Promising ICIS Are Explored in Sarcoma, But Disparate Histologies Are Challenging

Robert G. Maki, MD, PhD, FACP, FASCO

Patients with sarcoma may respond to treatment with immune checkpoint inhibitors, but identifying patients who are most likely to respond to this therapy is an ongoing obstacle and suggests the need for further research, said Robert G. Maki, MD, PhD, FACP, FASCO, in a presentation at ESMO Sarcoma and GIST Virtual Symposium.¹

“As we also saw, regardless of whether there were immune checkpoint inhibitors involved or engineered T-cell receptors involved, there are very few patients who make it out to that [survival] tail,” Maki, professor of medicine at the University of Pennsylvania School of Medicine and Abramson Cancer Center in Philadelphia, said during his presentation at the virtual symposium. “Our goal, much as was the case for the early days of melanoma, is to find that improved tail of that survival curve.”

Currently, there is 1 immunotherapy approved in Europe and elsewhere (not in the United States) for the treatment of patients with sarcoma—mifamurtide (Mepact)—which is a non specific immunotherapy for osteogenic sarcoma. Maki questioned whether mifamurtide could also be helpful to some degree in patients with other soft tissue sarcomas, for example.

One thing that is known so far is that vaccines have not been particularly helpful in patients with sarcoma, which may be due to the fact that vaccines have not been well studied in this patient population in a consistent way. Maki noted that the best data in this area looked at mostly patients with melanoma who were treated with vaccines.²

“This supposedly is one of the more commonly responding cancers to immunotherapy, so it makes us think that the use of vaccines in sarcomas would even be less helpful,” Maki said.

Immunotherapy Studies

The SARC28 trial (NCT02301039) was the first published data on immune checkpoint inhibitors in this area and included 80 patients who were treated with single agent pembrolizumab (Keytruda). Three out of 70 evaluable patients were PD-L1 positive, and 7 out of 40 patients had partial responses to the treatment. Of note, the responses were somewhat concentrated in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.

Another study³ (OSCAR trial; NCCH1510) looked at treating patients with sarcoma with nivolumab (Opdivo). Patients in the study had clear-cell sarcoma or alveolar soft part sarcoma. Maki noted that patients with alveolar soft part sarcoma responded to immune checkpoint inhibitors, which was seen in this study, but progression-free survival (PFS) was not very long in either group of patients. “Clearcell sarcoma, even though it looks somewhat

like melanoma, logically does not behave like melanoma when it comes to immune checkpoint inhibitors,” Maki explained. “This study certainly makes it clear.”

A single-center study assessed all patients with advanced sarcoma who were treated with PD-1 inhibitors and potentially with another agent in trials.⁴ Of these 134 patients, 16% had a complete or partial response.

“This reinforces the data from some of the combination studies or the single-agent studies in terms of which histologies we should really focus on when it comes to the use of these immune checkpoint inhibitors,” Maki said.

The PEMBROSARC study (NCT02406781) originally enrolled 50 patients with sarcoma who were treated with a PD-1 inhibitor and metronomic chemotherapy, which originally showed limited activity in select patients.⁵ Once the trial was expanded to look at patients with evidence of tertiary lymphoid structures, then this regimen demonstrated a response in patients with either evidence of tertiary lymphoid structures or specific gene expression profiles. In this expanded trial, patients had a median PFS of 4.1 months compared with

1.4 months in the original study. In addition, approximately a third of patients were progression-free at 12 months.

“This may be about the most we can expect even in a selected population,” Maki said.

Engineered T cells have shown some promise for the treatment of certain types of sarcoma. For example, engineered T cells, which involve an engineered T cell receptor linked to other activating portions of lymphocytes, were assessed in a study focused on SPEAR T cells to treat patients with HLAA2 positive sarcoma. Results demonstrated that patients with NY-ESO-1 positive tumors could respond to this cellular therapy. In addition, some patients had durable responses for at least 6 to 12 months, if not longer. Researchers also found that other targeted T cells including MAGE-A4-specifi c SPEAR T-cells have provided a response in this patient population.

Of note, CAR T cells are not for everyone, Maki said. Several things need to be known including the target and context. Other factors that may impact whether a patient may benefit from CAR T cells include its therapeutic toxicity and the ability to fi nd new targets that may be more generalizable.

There have been several new developments in immunotherapy for patients with sarcoma, especially as “this is the golden age of looking at immune checkpoints and either activating or inactivating these overall,” Maki noted. For example, more has been learned about how PD-1 or PD-L1-specific antibodies bind to their targets, which may provide some insight into how to combine these sorts of therapies with one another. Another approach is to use small molecules or even engineer any number of larger or smaller molecules with targets such as cytotoxic agents that are linked to antibodies or antibody-like structures to achieve a benefit for patients.

Other Targets

Other newer targets are being examined including B7-H3, which Maki noted was “one of the most exciting ones at least in other cancers such as prostate cancer.”

In particular, this is an antibody-drug conjugate against a target widely expressed in several cancers. Maki is hoping to see some sarcoma-specific studies on this target in the near future.

There are several other targets currently under investigation including TIM3, although it has not shown dramatic activity in cancers across the board; LAG3, which has shown surprising activity in melanoma, although it is unclear whether combinations with LAG3 inhibitors will be useful in patients with sarcomas; TIGIT, although it is unclear whether using this with a PD-1 inhibitor is benefi cial in comparison to PD-1 alone; STING agonists, which are currently being investigated in intravenous and intratumoral injection studies; and OX40 or CD40, although there are not enough data except in pancreatic cancer, in which there are hints of activity.

A big question that persists in this area is whether to compare or combine treatments.

“It’s pretty clear that if you had a randomized trial of a PD-1 inhibitor with or without a CTLA-4 inhibitor, that should win versus pazopanib [Votrient],” Maki said. “If you choose your subtypes of sarcomas carefully, such as [undifferentiated pleomorphic sarcoma] and/or angiosarcoma, we’re certainly seeing combinations.”

Maki concluded the presentation with the idea of whether we can use data from phase 2 studies to “declare victory.”

“There’s an NCCN [National Comprehensive Cancer Network] listing for some of these agents for use at least in the United States,” he said. “Do we need to have randomized data for authorization of all of these agents? It’s difficult to use phase 2 data without very strong historical controls to be able to ask for approval from regulatory authorities.”

REFERENCES

1. Maki RB. Immunotherapy for sarcomas: what have we learned so far? Presented at: ESMO Sarcoma and GIST Virtual Symposium; January 31-February 2, 2022; Virtual.

2. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10(9):909-915. doi:10.1038/nm1100

3. Kawai A, Nishikawa T, Kawasaki M, et al. Effi cacy and safety of nivolumab monotherapy in patients with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR Trial, NCCH1510): a multicenter, phase 2 clinical trial. Presented at: Connective Tissue Oncology Society 2020 Virtual Annual Meeting; November 18-21, 2020. Accessed February 7, 2022.

4. Klemen ND, Hwang S, Bradic M, et al. Long-term Follow-up and patterns of response, progression, and hyperprogression in patients after PD-1 blockade in advanced sarcoma. Clin Cancer Res. 2021. doi:10.1158/1078-0432.CCR-21-3445

5. Toulmonde M, Penel N, Adam J, et al. Use of PD-1 Targeting, macrophage infiltration, and IDO pathway activation in sarcomas. JAMA Oncol. 2018;4(1):93-97. doi:10.1001/jamaoncol.2017.1617