Immunotherapy for Sarcoma

Using your immune system to fight your cancer

Obligatory—This is not medical advice

Immunotherapy is now in the mainstream. People have heard about its effects in no small part due to recent articles in the New York Times, and elsewhere. Given its prevalence now—medicare part B data from 2021 shows there were over 200,000 claims for pembrolizumab alone—it’s important to understand how it can be used for patients with cancer.

Although it doesn’t have the same side effects that most people associate with chemotherapy, it can still have life threatening complications. I would say that in most patients these side effects are reversible with accessible immunosuppression (corticosteroids). Surprisingly enough, even though FDA approvals for these medications have been there for nearly a decade, we’re still learning about how they work. The same was true of chemotherapy. I’ll compose something about our most commonly prescribed medication for patients with sarcomas, doxorubicin, in a separate substack. Let’s stay on the topic per above for now, though. If you’d like a more in depth look at immunotherapy for patients with sarcoma, see this recent publication in the Oncologist in the footnotes.¹

What is Immunotherapy?

Immunotherapy is one of multiple families of medications that we use for treatment of cancers, and other conditions. I’ll stick with cancer for now. I break treatments into three distinct groups:

• Cytotoxics: medications designed to kill cancer cells, usually by breaking DNA or altering cellular means of replication.  

• Targeted therapies: Medications that inhibit specific proteins in the cell, usually oncogenes, that drive cancers to grow. There are multiple generations of these that may be more or less precise

• Immunotherapy: Medications that rely on a patient’s immune system to target and destroy cancer cells.

These are not very precise, and there are many grey areas, but if we’re to discuss something it’s useful for sake of reference.

Most of these treatments in the present day are antibodies that take off the brakes and help the immune system ‘unmask’ cancer cells. These rely on multiple pathways that may be beyond the realm of this discussion, but I will include a figure below which outlines common mechanisms.

An open access article by Dutta et al. Can serve as a useful reference. The figure below is from their work. ²

Dutta et al. Biology. 2023 (reference #2)

As you can see, this is a complex interplay of cellular machinery. We know that some cancers are more sensitive to this kind of treatment than others. A large body of work now is attempting to either sensitize cancers to immunotherapy and determine which cancers are most likely to respond to immunotherapy.

Immunotherapy for patients with sarcoma

Multiple trials have been conducted in the sarcoma space evaluating the role of immunotherapy in treating our patients. I have included information about these, below.

Husain et al. The Oncologist. 2023. (reference #1)

SARC028 was a multicenter trial conducted in the United States to determine the response rate (percentage of patients with tumors that shrank more than 30%). In total, 86 patients were accrued into two cohorts: bone sarcomas and soft tissue sarcomas.³

7 of 40 patients in the soft tissue sarcoma arm had a response, these were:

• 4 of 10 patients with pleomorphic sarcoma

• 2 of 10 patients with liposarcoma

• 1 of 10 patients with synovial sarcoma

2 of 40 patients with bone sarcoma had a response: 1 patient with osteosarcoma and one with chondrosarcoma.

Tawbi et al. Lancet Oncology. 2017. (Reference #3)

All in all, 11% of treated patients had treatment related adverse events (9/84). This is in line with other forms of immunotherapy. It’s important to recognize that these side effects can vary significantly. Patients can incur lifelong adrenal insufficiency and be dependent on hormones. Others can have inflammation of their lungs called pneumonitis which ends up with an intensive care unit stay.

All in all, how do I interpret these results? This is more of an exploratory or hypothesis generating trial. There’s hope as some subtypes of sarcoma had a higher numerical response rate than seen in other studies. It may form the basis for future trials.

Another commonly cited clinical trial was that performed by SWOG evaluating response rate of angiosarcoma to the combination immunotherapy of ipilimumab and nivolumab. ⁴  These antibodies work on different targets that regulate the immune system.

There were 16 patients with angiosarcoma included in this study which looked at the same endpoint as SARC028, response rate. This was determined to be 25% (4 patients responded in the treatment group). Interestingly, the majority of patients who had cutaneous, or skin origin, angiosarcoma responded. For this reason, many of us prefer giving this combination for patients with angiosarcoma, if immunotherapy is considered.

Wagner et al. JITC. 2021. (Reference #4)

What are my comments regarding above? We need more, larger trials to determine the true nature of this therapy in patients with sarcoma. I think that there is preliminary evidence of efficacy for some disease types and this may justify later line therapy for patients who may tolerate it.

An ongoing trial, also led by SARC, SARC032 will be looking at the role of neoadjuvant pembrolizumab in combination with radiation for patients with extremity soft tissue sarcoma.⁵ While these data are maturing, they are highly anticipated. Studies conducted in other tumor types have shown a potential role for neoadjuvant immunotherapy in the right patients.⁶⁷

This all does not even reference some of the cellular therapies being utilized for some of our rarer subtypes of sarcoma. A group I took part in just published a review for Synovial Sarcoma. ⁸ For patients with synovial sarcoma there are multiple pathways and families of immunotherapies being trialed. That article has a more detailed analysis than we can cover here.

In summary, our knowledge of immunotherapy is expanding rapidly. There may be a role for its use in select patients with sarcoma. I’ve left out alveolar soft part sarcoma intentionally above and will be reviewing the trials that have led to its FDA approvals soon.

1. https://academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyad052/7076257

2. https://pubmed-ncbi-nlm-nih-gov.ucsf.idm.oclc.org/36829496/

3. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30624-1/fulltext

4. https://pubmed.ncbi.nlm.nih.gov/34380663/

5. https://ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.TPS11588

6. https://www.nejm.org/doi/full/10.1056/NEJMoa2211437

7. https://www.nejm.org/doi/full/10.1056/NEJMoa1910549

8. https://pubmed.ncbi.nlm.nih.gov/36761952/