Crizotinib Shows Long-Term Efficacy in Metastatic Lung Spindle Cell Carcinoma with TPM3-ROS1 Fusion: A Case Report
Lung cancer remains one of the deadliest cancers worldwide, but targeted therapies have revolutionized outcomes for patients with specific genetic changes. However, rare subtypes like spindle cell carcinoma (SpCC)—a type of sarcomatoid carcinoma made of long, spindle-shaped tumor cells—have left doctors with limited treatment options. Now, a new case study offers hope: a patient with metastatic lung SpCC harboring a TPM3-ROS1 fusion saw significant tumor shrinkage and improved quality of life with the targeted drug crizotinib.
The Patient’s Journey
In November 2017, a 72-year-old Chinese man was admitted to Beijing Tsinghua Changgung Hospital with worsening cough, shortness of breath, and intermittent fever. He had no history of smoking or family cancer. Imaging revealed a 18×15mm irregular mass in his right upper lung, enlarged mediastinal lymph nodes, pleural invasion, and metastasis to his left adrenal gland. A brain MRI also showed a tumor in his right cerebellum.
A CT-guided biopsy confirmed the tumor was lung SpCC—rare, aggressive, and difficult to treat. Immunohistochemical staining showed the cells were positive for pan-cytokeratin (AE1/AE3), vimentin, and thyroid transcription factor 1 (TTF-1), but negative for markers like ALK or P40. The patient was diagnosed with stage IV disease (the most advanced), with an Eastern Cooperative Oncology Group (ECOG) performance score of 3 (meaning he needed significant help with daily activities).
Genetic Discovery: TPM3-ROS1 Fusion
Doctors tested both the tumor tissue and blood (circulating tumor DNA, or ctDNA) for genetic changes. Next-generation sequencing revealed a TPM3-ROS1 fusion—a rare genetic abnormality where the TPM3 gene (which makes an actin-binding protein linked to tumor invasion) fuses with ROS1 (a gene that drives abnormal cell growth when mutated). The fusion was present in 37.9% of the tumor cells, and no other targetable mutations were found.
Crizotinib: A Targeted Breakthrough
ROS1 fusions are well-studied in non-small cell lung cancer (NSCLC), where they’re the third most common actionable alteration. The U.S. Food and Drug Administration (FDA) approved crizotinib—a drug that blocks ALK, ROS1, and MET kinases—for ROS1-rearranged NSCLC in 2016. Clinical trials showed crizotinib works remarkably well: 72% of patients saw their tumors shrink (objective response rate, ORR), and the average time without progression (progression-free survival, PFS) was 19.2 months.
Given this data, doctors prescribed crizotinib (250mg twice daily) starting in December 2017. The results were rapid:
- 1 month later: The patient’s cough and shortness of breath disappeared.
- 4 months later: A follow-up CT scan showed the lung tumor and mediastinal lymph nodes had shrunk. Pleural fluid (build-up around the lungs) was nearly gone, and the left adrenal metastasis vanished.
- 6 months later: While the brain tumor grew slightly, full-brain radiation and the anti-angiogenesis drug bevacizumab (750mg every 3 weeks) controlled it. The lung and adrenal tumors remained stable.
For 13 months, the patient took crizotinib (and 6 cycles of bevacizumab). His quality of life improved dramatically: he could perform daily activities independently (ECOG score 1), and his lung tumor continued to shrink.
What About Resistance?
While crizotinib worked well, targeted therapies often face acquired resistance—when tumors develop new mutations to evade the drug. Common resistance mechanisms for crizotinib include a ROS1 G2032R mutation (which changes the drug’s binding site). However, when doctors repeated ctDNA testing at 13 months (after a slight rise in the tumor marker CYFRA 21-1), they found no resistance mutations. The patient declined another tissue biopsy, so the cause of the marker rise remains unclear.
Seeking next steps, the patient joined a clinical trial for lorlatinib—a third-generation ALK/ROS1 inhibitor that may work even if crizotinib fails. Results are pending.
Why This Case Matters
SpCC is so rare that little is known about its molecular drivers. Prior studies found mutations in EGFR, KRAS, or MET in sarcomatoid carcinomas, but no ROS1 or ALK fusions had ever been reported in SpCC—until now. This case suggests that:
- ROS1 testing should be standard for SpCC: Even rare subtypes can have actionable mutations.
- Crizotinib works for SpCC with ROS1 fusions: The patient’s 13+ months of benefit aligns with NSCLC data.
- Brain metastases need extra care: Crizotinib struggles to cross the blood-brain barrier, so radiation or combination therapy may be necessary.
The Road Ahead
While this case is promising, more research is needed. Doctors still don’t know:
- If other ROS1 inhibitors (like ceritinib or lorlatinib) work better for crizotinib-resistant SpCC.
- How often TPM3-ROS1 fusions occur in SpCC.
- The best way to manage resistance when it emerges.
But for patients with rare lung cancers, this case is a beacon of hope. Targeted therapies aren’t just for common subtypes—they can work for the “uncommon” too.
This case report was originally published by Cun-Liang Cai, Ming-Qiang Zhang, Jun Guo, Li-Wan Wang, Jing-Quan Zhao, Wen-Jia Guo, and Xiang-Dong Mu from the Department of Respiratory and Critical Care Medicine at Beijing Tsinghua Changgung Hospital, Tsinghua University, in the Chinese Medical Journal (2019;132(24):3003–3005).
doi.org/10.1097/CM9.0000000000000556
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