Separating Treatment of Leiomyosarcomas From STS Umbrella

^1,2Yet, physicians continue to try to treat all sarcomas the same, making drug development for these types of tumors quite slow and frustrating.

The heterogeneity of STSs poses a constant challenge for the treatment of these tumors.³As Angela Pang, MBBS, MRCP, et al state in their paper on the current treatment paradigm for STS, “With a revolution in the understanding of the genomics and relevant pathways involved in the pathogenesis of each sarcoma subtype, accurate identification of the sarcoma subtype is critical in directing treatment for patients with metastatic STS.”

Gastrointestinal stromal tumors (GIST) are one of the few sarcomas that have been separated from the pack.⁴Targeted therapies have been approved for the treatment of GIST alone, including the tyrosine kinase inhibitor (TKI) imatinib (Gleevec), which has made a big difference for patients with GIST. Only by separating this patient population could advances be made.

Another group of sarcomas that would benefit from differentiation from the STS umbrella is leiomyosarcoma, which is one of the most common subtypes, accounting for approximately 11% to 15% of STS, although the exact amount is hard to determine.^1,5According to a characterization of the taxonomy of STS subtypes published in Nature Reviews Cancer, leiomyosarcomas have close ties to GIST and rhabdomyosarcomas.⁶

Leiomyosarcomas are tumors that occur in smooth muscle tissues.¹They frequently are found in the retroperitoneum, uterus, dermis, and vessels, though they can also occur in the bone.^1,5They are pleomorphic myogenic sarcomas that are commonly aggressive and associated with a shorter relapse-free survival.¹

Prognostic factors for leiomyosarcomas are strongly tied to the location of the tumor and its size. Retroperitonael and vascular tumors have a poorer prognosis, whereas cutaneous leiomyosarcomas have a better prognosis than some of the other subtypes.⁷Patients with hereditary retinoblastomas caused by a germline RB1 mutation have an increased risk of developing STS, especially leiomyosarcomas.⁸This subgroup of sarcomas covers a wide range of variants that would benefit from more treatment options and a more individualized approach.

IMPORTANCE OF DIFFERENTIATION

When patients are diagnosed with STS, they are generally treated with surgery, radiation, chemotherapy, or a combination of these modalities.⁴However, responses to these modalities often differ by STS subtype.

In a study of adjuvant radiotherapy in uterine sarcomas, investigators randomized 224 patients, including 99 with uterine leiomyosarcoma and 1 with myxoid leiomyosarcoma, to either pelvic radiation or observation. The study showed that there was no overall survival (OS) or progression-free survival (PFS) benefit in the patients with leiomyosarcoma who received radiation.⁸Responses to chemotherapy also vary with leiomyosarcomas. First-line anthracycline-based chemotherapy is standard for patients with advanced STS.⁴Ifosfamide is one of the standard chemotherapies given to patients with STS in the frontline, yet patients with leiomyosarcoma may not benefit as significantly from ifosfamide as from other chemotherapy monotherapies or combinations. When examining the outcomes of patients with STS treated with ifosfamide-containing chemotherapy, patients with leiomyosarcoma showed a higher risk of progression than those with synovial sarcoma.⁹

Also, they showed a lower benefit in terms of OS with ifosfamide-based treatment than with doxorubicin monotherapy. Regorafenib (Stivarga) is a multikinase inhibitor that has shown antitumor activity in STS and has been approved for the treatment of GIST. Outside of GIST, regorafenib has shown activity in non-adipocytic sarcomas.¹⁰In the REGOSARC trial of patients with STS, which excluded patients with GIST, those in the leiomyosarcoma cohort showed a PFS of 3.7 months (95% CI, 2.5-5.0) and a median OS of 21 months (95% CI, 7.2 to not reached). Twenty-four patients (86%) in this cohort had stable disease with regorafenib. Patients in the other sarcoma cohort showed a similar PFS and no significant difference in OS, but those with liposarcoma showed a worse PFS and OS compared with placebo. Other TKIs have also shown limited benefit for patients with leiomyosarcoma.

