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Retsevmo ® ▼ (selpercatinib)
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What is the mechanism of resistance to Retsevmo® (selpercatinib)?
On-target resistance mechanisms, including G810s solvent front mutations, and bypass mechanisms, including MET amplifications or KRAS G12D mutations, have been identified.
Mechanism of resistance analysis in RET activated NSCLC and MTC
Please refer to Expanded Names for Genomic Alterations for expanded names of alterations.
LIBRETTO-001 mechanism of resistance cohort analysis
Acquired resistance to selpercatinib occurs via on-target and bypass mechanisms. At the data cutoff of January 2023, a cohort of 115 patients from the LIBRETTO-001 study was analyzed to understand the mechanisms of resistance (MoR) and guide treatment strategies against potent rearranged during transfection (RET) inhibition.1
Key eligibility criteria for inclusion in the resistance analysis cohort were
- patients who experienced clinical benefit,
- later discontinued treatment due to progressive disease (PD),
- available plasma for circulating tumor DNA (ctDNA) analysis at baseline and PD (Guardant360, 74 genes), and
- a locally confirmed RET mutation.1
In the largest prospective dataset studying MoR to RET inhibition, acquired MoR was identified in 45% of ctDNA at the time of disease progression. On-target MoR, including RET SF G810 mutations, were more common in medullary thyroid cancer (MTC) than non-small cell lung cancer (NSCLC). Bypass MoR (30%) included RAS/RAF activating and potentially targetable MET amplifications.1
Mechanism of Resistance Study Results presents the mechanism of resistance study results.
|
NSCLC n (%) |
MTC n (%) |
Resistance Mechanism |
26 (37) |
26 (59) |
Unknown |
45 (63) |
18 (41) |
On-target |
9 (13) |
19 (43) |
SF G810C/S/R |
8 |
16 |
V804M/L |
1 |
8 |
V804M/L and G810C/S |
0 |
5 |
Bypass |
20 (28) |
14 (32) |
BRAF V600E/Amp |
4 |
5 |
KRAS G12D/R |
1 |
4 |
MET Amp |
5 |
2 |
NTRK1 fusion |
2 |
1 |
Abbreviations: Amp = amplification.
To optimally guide post-selpercatinib treatment strategies, more comprehensive testing (including tissue next-generation sequencing) may be warranted to study the 55% of patients with unknown MoR.1
Baseline Characteristics of Patients in the Mechanism of Resistance Cohort (N=115) presents the baseline characteristics of the resistance analysis cohort from LIBRETTO-001.
Characteristic |
NSCLC (n=71) |
MTC (n=44) |
Age, years, median (range) |
58 (30, 77) |
56 (22,76) |
Sex, n (%) |
||
Male |
28 (39) |
28 (64) |
Female |
43 (61) |
16 (36) |
Race, n (%) |
||
White |
39 (55) |
40 (91) |
Asian |
24 (34) |
2 (5) |
Black |
5 (7) |
0 |
Others |
3 (4) |
2 (5) |
Smoking history, n (%) |
||
Current smoker |
1 (1) |
1 (2) |
Former smoker |
18 (25) |
9 (20) |
Never a smoker |
52 (73) |
33 (75) |
Missing |
0 |
1 (2) |
Line of therapy, n (%) |
||
1st line |
17 (24) |
5 (11) |
2nd line |
44 (62) |
35 (80) |
Previous multitargeted kinase inhibitor, n (%) |
||
Yes |
11 (15) |
36 (82) |
No |
60 (85) |
|
RET enrolling alteration, n (%) |
||
KIF5B-RET: 51 (72) |
M918T: 26 (59) |
|
CCDC6-RET: 9 (13) |
V804M/L: 1 (2) |
|
NCOA4-RET: 1 (1) |
Extracellular cysteine: 8 (18) |
|
Extracellular cysteine: 8 (18) |
Others: 9 (20) |
|
Local lab assay for RET enrolling alteration, n (%) |
||
Tissue-based |
64 (90) |
41 (93) |
NGS |
59 (83) |
30 (68) |
PCR (or FISH/others) |
5 (7) |
11 (25) |
Liquid biopsy |
7 (10) |
3 (7) |
Abbreviations: FISH = fluorescence in situ hybridization; MTC = medullary thyroid cancer; NGS = next-generation sequencing; NSCLC = non-small cell lung cancer; PCR = polymerase chain reaction; RET = rearranged during transfection.
