Lynch-associated lung and colorectal cancers responded to immunotherapy

What happened, in summary

This 59-year-old non-smoking woman had 2 years of recurrent right-sided chest pain before CT in March 2023 found a right middle-lobe lung mass. She underwent lung resection 1 week later. Pathology showed a poorly differentiated invasive lung adenocarcinoma with visceral pleural invasion, negative margins, and station 7 lymph-node involvement. Testing showed TTF-1 and Napsin A positivity, KRAS and PTEN mutations, and PD-L1 TPS 15%. She received 4 cycles of pemetrexed and carboplatin with concurrent radiotherapy starting May 6, 2023, then entered surveillance. In March 2025, new evaluation found a rectal mass, a cecal adenocarcinoma, and a right paraspinal lesion. The rectal tumor showed loss of MLH1 and PMS2. Biopsy of the paraspinal mass confirmed metastatic lung adenocarcinoma, also showing mismatch-repair deficiency. Reanalysis of the original lung tumor confirmed dMMR features, linking the lung and colorectal cancers to Lynch syndrome. Germline testing in July 2025 identified a heterozygous MLH1 frameshift mutation, p.P496Afs*10, in the patient and both children. Her family history also included early colorectal cancer in her brother. She began iparomlimab plus tuvonralimab every 3 weeks on April 8, 2025. After 2 cycles, pleural disease and pelvic involvement improved, with no new lesions or immune-related adverse events. After 5 cycles, pelvic MRI showed further reduction in intestinal wall thickening and local invasion, colonoscopy did not identify obvious malignant tissue, the paraspinal metastasis remained stable, and tumor markers stayed normal. She continued immunotherapy with an ongoing response. The diagnosis also led to genetic counseling and intensified surveillance for relatives carrying the same MLH1 mutation.