KRAS G12C Stage IV lung adenocarcinoma with synchronous urothelial carcinoma and durable response

What happened, in summary

This 74-year-old man presented with suspected lung cancer and excellent functional status despite diabetes and stroke-related right hemiparesis. He was diagnosed with Stage IV lung adenocarcinoma, T2N2M1, with homolateral pulmonary metastases. The lung tumor was PD-L1 positive with a tumor proportion score of 5% and carried a KRAS G12C mutation, while no EGFR or ALK driver was reported. He began carboplatin, pemetrexed, and pembrolizumab every 3 weeks for 4 cycles, followed by maintenance pemetrexed plus pembrolizumab for 5 cycles. Because of worsening general condition and major fatigue, pemetrexed was stopped and pembrolizumab continued briefly. Pembrolizumab was then stopped when nodal disease increased and kidney damage appeared. Biopsy of abnormal renal hilar lymph nodes revealed a second cancer: Stage IV renal urothelial carcinoma, positive for GATA3 and CK7 and negative for TTF1, confirming it was distinct from the lung adenocarcinoma. Surgery was not offered because of nodal disease and the concurrent metastatic lung cancer. He received gemcitabine plus carboplatin for 6 cycles, achieving partial response for 11 months, then reduced-dose gemcitabine/carboplatin for 8 cycles after nodal recurrence. Avelumab maintenance was tried, but renal and periaortic nodes recurred after 2 months. Enfortumab vedotin was then started through early access. After 12 weekly injections, scans showed complete response of renal and nodal urothelial disease while the lung lesions stayed stable. Dose reductions and treatment holds were needed for blistering skin toxicity and later neuropathy. After 16 months, treatment stopped with complete radiologic response, and PET 2 months later showed complete metabolic response.