Abstract 72P
Background
Two selective RET tyrosine kinase inhibitors have been approved to treat RET fusion-positive (RET+) non-small cell lung cancer and well-differentiated thyroid cancer. However, RET fusions have been reported in other solid tumors.
Methods
To identify the full spectrum of RET+ solid tumors and their molecular characteristics, a retrospective analysis was executed on RET+ solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ).
Results
A total of 378 RET+ solid malignancies were identified in 15 different tumor types and carcinoma of unknown primary (CUP) that underwent next-generation RNA sequencing. RET+ NSCLC and RET+ thyroid cancer constituted 66.9% and 11.1% of the RET+ solid malignancies respectively. RET+ colorectal adenocarcinoma and RET+ breast adenocarcinoma constituted 10.1% and 2.6% respectively. KIF5B (46.8%) is the most common fusion partner followed by CCDC6 (28.3%) and NCOA4 (13.8%) in RET+ solid tumors. KIF5B-RET is the dominant fusion variant in RET+ NSCLC, NCOA4-RET is the dominant variant in RET+ colorectal carcinoma, and CCDC6-RET is the dominant variant in thyroid cancer. Baseline characteristics of RET+ tumors by type is shown in the table. The mean junctional read per tumor sample was 45.2% +/- 42.6 standard deviation (SD) in NSCLC which was relatively similar to CUP which had 48.8% +/- 52.1 SD. The mean tumor mutation burden for all RET+ tumors is 5.48 +/- 6.51 (SD). The most common single gene alterations in RET+ tumors were TP53 (34.8%), ARID1A (10.8%) and RNF43 (6.7%). RET+ CRC had a median TMB of 20 Mt/Mb with MSI-H seen in 63%. There was no correlation between RET fusion partners and MSI status. Table: 72P
| NSCLC | Thyroid | Colorectal | Breast | CUP | Pancreatic | |
| N | 253 | 42 | 38 | 10 | 10 | 8 |
| Age | ||||||
| Median (range) | 66 (27-89) | 81.0 (9-84) | 72.5 (34-88) | 59.5 (35-75) | 71.5 (41-87) | 68.5 (55-81) |
| Mean (SD) | 64.7 (12.02) | 51.1 (21.1) | 67.9 (12.7) | 58.8 (15.7) | 68.8 (13.9) | 67.3 (9.0) |
| Sex | ||||||
| Male | 113 | 14 | 15 | 0 | 6 | 5 |
| Female | 140 | 28 | 23 | 10 | 4 | 3 |
| Fusion partner | ||||||
| KIF5B- | 173 | 1 | 0 | 0 | 0 | 0 |
| CCDC6- | 56 | 26 | 8 | 3 | 3 | 2 |
| NCOA4- | 5 | 10 | 24 | 4 | 2 | 2 |
| ERC1- | 3 | 0 | 0 | 0 | 0 | 1 |
| KIF13A- | 5 | 0 | 0 | 0 | 0 | 0 |
| GPHN- | 0 | 0 | 2 | 0 | 0 | 0 |
| Sequencing methods | ||||||
| Targeted RNA (Archer) | 44 | 3 | 2 | 3 | 2 | 0 |
| WTS | 209 | 39 | 36 | 7 | 8 | 8 |
| Mean junction read (SD) | 45.2 (42.6) | 18.7 (35.9) | 22.7 (26.8) | 16.7 (10.8) | 48.8 (52.1) | 38.4 (80.9) |
| PD-L1 (22C3) | ||||||
| <1% | 70 | NA | NA | 2 | NA | NA |
| 1-49% | 71 | NA | NA | 2 | NA | NA |
| >= 50% | 92 | 1 | NA | 0 | NA | NA |
| TMB | ||||||
| 0-5 | 174 | 39 | 9 | 6 | 7 | 6 |
| >5-10 | 55 | 0 | 4 | 4 | 2 | 2 |
| >10 | 4 | 1 | 22 | 0 | 1 | 0 |
| Microsatellite | ||||||
| Stable | 244 | 41 | 14 | 10 | 9 | 8 |
| Unstable | 1 | 0 | 24 | 0 | 1 | 0 |
Conclusions
Outside of approved indications of NSCLC and thyroid cancers, RET fusions were identified in multiple tumor types such as colorectal, breast, cancer of unknown primary and pancreatic cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
M. Nagasaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Caris Life Sciences, Daiichi Sankyo, Novartis, EMD Serono, Janssen, Pfizer, Genentech, Mirati, Regeneron, Silverback; Financial Interests, Personal, Speaker’s Bureau: Takeda, Blueprint Medicines; Financial Interests, Personal, Expert Testimony: Lilly; Financial Interests, Personal, Other, Travel: AnHeart. Y. Baca: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. J. Xiu: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. M.N. Al-Hallak: Financial Interests, Personal, Speaker’s Bureau: Ipsen. C. Kim: Financial Interests, Personal, Advisory Board: Novartis, Janssen, AstraZeneca, Sanofi, PierianDx, Diffuse Pharmaceuticals, Mirati; Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Novartis, Genentech, Regeneron, Debiopharm, Karyopharm. J.J. Nieva: Financial Interests, Personal and Institutional, Research Grant: Merck, Genentech; Financial Interests, Personal, Advisory Board: Mindmed, AstraZeneca, Naveris, G1 Therapeutics, Aadi Biosciences; Financial Interests, Personal, Ownership Interest: Epic Sciences, Quantgene, Indee Bio. J.J. Swensen: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. D. Spetzler: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. W.M. Korn: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. M.A. Socinski: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bayer, Roche, Celgene, Bristol Myers Squibb, Takeda, Genentech, Novartis, Lilly; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Roche, Takeda. B. Halmos: Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim, AstraZeneca, Merck, Bristol Myers Squibb, Advaxis, Amgen, AbbVie, Daiichi Sankyo, Pfizer, GSK, Beigene, Janssen; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Veracyte, Janssen, Takeda, Merck, Bristol Myers Squibb, Genentech, Pfizer, Eli Lilly. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer, Roche; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology; Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics, Elevation Oncology; Financial Interests, Institutional, Invited Speaker: Pfizer, Mirati, JNJ/Janssen, Merus. All other authors have declared no conflicts of interest.