In non–small cell lung cancer (NSCLC) cell lines, CDKN2A-deficient cancers have up to 100-fold lower IC50 to pemetrexed compared to CDKN2A-proficient cancers.9 Among patients with NSCLC, MTAP deficiency predicts superior responses to pemetrexed including those with brain metastases.10 In MTAP-deficient bladder cancer cell lines, the IC50 of pemetrexed is up to 40-fold lower compared to MTAP-proficient cells.11 A recent report identified dramatic remission from pemetrexed in patients with locally advanced and metastatic chordoma harboring CDKN2A loss, a historically untreatable malignancy.12 The gene discussed is CDKN2A; the disease is urinary bladder carcinoma.