Abstract 694P
Background
srcRCC is an aggressive variant of RCC that frequently presents as advanced-stage disease refractory to traditional systemic treatments for ccRCC. Emerging potential treatment strategies for metastatic srcRCC include immune checkpoint inhibitors (ICPIs) and novel synthetic lethality agents that exploit the genomic loss of MTAP.
Methods
66 srcRCC and 841 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).
Results
MTAP deletion was significantly enriched in srcRCC compared to ccRCC (15% vs. 6%, P=.005). CDKN2A/B co-deletion was frequent in MTAP-deleted tumors as a consequence of single 9p21 deletion events. VHL and PBRM1 GAs were significantly increased in MTAP-intact ccRCC, but not in MTAP-intact srcRCC (see the table). Frequency of GAs in SETD2, BAP1, TP53, and TERT did not significantly differ between the groups. NF2 GAs were more frequent in both MTAP-deleted srcRCC (P=.054) and ccRCC (P=.004). All cases were MS stable and exhibited low TMBs. PD-L1 IHC low- and high-positive expression was variable in the cohorts but did not reach significance in statistical comparisons. Table: 694P
| MTAP-deleted srcRCC (n=10) | MTAP-intact srcRCC (n=56) | P value | MTAP-deleted ccRCC (n=46) | MTAP-intact ccRCC (n=795) | P value | |
| Males/Females | 80%/20% | 68%/32% | NS | 85%/15% | 70%/30% | NS |
| Median age (range), yrs | 59 (32-75) | 61 (30-89) | NS | 59 (31-81) | 62 (24-89) | NS |
| CDKN2A | 100% | 25% | <.0001 | 94% | 7% | <.0001 |
| CDKN2B | 90% | 20% | <.0001 | 85% | 5% | <.0001 |
| VHL | 70% | 52% | NS | 59% | 76% | .01 |
| PBRM1 | 20% | 18% | NS | 28% | 47% | .01 |
| SETD2 | 0% | 18% | NS | 17% | 29% | NS |
| BAP1 | 10% | 18% | NS | 17% | 15% | NS |
| TP53 | 30% | 39% | NS | 13% | 13% | NS |
| PTEN | 0% | 18% | NS | 20% | 12% | NS |
| TERT | 0% | 20% | NS | 17% | 8% | NS |
| NF2 | 40% | 13% | .05 | 11% | 2% | .004 |
| MET | 0% | 7% | NS | 6% | 2% | NS |
| Median TMB | 3.8 | 3.8 | NS | 1.3 | 2.8 | NS |
| TMB ≥10 mt/Mb | 0% | 7% | NS | 0% | 1% | NS |
| PD-L1 Low (1-49%) | 50% (4) | 19% (16) | NS | 28% (25) | 28% (300) | NS |
| PD-L1 High (≥50%) | 25% | 44% | NS | 12% | 4% | NS |
Conclusions
MTAP deletion is significantly enriched in srcRCC versus ccRCC and is accompanied by increased GAs in NF2. Studies of anti-PRMT5 drugs that exploit MTAP deletion in the treatment of clinically advanced srcRCC appear warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
A. Necchi: Financial Interests, Personal, Research Grant: Merck Share & Dohme; Financial Interests, Personal, Other, Consulting fees: Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Consulting fees: Roche; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca; Financial Interests, Personal, Research Grant: Millenium Pharmaceuticals; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal, Research Grant: Novartis. P. Grivas: Financial Interests, Personal, Other, Consulting fees: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Clovis Oncology; Financial Interests, Institutional, Research Grant: Clovis Oncology; Financial Interests, Personal, Other, Consulting fees: Bayer; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Personal, Other, Consulting fees: Genentech; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Personal, Other, Consulting fees: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Other, Consulting fees: Merck; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Personal, Other, Consulting fees: Mirati; Financial Interests, Institutional, Research Grant: Mirati; Financial Interests, Personal, Other, Consulting fees: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other, Consulting fees: QED therapeutics; Financial Interests, Institutional, Research Grant: QED therapeutics; Financial Interests, Institutional, Research Grant: Bavarian nordic; Financial Interests, Institutional, Research Grant: Debiopharm; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: OncoGenex Pharmaceuticals; Financial Interests, Personal, Other, consulting fees: EMD Serono; Financial Interests, Personal, Other, consulting fees: Exelixis; Financial Interests, Personal, Other, consulting fees: F. Hoffman La Roche; Financial Interests, Personal, Other, consulting fees: Foundation Medicine Inc.; Financial Interests, Personal, Other, consulting fees: Genzyme; Financial Interests, Personal, Other, Consulting fees: Heron Therapeutics; Financial Interests, Personal, Other, Consulting fees: Janssen; Financial Interests, Personal, Other, Consulting fees: Seattle Genetics. P.E. Spiess: Non-Financial Interests, Personal, Leadership Role: NCCN Panel on bladder and penile cancer; Non-Financial Interests, Personal, Leadership Role: Global Society of Rare GU Tumors. E. Sokol: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. S. Ramkissoon: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. E. Severson: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. R.S.P. Huang: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. D.I. Lin: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. D.A. Mata: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. B. Decker: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. K. Mcgregor: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. N.A. Danziger: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La-Roche LTd. J.S. Ross: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. All other authors have declared no conflicts of interest.