Case Reports

Significant clinical response induced by vismodegib in advanced sarcoma: Hedgehog pathway inhibition

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A routine computerized tomography (CT) scan of the thorax-abdomen and pelvis in August 2016 revealed recurrence of disease, with multiple lung nodules as well as metastases in the retroperitoneum. She received 6 cycles of gemcitabine and docetaxel with stability of disease. The patient was then started on a PI3K inhibitor as part of a clinical trial, as genotypic analysis of the tumor revealed an activating mutation of the PI3K gene. The patient’s course was complicated by acute obstructive renal failure requiring a double J stent for right-sided hydronephrosis.

Repeat imaging revealed disease progression, and the patient was then switched to liposomal doxorubicin alone for 4 months and then in combination with olaratumab. She received the combined treatment for a total of 3 months, which was then stopped when she was found to have new peritoneal implants and worsening ascites. At this time, tissue was sent for FoundationOne® next generation sequencing (NGS)-based genomic testing, and the patient received one dose of nivolumab.

In January 2018, 2 days after receiving her first dose of nivolumab, the patient required admission for worsening abdominal pain secondary to progression of her disease ( FIGURE 1 ). She was found to have acute kidney injury on top of chronic kidney disease due to hydronephrosis requiring a left-sided double J stent. She also had transaminitis resulting from a common bile duct stricture treated with a biliary stent and worsening ascites requiring regular paracentesis. This was all in the context of new or growing metastatic implants.

At this time, the result of the FoundationOne genomic testing revealed PTCH1 loss of exons 1-24 and CDKN2A/B loss. Mutation of tumor suppressor gene PTCH1 leads to Hedgehog pathway activation and therefore the patient was started on vismodegib on January 22, 2018. She was discharged from the hospital in stable condition a day later, on January 23.

The patient’s clinical status subsequently improved, with significant reduction in her chronic abdominal pain and very minimal side effects. Clinically, the patient’s acute kidney injury resolved (from a creatinine of 272 μmol/L at discharge to 85 μmol/L after a week of treatment) and her liver enzymes normalized (from an alkaline phosphatase of 301 U/L to 83 U/L, and alanine transaminase of 111 U/L to 38 U/L). CT scan of her chest and abdomen, which was performed 1 month post treatment, revealed stability of disease with absence of ascites ( FIGURE 2 ). The patient continued to have a good response to treatment for 6 months, with no recurrence of pain or ascites.

Six months later, in July 2018, the patient developed increasing pain and a CT scan revealed worsening of abdominopelvic carcinomatosis. In this context, vismodegib was discontinued on July 17. In the next 5 months, she went on to receive carboplatin and paclitaxel, gemcitabine, and nivolumab consecutively with no response. She was admitted to hospital on December 30 for a pain crisis. She passed away on January 9, 2019, from fecal peritonitis.


To the best of our knowledge, this is the first patient with metastatic sarcoma to receive vismodegib, a Hedgehog signaling pathway inhibitor. She achieved an excellent clinical response with progression- free disease for approximately 6 months after starting treatment.

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