CCDC6-RET fusion at baseline and developed oligoclonal resistance. The woman had previously been treated with carboplatin plus pemetrexed (Alimta) and bevacizumab (Avastin), followed by docetaxel. Rapid clearance of the CCDC6-RET fusion was seen on ctDNA after 2 weeks of pralsetinib, and the patient had a partial response that was maintained for 6 months. Evidence of radiographic progression was seen at month 8, and the CCDC6-RET fusion re-emerged on ctDNA with two independent mutations — G810C and T729_L730insL.

“It will be imperative to identify larger sample sizes as well as patients who have developed resistance after being on pralsetinib for longer to get a better perspective on the true landscape of resistance,” he said.

Discussant Joel Neal, MD, PhD, of Stanford University Medical Center in California, pointed out that three major kinds of resistance mechanisms have been described with TKIs.

“One is target alteration, in which TKIs become resistant with point mutations; a second is bypass tracts, where a second receptor tyrosine kinase or downstream signaling activates; and the third is histologic transformation, demonstrating neuroendocrine transformation or epithelial-mesenchymal transition,” he said.

In the current analysis, “surprisingly few had point mutations,” said Neal, suggesting that target inhibition is relatively potent. “Remember that ctDNA can’t identify histological transformation.”

Neal noted that MET plus RET combination strategies might overcome some cases of resistance in patients with off-target mutations.