Mechanism of resistance molecular analysis
Hadoux et al (2023) Analysis
Hadoux et al (2023) evaluated the molecular mechanisms of resistance, its frequency, and the pattern of treatment failure in 46 patients with MTC who were initiated on RET inhibitors between March 2018 and March 2022.2
Of the 46 MTC patients treated with RET inhibitors during the study, 26 had discontinued treatment by the April 2023 data cutoff due to disease progression (n = 16), death (n = 4), or toxicity (n = 6).2
The most common RET mutations at baseline were p.M918T (n = 29) and p.C634X (n = 6). No primary resistance was found among 14 patients with pre- and post-RET inhibitor molecular profiles before treatment.2
Post-RET inhibitor profiles revealed bypass resistance mechanisms in 75% of cases, including mutations in RAS genes (50%), FGFR2 and ALK fusions, and MYC p.P44L. Resistance due to RET solvent front and hinge region mutations was observed in 25% of cases.2
Patient Characteristics Based on RET Inhibitor Status presents the patient characteristics based on RET inhibitor status at the data cutoff of April 2023.
Characteristic |
RET inhibitor Discontinued (n=26) |
RET Inhibitor Ongoing (n=19) |
Age, years, median (IQR) |
62 (53-68) |
50 (34-71) |
Sex, n (%) |
||
Male |
17 (65) |
16 (84) |
Female |
9 (35) |
3 (16) |
RET mutation, n (%) |
||
M918T |
16 (64) |
13 (68) |
C634X |
5 (20) |
1 (5.3) |
Other |
4 (16) |
5 (26) |
Unknown |
1 |
0 |
RET inhibitor received, n (%) |
||
Selpercatinib |
12 (46) |
14 (74) |
Pralsetinib |
11 (42) |
3 (16) |
Investigational RET inhibitor agent |
3 (12) |
2 (11) |
RECIST 1.1 response under RET inhibitor, n (%) |
||
Complete response |
1 (3.8) |
1 (3.8) |
Partial response |
11 (42) |
12 (63) |
Stable disease |
8 (31) |
6 (32) |
Not evaluable |
6 (23) |
0 |
Abbreviations: IQR = interquartile range; RET = rearranged during transfection; RECIST = Response Evaluation Criteria in Solid Tumors.
Rosen et al (2022) analysis
Rosen et al (2022) analyzed the pretreatment and post-progression 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.3
The study population included 52 patients with RET fusion-positive tumors and 20 patients with RET-mutant tumors.3 Mitogen-activated protein kinase (MAPK)-activating alterations were not found in the lung cancer specimens based on pretreatment genomic profiling.3
Of the 72 patients, 27 progressed on selpercatinib, and of those patients, 18 had adequate tumor specimens for pre-treatment and post-progression genomic sequencing.3
Comparative Analysis of Tumor Types, RET Alterations, and Resistance Outcomes (n=18) provides a comparative overview of tumor types, initial RET alterations, and associated resistance mechanisms.
Tumor Type |
RET Alteration |
Resistance Results |
HGNEC |
TAF3-RET |
KRAS G12D |
Lung Adenocarcinoma |
ERC1-RET |
KRAS G12D |
Lung Adenocarcinoma |
KIF5B-RET |
KRAS G12D |
Lung Adenocarcinoma |
KIF5B-RET |
MET amp |
Lung Adenocarcinoma |
KIF5B-RET |
MET amp (fc 2.1), BRAF, D584N |
Lung Adenocarcinoma |
KIF5B-RET |
RET G810S/L870F, KRAS G12A/R |
Lung Adenocarcinoma |
KIF5B-RET |
NRAS G13D |
Lung Adenocarcinoma |
CCDC6-RET |
FGFR1 amp (fc 2.4) |
LCNEC |
KIF5B-RET |
RET G810C |
Medullary Thyroid Cancer |
M918T, V804M |
RET Y806C, KRAS G12D/13D |
Papillary Thyroid Cancer |
CCDC6-RET |
PIK3CA R115Q |
Lung Adenocarcinoma |
KIF5B-RET |
NA |
Papillary Thyroid Cancer |
CCDC6-RET |
NA |
Medullary Thyroid Cancer |
M918T |
NA |
Lung Adenocarcinoma |
KIF5B-RET |
NA |
Lung Adenocarcinoma |
KIF5B-RET |
NA |
Lung Adenocarcinoma |
KIF5B-RET |
NA |
Lung Adenocarcinoma |
CCDC6-RET |
NA |
Abbreviations: amp = amplification; fc = fold change; HGNEC = High-grade neuroendocrine carcinoma of the colon and rectum; LCNEC = large cell neuroendocrine carcinoma of the lung; NA = not available; RET = rearranged during transfection.