PD-1 checkpoint inhibitors are increasingly being explored as a treatment for STS. In the phase II SARC-028 study of pembrolizumab (Keytruda) in subtypes of patients with STS and bone sarcomas, the objective response rate (ORR) was 19% for patients with STS and 40% had stable disease.¹¹No responses were seen in patients with leiomyosarcoma in this trial, however. Yet researchers found 1 patient with uterine leiomyosarcoma who showed a complete pathologic response to pembrolizumab in all but 1 metastatic site in a phase Ib study.¹²

The patient showed PTEN loss, reduced infiltration of PD-1—positive lymphocytes, and diminished expression of neoantigens. Leiomyosarcoma is 1 of the STS subtypes that has shown a high proportion of PD-L1 expression. In a study of PD-1 and PD-L1 expression in STS, 58% of samples showed PD-L1 expression.¹³Among patients with leiomyosarcoma, 45% had PD-1—positive expression and 70% had PD-L1 expression. Interestingly, with STS, expression was associated with a poor prognosis by multivariate analysis. Among patients with leiomyosarcoma, PD-1/PD-L1 positivity also tended to be found in those with a higher tumor stage, also accounting for a poor prognosis. The true impact of checkpoint inhibitors on patients with leiomyosarcoma is still unknown.

TREATING LEIOMYOSARCOMAS SEPARATELY

Treatments are starting to be investigated aimed at treating patients with leiomyosarcoma rather than all STSs. Gemcitabine and docetaxel (Taxotere) have shown responses in patients with leiomyosarcoma, particularly in patients with uterine leiomyosarcoma. A phase II trial of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma, 85% of which had uterine leiomyosarcoma, showed an ORR of 53% (95% CI, 35%-70%) with 3 of 34 patients achieving a complete response.¹⁴Responses were also seen in 50% of patients who had progressed following treatment with doxorubicin. The median time to progression was 5.6 months.

In a phase III trial of frontline gemcitabine and docetaxel in patients with uterine leiomyosarcoma, gemcitabine and docetaxel showed responses in 31.5% of 54 patients.¹⁵The median PFS was 6.2 months and the median OS was 26.9 months with the doublet. The addition of bevacizumab (Avastin) to gemcitabine and docetaxel did not show a significant improvement in PFS or OS, but the ORR was increased with the triplet (35.8%). Docetaxel and gemcitabine is now a standard of care in patients with uterine leiomyosarcoma, although the benefit has been called into question.³

Trabectedin (Yondelis), a marine-derived drug, has received a category 1 recommendation in the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of patients with liposarcomas and leiomyosarcomas, known collectively as L-sarcomas.⁴For all other types of STS, the combination has a category 2A recommendation.

This recommendation for L-sarcomas was based on a phase III trial of trabectedin versus dacarbazine in the second line for patients with advanced L-sarcomas. Trabectedin showed a median PFS of 4.2 months compared with 1.5 months with dacarbazine (HR, 0.55; P <.001).16 The median OS with trabectedin was 12.4 months versus 12.9 months with dacarbazine (HR, 0.87; P = .37).

Eribulin (Halaven) has also shown benefit in the L-sarcomas and received a category 1 recommendation from the NCCN for the treatment of L-sarcomas based on a phase III trial in which previously treated patients demonstrated an OS of 13.5 months with eribulin compared with 11.5 months with dacarbazine (HR, 0.77; 95% CI, 0.62-0.95; P = .0169).¹⁷Other types of STS were not included in these studies of eribulin and trabectedin.

PRECISION MEDICINE IN LEIOMYOSARCOMA

According to a recent presentation at the 2017 ASCO Annual Meeting, 50% of all STS have complex genomic profiles, whereas 15% to 30% commonly have reciprocal translocations, and the remainder commonly have amplifications.¹⁸Leimyosarcoma was marked as one of the main subtypes with a complex profile.^4,18

In their genomic analysis of 587 patients with sarcoma from the American Association of Cancer Research&rsquo;s GENIE Consortium, 56% had a complex genomic profile. Of these patients, 34% had leiomyosarcoma, the most frequent histology. Patients with leiomyosarcoma frequently showed mutations in TP53, RB1, ATM, and APC. Amplifications of MYOCD are also common in a subset of leiomyosarcomas, as well as chromosome 10 deletions in PTEN.⁶

Clinical trials are ongoing to further study the genomic landscape of leiomyosarcomas and derive better treatment options for patients with this sarcoma subtype. These include the MULTISARC study, a phase III precision medicine trial for patients with STS tested with next-generation sequencing to guide subsequent therapies for each patient in the experimental arm.¹⁸The Cancer Genome Atlas project is also working on a comprehensive genomic analysis of specific STS, including leiomyosarcoma.⁶Hopefully these studies will help determine better treatments for patients specifically with leiomyosarcoma, rather than as a subset of STS.

References:

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