Addition of Doxorubicin to Zalifrelimab/Balstilimab Leads to Responses in Advanced Soft Tissue Sarcoma

The activity generated by the combination of doxorubicin, zalifrelimab (AGEN1884), and balstilimab (AGEN2034) in patients with advanced/metastatic soft tissue sarcoma indicated a potential pathway for the use of immunotherapy in this patient population, which has historically been associated with immunologically cold tumors, according to Breelyn Wilky, MD.

Data from a single-arm, open-label phase 2 trial (NCT04028063) presented at the 2023 ASCO Annual Meeting showed that efficacy-evaluable patients treated with the combination (n = 28) experienced a 6-month PFS rate of 46.4% (95% CI, 28%-65%) and a median PFS of 24.4 weeks (95% CI, 23.4-72.9). In patients evaluable for response (n = 30), the objective response rate (ORR) was 33.3% (95% CI, 17%-53%), and the disease control rate (DCR) was 80.0% (95% CI, 61%-92%).

Notably, in stage 1 of the trial, patients received a priming cycle of zalifrelimab and balstilimab prior to the addition of doxorubicin in cycle 2. In stage 2, doxorubicin was started in cycle 1 with the other 2 agents. Among 16 evaluable patients treated in stage 1, the ORR was 56.2% (95% CI, 30%-80%) with a DCR of 88% (95% CI, 62%-98%) and a median PFS of 31.7 weeks (95% CI, 24– not applicable [NA]). In 14 evaluable patients treated in stage 2, the ORR was 7% (95% CI, 0%-34%) with a DCR of 71% (95% CI, 42%-92%) and a median PFS of 23.5 weeks (95% CI, 11-NA).

“In the future, we will try to better understand whether a priming cycle of immunotherapy is needed before using chemotherapy in [patients with] sarcoma,” Wilky said.

In an interview with OncLive®, Wilky discussed the rationale for investigating the addition of doxorubicin to zalifrelimab and balstilimab in patients with advanced/metastatic soft tissue sarcoma, expanded on results from the phase 2 trial, and emphasized the need for continued research for the potential role of immunotherapy in this patient population. Wilky is the director of Sarcoma Medical Oncology, the Cheryl Bennett and McNeilly Family Endowed Chair in Sarcoma Research, the deputy associate director for Clinical Research, Medical Oncology, at the University of Colorado Cancer Center, the Colorado University Anschutz Medical Campus, in Aurora.

OncLive: Could you share the rationale for investigating the combination of zalifrelimab, balstilimab, and doxorubicin in patients with advanced/metastatic soft tissue sarcoma?

Wilky: I take care of patients with sarcomas, which are rare cancers of bone and soft tissue. There has been a huge interest with the advances in immune therapy, including checkpoint inhibitors in other cancers, to determine whether they can also work for [patients with] sarcomas.

Checkpoint inhibitors to PD-1 and CTLA-4 only help a very small fraction of [patients with] sarcoma. The reason is that [these] tend to be very [immunologically] cold tumors. The hope of the study was that the addition of chemotherapy to doxorubicin may make these tumors a little bit hotter and improve the responses to checkpoint inhibitor therapy.

We think of doxorubicin as a commonly used chemotherapy agent, but it has been shown to be a very robust booster of immunogenic cell death in laboratory models. Zalifrelimab is an anti–CTLA-4 antibody, and balstilimab is an anti–PD-1 antibody.

The rationale was to see if we could warm up the tumors and create this damage signal using doxorubicin that could then be potentiated by boosting the immune cells with the PD-1 and CTLA-4 inhibitors.

What efficacy findings from this study were presented at the 2023 ASCO Annual Meeting?

We enrolled a total of 30 [efficacy-]evaluable patients with advanced or metastatic soft tissue sarcomas, and we presented the results for the entire study. We found that there were patients who had considerable benefit, including in subtypes that we may not normally expect to respond to checkpoint inhibitors or to doxorubicin. The ORR was 33.3% with a disease control rate of 80%.

What was interesting is that we made a change in the treatment plan halfway through the study. We changed from patients having a priming introductory cycle of immunotherapy before chemotherapy started, and we found that those patients did quite well.

Did outcomes differ based on disease stage?

All patients were either locally advanced or metastatic. Therefore, the outcomes did not differ based on the stage because they were all advanced. We did have several patients have such a good response that they were able to go to surgery and remove the remainder of their disease, which was not expected.

What safety findings were reported with this combination?

Overall, most of the safety was in line with what we would expect with doxorubicin, [meaning] the usual hematologic toxicity, mucositis, nausea, and vomiting. There were significant immune-related adverse effects [irAEs] occurring in 12% of patients who required steroids or tumor necrosis factor–alpha blockade. Those [irAEs] included colitis, pancreatitis, diabetes, diabetic ketoacidosis, and thyroiditis.

What are some of the next steps or future implications of this research?

We had a lot of great discussions about this [at the 2023 ASCO Annual Meeting] because there were multiple studies being presented combining chemotherapy with immune therapy for [patients with] sarcomas. It comes down to this timing question: do sarcomas do better with chemotherapy and immunotherapy at the same time? Is it better to incorporate the immune therapy before or after starting chemotherapy?

These are all studies that we need to perform using samples from patients that were treated on this trial, but also by modeling this in the laboratory in mouse models. For the foreseeable future, we're going work on looking at those correlative studies and then hopefully be able to design a next-generation immunotherapy trial.

We are really excited to have seen these results. There were patients who were essentially cured of their cancer, at least for the foreseeable future, as a result of this therapy. It makes me passionate to try to understand how to make it work for more patients.

Reference

Wilky BA, Maleddu A, Mailhot A, et al. A single-arm, open-label phase 2 trial of doxorubicin plus zalifrelimab, a CTLA-4 inhibitor, with balstilimab, a PD-1 inhibitor, in patients with advanced/metastatic soft tissue sarcomas. J Clin Oncol. 2023;41(suppl 16):11501. doi:10.1200/JCO.2023.41.16_suppl.11501