Solomon et al (2020) analysis
Solomon et al (2020) performed plasma ctDNA analyses from patients enrolled in the LIBRETTO-001 trial (NCT03157128) who experienced disease progression after selpercatinib response.4
Compared to their detectable ctDNA samples at baseline, solvent front RET G810 mutations were identified in
- 2 of 3 patients with MTC, and
- 1 of 6 patients with NSCLC.4
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.4
Lin et al (2020) analysis
Lin et al (2020) analyzed 23 post-treatment biopsies from 18 patients with RET fusion-positive NSCLC treated with RET-selective inhibitors. The median PFS was 6.3 months [95% CI: 3.6, 10.8). Acquired RET mutations, specifically at the G810 residue, were found in 10% of cases. Additionally, 15% of cases showed MET amplification without concurrent RET mutations, and one had KRAS amplification. No other significant driver alterations were detected, and none of the resistant tumor specimens showed signs of histologic transformation.5
Baseline Characteristics of Patients with RET Fusion-Positive Lung Cancer Resistant to RET Inhibitors presents the baseline characteristics for a cohort of 18 patients with RET fusion-positive lung cancer who developed resistance to RET inhibitors.
Characteristic |
n (%) N=18 |
Age, years, median (range) |
56.5 (30, 77) |
Female |
10 (56) |
Never or light smoker |
18 (100) |
Adenocarcinoma |
18 (100) |
RET fusion |
|
KIF5B-RET |
12 (67) |
CCDC6-RET |
4 (22) |
Other |
2 (11) |
RET inhibitor prior to biopsy |
|
Selpercatinib |
10 (56) |
Pralsetinib |
7 (39) |
Pralsetinib, then selpercatinib |
1 (6) |
Prior lines of therapy |
|
0 |
3 (17) |
1 |
10 (56) |
≥2 |
5 (28) |
Prior platinum chemotherapy |
13 (72) |
Prior multikinase inhibitor with anti-RET activity |
4 (22) |
Abbreviations: RET = rearranged during transfection.
RETgistry initial results on the frequency of RET resistance
The RETgistry is an international consortium with the objective of explaining mechanisms of resistance to RET tyrosine kinase inhibitors (TKI). In a retrospective analysis across 16 institutions, patients with advanced solid tumors with an oncogenic RET alteration who had progressed on RET TKI therapy were identified. Prior TKI therapies that patients progressed on were
- selpercatinib (n=70)
- pralsetinib (n=14), and
- selpercatinib followed by pralsetinib (n=4).6
Identified tumor types and RET alterations included
- NSCLC (n=72) with KIF5B (69%), CCDC6 (21%), and other fusions (10%)
- MTC (n=13) with M918T (54%), other fusions (46%)
- papillary thyroid cancer (n=2) with 100% unspecified RET fusions, and
- anaplastic thyroid cancer (n=1) with 100% unspecified RET fusions.6
The median duration of RET TKI prior to biopsy was 16.5 months (95% CI, 14.0-19.6) and median progression-free survival was 14.1 months (95% CI, 9.3-17.0). Biopsy results showed acquired RET mutations in 14% of samples, with G810 substitution being the most common mutation found in 12% of samples.6
The results showed 43 cases of potential off-target resistance gene alterations, for example, bypass receptor tyrosine kinase activation, that included
- MET amplification (14%)
- BRAF V600E or fusion (2%)
- KRAS gain or mutation (5%)
- ERBB2 amplification (2%)
- EGFR amplification (3%)
- ROS1 fusion (1%), and
- activating PIK3CA mutation or PTEN loss (4%).6
Case reports of selpercatinib resistance
The patients described in the following case reports began selpercatinib after disease progression on treatments which included
- carboplatin/pemetrexed/pembrolizumab, and subsequent treatment with lenvatinib ( )4
- chemotherapy, three MKIs, and another investigational, selective RET TKI ( )4
- sorafenib, vandetanib, cabozantinib, sitravatinib, agerafenib, and vandetanib plus everolimus ( )7
- carboplatin/pemetrexed/bevacizumab, pemetrexed/bevacizumab maintenance ( )7, and
- whole brain radiation and chemotherapy with carboplatin and etoposide. ( )8
Patient 1
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.4
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.4
Patient 2
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.4
Patient 3
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 RETY806C/N and RETG810C/S.7
