Enrollment in Histologically-Specific Trials Improves Outcomes in Soft Tissue Sarcoma

Elise Nassif, MD

In the realm of soft tissue sarcoma, early enrollment to clinical trials that are more specific to the molecular profile or histology of a patient’s disease can improve outcomes, according to Elise Nassif, MD.¹

“Any type of screening based on either histology or biomarkers was more beneficial for patients,” Nassif said. “[The analysis showed] that patients included in trials that were screening for biomarkers had a median progression-free survival [PFS] of 2.8 months. The histotype-tailored trials had a median PFS of 4.1 months, and the pan-tumor trials had a median PFS at 1.6 months. [The] histotype-tailored approach is definitely beneficial for phase 3 trials and [in] early phase trials.”

In an interview with OncLive^®, Nassif, a post-doctoral fellow at The University of Texas MD Anderson Cancer Center and a PhD candidate at Centre Léon Bérard in Lyon, France, discussed the evolving standard of care for patients with soft tissue sarcoma and the benefits of early phase inclusion, as well as histotype testing for this population.

OncLive^®: Could you speak to the unmet need that exists in terms of standard-of-care treatments for patients with soft tissue sarcoma? What did you seek to accomplish with this research?

Nassif: The drug development pipeline in soft tissue sarcomas has recently failed in several phase 3 trials. This [represented an opportunity] for the sarcoma community to rethink the drug development pipeline. [We are moving towards] a more [histology]-tailored approach. For the past 10 years, we have had major failures with promising phase 2 drugs that crashed in phase 3 trials. [This includes agents such as] palifosfamide [Zymafos], ifosfamide [Ifex], and olaratumab [Lartruvo], which failed to prove any benefit for patients with pan-histology soft tissue sarcomas in phase 3 trials.

Right now, our standard of care [is] still anthracycline-based chemotherapy, which has been [standard] for 4 years. [We often add on] ifosfamide, which will yield [a] median PFS in first-line of 6 to 8 months, [and a] median overall survival [OS] of 18 to 20 months. The major developments that have been made for the past 10 to 20 years in terms of OS are more likely due to [the] progress in local treatments rather than systemic treatments.

When we consider active second-line treatments today in soft tissue sarcomas, our median PFS rates [are] over 40% at 3 months. There is clearly a big need for new drugs to be developed. At the 2021 ESMO Congress, we saw a success of the drug development pipeline in trabectedin. We [also] saw Patricia Pautier, MD, of the Institut Gustave Roussy Cancer Campus, present how the addition of trabectedin [Yondelis] to doxorubicin in first-line setting benefitted patients in terms of survival.

This drug development pipeline has worked because it has, very early on within the early phase trials, identified subtypes [that] would not be sensitive to the drug. The whole drug development pipeline has [since] been histotype tailored. We do know that having a histotype-tailored approach benefits the drug development pipeline, but what we believe at Gustave Roussy and Centre Léon Bérard is that this approach also benefits patients.

What set the stage for this research?

The experience at Gustave Roussy and Léon Bérard has been changing over the past few years. The drug development pipeline, and all the early phase trials, have changed. We now have a bigger portfolio of early phase trials. In sarcoma centers, when the sarcoma team works hand-in-hand with the drug development pipeline, we are able to tailor which patient will be included onto which trial, and [whether they will] derive benefit from [from that study regimen].

It has [been] our experience that including some patients in early phase trials has shown benefit, and we wanted to put numbers on it. Also, [we wanted to] update the efficacy and survival data that had been published for patients with soft tissue sarcoma in early phase trials.

Could you expand on the patient population examined on this analysis?

We retrospectively looked at all the patients who were included in Gustave Roussy Cancer Center and Centre Léon Bérard early phase trials from 2012 to 2021. [In] this 8-year period, we included all soft tissue sarcomas, and only excluded bone sarcomas and gastrointestinal stromal tumors [GIST]. We did not have any other selection criteria, but the population was selected because it was [the same] population [originally] selected to be included in [the] trials [during that time frame].

It is representative of what we would expect from an early phase trial population, except for the little twist that we have several patients who were included in the first-line and second-line setting. When we look at the histotypes, we had 55 [patients with] well-differentiated liposarcomas, and 53 [patients with] leiomyosarcomas, which are the most frequent histotypes in soft tissue sarcomas. [The] population was also very fit because it is an early phase 1 trial population.

What were the key takeaways from the research?

We presented PFS and OS efficacy end points from patients included in early phase trials for soft tissue sarcoma. We showed that overall, our median PFS is 2.8 months, which compares very favorably with what is previously published for active second-line treatment in soft tissue sarcomas. [Historically, these] drugs have a PFS rates of more than 40% at 3 months. Furthermore, we show that when we break it down by line of treatment, we have a first-line median PFS of 8.3 months, a second-line median PFS of 5.4 months, and a third- or later-line median PFS of 2.6 months.

We also showed that including patients early on in those trials did not impact their OS or the overall cost of the disease. We [observed] a median OS of 36 months for patients included in first-line. [We know this is] too big of a median OS compared with historical controls, but this also shows that we have not been including all soft tissue sarcoma patients within [the] first-line setting in these trials.

[On our study] we selected the correct patients to be included within the first-line setting, [which mostly consisted of those with] well-differentiated liposarcomas or clear cell sarcomas. [These] are histotypes that we know are notoriously resistant to any chemotherapy or any standard-of-care treatments. These patients were included in first-line setting very safely, as there is no real standard of care.

Were any of the findings surprising?

[What] did not surprise us is that, although it is not significant, when we compare a biomarker approach with a histotype approach, we do [observe] a trend for a better median PFS in the histotype [approach]. What we see in our data, and what the whole community will agree with, is that having screening on either biomarker or histology is beneficial, not only for the trials for the whole drug development pipeline, but [also] for the patients. [When treating patients with] sarcomas today, we are still tailoring our approach, not on the biomarkers so much as we are tailoring to histology. Although we are all believers of molecular biology, we believe that histotype is still the most powerful tool to predict response to classes of drug and to predict benefit of any class of drug.

Reference

Nassif EF, Blay JY, Bahleda R, et al. Efficacy of early phase trials for soft-tissue sarcoma patients: the Centre Léon Bérard and Gustave Roussy Experience. Ann Oncol. 2021;32(5):1111-1128. doi:10.1016/annonc/annonc712