Atezolizumab Immunotherapy Receives FDA Approval for Alveolar Soft Part Sarcoma

For adults and children older than 2 with unresectable or metastatic alveolar soft part sarcoma, atezolizumab (Tecentriq, Genentech, Inc.) immunotherapy received US Food and Drug Administration (FDA) approval on 9 December 2022.

What Is Alveolar Soft Part Sarcoma?

Known in English as "alveolar soft part sarcoma" (ASPS), this is a very rare connective tissue cancer with aggressive biology and an unknown cell of origin. It occurs most often at ages 15-35, commonly in the legs, and is more frequent in men. Metastases, or spread to other tissues and organs, can occur as late as 30 years afterwards, so long-term follow-up is necessary.

This rare cancer arises from chromosomal abnormalities that fuse genes, such as changes involving chromosome 17 and the X chromosome. In its development, the gene TFE3 fuses with another chromosomal region called ASPCR1. The resulting abnormal gene produces a particular protein responsible for tumour formation.

The tumour develops deep in tissues such as muscle, nerves and bone, most commonly in muscle. The thigh, leg and hip are frequent sites. Less common sites include the head and neck, usually in children, the female genital organs and the abdominal cavity.

It can be difficult to detect early because it begins as a painless lump. By diagnosis it has often spread, particularly to the lungs. ASPS tends to spread early because it forms a network of blood vessels through which cancer cells can travel.

ASPS is among the rarest sarcomas. Soft tissue sarcomas account for 1% of cancers, and ASPS comprises only 0.2% to 1% of soft tissue sarcomas. Around 80 cases are diagnosed annually in the United States.

Treatment involves surgical removal followed by radiotherapy. Chemotherapy has not proved effective. Limited advanced-stage options and frequent late diagnosis generally contribute to a poor prognosis.

The First Immunotherapy Approval for Sarcoma

This marked the first FDA approval of an immunotherapy for a soft tissue sarcoma.

Atezolizumab’s effectiveness was evaluated in 49 adult and paediatric patients with unresectable or metastatic disease in the open-label, single-arm Study ML39345.

Eligible patients required histologically or cytologically confirmed alveolar soft part sarcoma that could not be treated surgically, together with ECOG performance status ≤2.

Patients were excluded for primary central nervous system cancer or symptomatic brain metastases on imaging, clinically significant liver disease, or a history of idiopathic pulmonary fibrosis, pneumonia, organising pneumonia or active pneumonia.

Adults received 1200 mg intravenously and paediatric patients received 15 mg/kg, up to a maximum 1200 mg, every 21 days until progression or unacceptable toxicity.

The main efficacy measures, determined by independent review using RECIST v1.1, were overall response rate and response duration.

Results

Overall response was 24% (95% CI: 13, 39). Among 12 objective responders, 67% had responses lasting at least 6 months and 42% at least 12 months.

Median age was 31, range 12-70. There were 47 adults, of whom 2% were ≥65, and 2 paediatric patients aged ≥12. Participants were 51% female, 55% White, 29% Black or African American, and 10% Asian.

The most common adverse effects (≥15%) were musculoskeletal pain (67%), fatigue (55%), rash (47%), cough (45%), nausea, headache and hypertension (each 43%), vomiting (37%), constipation and shortness of breath (each 33%), dizziness and bleeding (each 29%), insomnia and diarrhoea (each 27%), fever, anxiety, abdominal pain and hypothyroidism (each 25%), reduced appetite and arrhythmia (each 22%), flu-like illness and weight loss (each 18%), and allergic rhinitis and weight gain (each 16%).

The recommended adult atezolizumab dose is 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks, until progression or unacceptable toxicity. For children aged 2 and older, the recommended dose is 15 mg/kg, up to a maximum 1200 mg, every 3 weeks until progression or unacceptable toxicity.