Patient 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-RETG810C kinase, and BaF3/CCDC6-RETG810C cells that were resistant to apoptosis initiated by selpercatinib.7
Patient 5
A 62-year-old man with high-grade neuroendocrine carcinoma of thoracic origin developed metastases to the skin, liver, and brain. After initial treatment with radiation and chemotherapy, his disease progressed with liver metastases. Cell-free DNA analysis identified a KIF5B-RET fusion and PTEN mutation, leading to his enrollment in the LIBRETTO-001 trial, starting at selpercatinib120 mg twice daily. He showed symptom improvement within two weeks, and CT scans revealed a 39% tumor reduction. Increasing the dose to 160 mg twice daily deepened the response to a 44% reduction. However, after 10 months, the disease progressed with new liver and brain metastases, leading to hospice care. Resistance was associated with increased KIF5B-RET fusion, PTEN mutation, and EGFR copy number variation, with no RET kinase domain mutations detected. Resistant tumor biopsy revealed an additional KHDRBS1-NTRK3 fusion alongside the pre-existing KIF5B-RET fusion.8
RET-selpercatinib complex crystal structure
Analyses showed that selpercatinib binds differently than other TKIs by
- docking one end in the front cleft of RET without breaching the gate
- wrapping around the outside space that is formed by the side chain of K758 of the gate wall, and
- burying the other end of the molecule in the BP-II pocket of the back cleft.7
The result of this method is high-affinity binding without disrupting gate-keeper mutations.7
References
1Solomon B, Drilon A, Wirth L, et al. Mechanisms of resistance to selpercatinib in RET activated NSCLC and MTC from the LIBRETTO-001 trial. Poster presented at: 2024 European Society For Medical Oncology (ESMO) 49th Congress; September 13-17th; Barcelona, Spain. Accessed September 17th, 2024. https://oncologypro.esmo.org/meeting-resources/esmo-congress-2024/mechanisms-of-resistance-to-selpercatinib-in-ret-activated-nsclc-and-mtc-from-the-libretto-001-trial
2Hadoux J, Al Ghuzlan A, Lamartina L, et al. Patterns of treatment failure after selective rearranged during transfection (RET) inhibitors in patients with metastatic medullary thyroid carcinoma. JCO Precis Oncol. 2023;7:e2300053. https://doi.org/10.1200/PO.23.00053
3Rosen EY, Won HH, Zheng Y, et al. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers. Nat Commun. 2022;13(1):1450. https://doi.org/10.1038/s41467-022-28848-x
4Solomon BJ, Tan L, Lin JJ, et al. RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies. J Thorac Oncol. 2020;15(4):541-549. https://doi.org/10.1016/j.jtho.2020.01.006
5Lin JJ, Liu SV, McCoach CE, et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol. 2020;31(12):1725-1733. https://doi.org/10.1016/j.annonc.2020.09.015
6Cooper AJ, Drilon AE, Rotow JK, et al. First results from the RETgistry: a global consortium for the study of resistance to RET inhibition in RET-altered solid tumors. J Clin Oncol. 2023;41(16 suppl):9065-9065. https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9065
7Subbiah V, Shen T, Terzyan SS, et al. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Ann Oncol. 2021;32(2):261-268. https://doi.org/10.1016/j.annonc.2020.10.599
8Subbiah V, Shen T, Tetzlaff M, et al. Patient-driven discovery and post-clinical validation of NTRK3 fusion as an acquired resistance mechanism to selpercatinib in RET fusion-positive lung cancer. Ann Oncol. 2021;32(6):817-819. https://doi.org/10.1016/j.annonc.2021.02.010
Appendix
Alteration |
Expanded Name |
CCDC6 |
Coiled-coil domain containing 6 |
BRAF |
B-rapidly accelerated firosarcoma |
EGFR |
Epidermal growth factor receptor |
ERBB2 |
erb-b2 receptor tyrosine kinase 2 |
FGFR |
fibroblast growth factor receptor |
KIF5B |
Kinesin family member 5B |
KRAS |
Kirsten rat sarcoma |
M918T |
Missense, position 918, M to T |
MET |
Mesenchymal to epithelial transition |
NRAS |
Neuroblastoma rat sarcoma |
PIK3CA |
Phosphatdylinositol-4, 5-biphosphate 3-kinase catalytic subunit alpha |
PTEN |
Phosphatase and tensin homolog |
RET |
Rearranged during transfection |
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Date of Last Review: 20 August 2024