The RETgistry study looked at tumor samples from biopsies of RET patients whose cancers stopped responding to RET-targeted drugs (selpercatinib or pralsetinib) to understand why resistance happens. The study showed that 14% of cases developed new alterations in the RET gene, while most resistance was caused by other genetic changes (“off-target”) especially involving a gene called MET. The study also showed that in some cases no clear new alteration was found, meaning resistance can be complex. These findings underscore the importance of repeat biopsies at progression to identify new targets and guide treatment decisions, including combination therapies.
Highlights:
This is one of the largest global studies looking at why RET-targeted treatments stop working
Researchers from 20 institutions studied tumor biopsies from 109 RET-altered cancer patients after their cancer progressed on selpercatinib or pralsetinib, one of the biggest collections of RET cancer data ever assembled.
This study highlights the central role of off-target alterations in mediating resistance to RET inhibitors
The most common alteration was found in a gene called MET. This matters because doctors may be able to test for MET and guide the treatment accordingly, for example, by adding a MET inhibitor.
The critical need of investigating new therapy combinations for RET cancer
The leading role of off-target alterations in mediating resistance to RET inhibitors, highlights the increasing importance of developing new clinical trials testing therapeutic combinations to tackle RET resistance.
The importance of biopsy at progression with RET inhibitors
Identifying the resistance mechanism through a biopsy at progression, not just at diagnosis, is key to help guide the next treatment decision.
Dr. Sarah Waliany, leader of the RETgistry study (Mass General Brigham Cancer Institute).
Landscape of Genomic Mechanisms of Resistance to Selective RET Inhibitors in RET-AlteredSolid Tumors: Analysis of the RETgistry Global Consortium
Results from the ‘RETgistry,’ a global consortium of patients with advanced RET-altered solid tumors who received selective RET therapies, were recently published. The study was led by Dr. Sarah Waliany from Dr. Jessica Lin’s team at Mass General Brigham Cancer Institute.
To understand the mechanisms of resistance to RET-directed therapies, the team performed a genomic analysis of tumors from 109 patients with RET-altered advanced solid tumors (lung: n=94; thyroid: n=15) who progressed on a RET inhibitor with a total of 143 post-RET inhibitor therapy progression biopsies (121 biopsies from lung). This was a global effort and one of the biggest collections of RET cancer tumors from 20 participating institutions.
In the cohort with lung cancer, the median age at diagnosis was 61 (range 23-86). 57.4% of the patients were female, and 72.3% had no prior smoking history. The most common RET fusion partners were KIF5B (75.5%) and CCDC6 (17.0%).
Of the 121 post-progression biopsies, 104 were obtained after selpercatinib and 17 after pralsetinib. Three patients underwent post-progression biopsies after both pralsetinib and selpercatinib.
The analysis showed that secondary RET mutations were present in 14.0% of the biopsies (lung cancer: 12.4%, thyroid carcinoma: 22.7%). More specifically, of the biopsies from patients with lung cancer, the single secondary RET resistance mutations included solvent front missense mutations in the G810 residue (n=11), the V804M gatekeeper mutation (n=1), and an insertion-deletion mutation impacting both V804 and G810 (n=1).
Interestingly, when looking at changes outside the RET gene (“off-target” changes), the most common ones involved:
- MET (18.2% overall; 15.0% were amplifications)
- TP53 (8.2%)
- APC (7.6%)
- KRAS (7.1%)
- KEAP1 (5.9%)
- CDKN2A/B (5.3%)
In about 27% of biopsy samples, no acquired genomic alterations were found after treatment, both overall and specifically in lung cancer cases.
Other genes with acquired alterations included ERBB2 (4.0%), PIK3CA (4.0%), EGFR (3.0%), and BRAF (2.0%). Acquired fusions were identified in ALK (3.1%) and ROS1 (1.1%).
In the RETgistry, only one of 75 (1.3%) tumor specimens from patients with advanced/metastatic lung cancer had features consistent with transformation from lung adenocarcinoma to small cell lung cancer as assessed by histopathologic review.
Importantly, this study highlights the predominant role of off-target alterations in mediating resistance to RET inhibitors including MET alterations.
Investigators also assessed whether clinical outcomes of patients on their first RET inhibitors were associated with distinct mechanisms of resistance. They first evaluated outcomes based on presence versus absence of secondary RET mutations. Within the subgroup with lung cancer, no statistically significant difference was observed in progression free survival (PFS) among patients with versus without on-target resistance.
They also compared clinical outcomes with first RET inhibitors in patients with versus without MET amplification detected. Median PFS was 7.8 months in those with versus 14.8 months in those without MET amplification (p=0.25). Median time to treatment discontinuation (TTD) was significantly shorter in patients with MET amplification at 8.4 months versus 19.0 months in those without MET amplification (p=0.025).
MET amplification emerged as a recurrent off-target alteration and is already known to cause resistance in other types of lung cancer, like those driven by EGFR mutations or ALK fusions, and it appears at similar rates (~15%) in these subtypes.
In real-world treatment, finding MET amplification after the cancer progresses is useful because doctors can switch strategies, for example, combining a MET inhibitor with the original targeted therapy. This study also highlights the importance performing biopsies after the cancer progresses to help guide the next treatment.
