Dr Martín-Broto on the Efficacy of Sunitinib Plus Nivolumab in Clear Cell Sarcoma

Javier Martín Broto MD, PhD, medical oncologist, Fundación Jimenez Diaz University Hospital, Fundación Jiménez Díaz Institute for Medical Research; leader, Research Group ATBsarc, Villalba General Hospital, CITIUS III (Seville), discusses findings from the clear cell sarcoma subgroup of the phase 2 IMMUNOSARC II trial (NCT03277924) investigating treatment with sunitinib (Sutent) plus nivolumab (Opdivo). Notably, these results were shared at the 

Patients between 12 and 80 years of age who presented with advanced, progressive, and measurable clear cell sarcoma were enrolled onto the trial following central pathology confirmation of their disease. Adult patients were treated with sunitinib at 37.5 mg per day during the first 2 weeks, and from then on, received the agent at 25 mg per day along with nivolumab at 240 mg every 2 weeks. Martín-Broto begins by saying that previous prospective trials in clear cell sarcoma primarily focused on MET inhibitors. This approach was based on a solid scientific rationale, making MET inhibition a logical therapeutic target for this specific sarcoma subtype, he says.

However, the outcomes of these trials were underwhelming, according to Martín-Broto. The median progression-free survival (PFS) in these studies ranged from approximately 2 to 4 months, the overall response rates (ORRs) werebetween 4% and 9%, and the median overall survival (OS) was less than 1 year, Broto reports. Despite the reasonable scientific background, the results were not particularly promising, and thus, these earlier trials with MET inhibitors did not offer significant clinical benefits for patients with clear cell sarcoma, he shares.

In contrast, the IMMUNOSARC II trial is showing encouraging results in efficacy-evaluable patients (n = 20). The primary end point of the investigation was the 6-month PFS rate, Martín-Broto continues. The outcome was notably positive, with a 6-month PFS rate of 51% (95% CI, 26%-75%), approximately double that observed in prior MET inhibitor trials, he emphasizes. Additionally, the median OS in IMMUNOSARC-II reached 17 months (95% CI, 8-26). The ORR showed further promise, with 17% of patients experiencing partial responses and 61% of patients achieving stable disease, Martín-Broto notes. These outcomes indicate a high clinical benefit rate with the regimen, with 36% (95%, CI 12%-61%) of patients remaining progression free at 1 year, he concludes.

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Javier Martín Broto MD, PhD, discusses the efficacy of treatment with sunitinib plus nivolumab in clear cell sarcoma, according to the IMMUNOSARC II trial.

Javier Martin-Broto, MD, PhD, medical oncologist, the University Hospital, leader, Villalba General Hospital, discusses future research directions of soft tissue sarcoma.

Targeted therapy could soon be part of the treatment paradigm for synovial sarcoma for the first time in the form of BRD9 inhibitors, Martin-Broto says, adding that an ongoing phase 1 trial (NCT04965753) is investigating FHD-609, a BRD9 inhibitor, in patients with advanced synovial sarcoma.

For patients with chondrosarcoma, DR5 agonists are under investigation, which could provide a key development for a patient population that is historically resistant to chemotherapy, Martin-Broto adds. Moreover, the addition of selinexor to chemotherapy has shown promise in specific subsets of sarcoma, Martin-Broto explains.

With the emergence of some potential targeted therapies, there is hope for improvements to the treatment landscape across soft tissue sarcomas in the coming years, Martin-Broto concludes.

Javier Martin-Broto, MD, PhD, discusses future research directions of soft tissue sarcoma.


Dr. Martin-Broto on Future Research Directions of Soft Tissue Sarcoma

Javier Martin-Broto, MD, PhD, medical oncologist, the University Hospital, leader, Villalba General Hospital, discusses the current treatment landscape in the first-line setting for soft tissue sarcomas.

The first-line treatment for patients with soft tissue sarcomas remains doxorubicin alone or in combination with ifosfamide (Ifex), and dacarbazine can be added for patients with leiomyosarcoma, Martin-Broto says. Though new treatments have emerged for the second line and beyond, an unmet need remains in the first-line setting, Martin-Broto explains.

A few targeted therapies have been developed for some soft tissue sarcomas; however, due to the vast number of subtypes of sarcoma, current targeted therapies may only be applicable for around 15% of all patients with soft tissue sarcomas, Martin-Broto continues.

Investigators are evaluating targeted therapies or synergistic combinations with chemotherapy to provide other first-line treatment options for more patients with soft tissue sarcoma, Martin-Broto adds. Correlative studies and prospective trials are required to deliver meaningful improvement to the first-line standard of care in soft tissue sarcoma, Martin-Broto concludes.

Javier Martin-Broto, MD, PhD, discusses the current treatment landscape in the first-line setting for soft tissue sarcomas.


Dr. Martin-Broto on the Current First-Line Treatment of Soft Tissue Sarcomas

Javier Martin-Broto, MD, PhD, medical oncologist, the University Hospital, leader, Villalba General Hospital, discusses the role of MDM2 amplification and p53 inactivation in patients with soft tissue sarcoma.

MDM2 amplification is commonly seen in specific subtypes of soft tissue sarcoma, such as well-differentiated and dedifferentiated liposarcoma, which are some of the most common sarcoma subtypes, Martin-Broto says. The amplification of an extra chromosome is present in these subtypes of sarcomas, leading to patients with well-differentiated and dedifferentiated liposarcomas to experience the inactivation of p53, Martin-Broto explains.

When MDM2 is amplified, it causes the inactivation of p53, which plays a key role in controlling the cell, Martin-Broto continues. This is an underlying mechanism that makes targeted treatments vital for patients with soft tissue sarcomas, Martin-Broto concludes.

Javier Martin-Broto, MD, PhD, discusses the role of MDM2 amplification and p53 inactivation in patients with soft tissue sarcoma.


Dr. Martin-Broto on MDM2 and P53 in Soft Tissue Sarcoma

Javier Martin-Broto, MD, PhD, medical oncologist, the University Hospital, leader, Villalba General Hospital, discusses the ongoing research of MDM2 agonists in patients with soft tissue sarcoma.

It is difficult to make arguments for or against MDM2 inhibitors currently under investigation in phase 3 trials for patients with sarcoma, Martin-Broto says. The first MDM2 agonist to release positive information is milademetan, which is being evaluated vs trabectedin in the phase 3 MANTRA trial (NCT04979442) in patients with dedifferentiated liposarcoma, Martin-Broto explains. Other MDM2 agonists, including BI 907828, are being explored, Martin-Broto continues. The phase 2/3 Brightline-1 trial (NCT05218499) is exploring BI 907828 vs doxorubicin in patients with dedifferentiated liposarcoma.

It may eventually be beneficial to evaluate MDM2 agonists in head-to-head comparative clinical trials, Martin-Broto adds. These agents all carry different affinity and safety profiles, and it remains too early to draw a conclusion as to which could provide the most benefit for patients, Martin-Broto concludes.

Javier Martin-Broto, MD, PhD, discusses the ongoing research of MDM2 agonists in patients with soft tissue sarcoma.


Javier Martin-Broto, MD, PhD

Articles

Dr Martín-Broto on the Efficacy of Sunitinib Plus Nivolumab in Clear Cell Sarcoma

Dr. Martin-Broto on Future Research Directions of Soft Tissue Sarcoma

Dr. Martin-Broto on the Current First-Line Treatment of Soft Tissue Sarcomas

Dr. Martin-Broto on MDM2 and P53 in Soft Tissue Sarcoma

Dr. Martin-Broto on the Ongoing Research of MDM2 Agonists in Soft Tissue Sarcoma