The combination of olaratumab and doxorubicin now replaces doxorubicin alone as a first-line treatment option [in patients with advanced soft-tissue sarcoma].— Melinda L. Yushak, MD, MPH
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THE BACKBONE treatment for soft-tissue sarcomas has long been anthracycline-based, but new approaches are coming. These novel strategies were discussed at the 2017 Debates and Didactics in Hematology and Oncology Conference in Sea Island, Georgia, by Melinda L. Yushak, MD, MPH, Assistant Professor of Hematology and Medical Oncology at Emory University, Atlanta.
For decades, not much has changed in the treatment of sarcomas. Since the 1970s, the standard first-line option has been doxorubicin, which renders a median overall survival of only 12 to 17 months.
Survival Improvement With Olaratumab
THE DISMAL SURVIVAL outcomes may change with the approval in 2016 of olaratumab (Lartruvo), a human monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFR-α). PDGF and PDGFR signaling plays a role in mesenchymal cell growth and angiogenesis.
“The combination of olaratumab and doxorubicin now replaces doxorubicin alone as a first-line treatment option,” Dr. Yushak said, adding that when patients have disease progression, single-agent high-dose ifosfamide or gemcitabine-based options can follow.
Approval of olaratumab was based on a phase Ib/II trial in which 66 patients with advanced soft-tissue sarcomas were randomized to receive olaratumab at 15 mg/kg on days 1 and 8 plus doxorubicin at 75 mg/m2 on day 1 for 8 cycles, followed by olaratumab until disease progression, while 67 received doxorubicin alone for eight cycles.1
Although median progression-free survival was 6.6 months with the combination vs 4.1 months with doxorubicin alone (hazard ratio [HR] = 0.672), the difference did not achieve statistical significance (P = .0615). Median overall survival, however, showed “quite a dramatic difference,” being 25.0 months with olaratumab/doxorubicin vs 14.7 months with doxorubicin alone (HR = 0.441; P = .0004). “This is very impressive survival in a sarcoma trial,” Dr. Yushak commented.
The combination did increase toxicity. Cardiac adverse events occurred in 14.1% of the olaratumab/doxorubicin group vs 9.2% with single-agent doxorubicin. Other adverse events of grade 3 or higher included neutropenia (51.5% vs 33.8%), anemia (12.5% vs 7.7%), and fatigue (9.4% vs 3.1%).
Evofosfamide for Soft-Tissue Sarcoma
THE ADDITION of evofosfamide, however, proved disappointing in one of the largest studies ever conducted in sarcoma, the phase III TH CR-406/SARC021 trial.2 Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard.
The SARC021 trial randomized 640 patients with unresectable or metastatic soft-tissue sarcomas to receive doxorubicin at 75 mg/ m2 plus evofosfamide at 300 mg/m3 on days 1 and 8 or doxorubicin alone for 6 cycles. The primary endpoint was not met; median overall survival was 18.4 months with the combination and 19.0 months with doxorubicin (HR = 1.08; P = .527), and median progression-free survival was also similar between the two groups.
However, in a subtype analysis, patients with synovial sarcomas appeared to benefit, demonstrating a median overall survival of 22.1 months with the doublet, vs 9.4 months with doxorubicin alone. “This makes sense when you think about the biology of synovial sarcoma. Alkylators work well there,” she commented. “While there’s really no role for the combination of evofosfamide and doxorubicin in all comers, there may be more to explore in synovial sarcoma.”
She cautioned that patient subsets in SARC021 were small. Nevertheless, ongoing trials are evaluating evofosfamide/doxorubicin in synovial sarcoma.
Aldoxorubicin: Possible Alternative to Doxorubicin
ALDOXORUBICIN HAS BEEN proposed as a safer alternative to doxorubicin, which conveys cardiac toxicity when given beyond a certain safety threshold. A doxorubicin conjugate, aldoxorubicin binds covalently to albumin and is then carried to the tumor where the acidic microenvironment causes cleavage.
In a study of 433 patients presented at the 2017 ASCO Annual Meeting, aldoxorubicin was compared to investigators’ choice of treatment (primarily doxorubicin).3 Most patients in both arms had received prior doxorubicin-based therapy.
NEW APPROACHES STUDIED IN SARCOMA
- Olaratumab and doxorubicin has replaced doxorubicin alone as a first-line treatment option in advanced soft-tissue sarcoma.
- The addition of evofosfamide to doxorubicin did not improve survival over doxorubicin monotherapy in this setting.
- Aldoxorubicin has a better safety profile than doxorubicin and was shown to improve progression-free survival in patients with leiomyosarcoma and liposarcoma.
- Response to pembrolizumab was limited to a few sarcoma subtypes, notably undifferentiated pleomorphic sarcoma.
- Studies of adjuvant and neoadjuvant therapies for sarcoma have produced mixed results.
- Standard chemotherapy produced better outcomes than histology-driven treatment in this setting.
The main effect of the newer agent was observed in leiomyosarcoma and liposarcoma. For these subtypes combined, median progression-free survival was 5.32 months with aldoxorubicin vs 2.96 months with investigators’ choice of therapy (HR = 0.62; P = .0070). This differed from the intent-to-treat analysis of the overall population, where median progression-free survival was slightly but not significantly higher with aldoxorubicin (4.11 vs 2.96 months; HR = 0.81; P = .0870). Median overall survival was approximately 12 months in both cohorts, and response rates were not statistically significantly higher with aldoxorubicin.
A clear difference was seen in toxicity profiles. Along with lower alopecia rates being associated with the newer agent, reduction in the rate of left-ventricular ejection fraction (< 50% from baseline) was also lower: 4.1% vs 19.1% with doxorubicin. Grade ≥ 3 adverse events overall, however, were slightly increased with aldoxorubicin (74.2% vs 64.3%)—primarily anemia, thrombocytopenia, neutropenia, and stomatitis.
The advantage with aldoxorubicin is that responders can continue on this drug indefinitely. “Some patients in the study received 40 cycles,” Dr. Yushak reported.
“What we know so far is that progression-free survival is prolonged by aldoxorubicin in patients with leiomyosarcoma and liposarcoma. There’s no overall survival benefit, but aldoxorubicin may be an option for some patients with recurrent disease,” she concluded.
“Whether aldoxorubicin will actually replace doxorubicin in the first-line setting was not answered by this trial,” she noted.
Immunotherapy: What Patients Are Asking About
“MOST OF MY PATIENTS come in saying they want ‘the Jimmy Carter drug,’” Dr. Yushak continued. While pembrolizumab (Keytruda) is indeed being studied in soft-tissue and bone sarcoma, its potential benefit appears to be limited to certain
subsets, according to the open-label phase II SARC028 trial of 80 previously treated patients.4 The population included 40 patients with soft-tissue sarcoma (leiomyosarcoma, liposarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma) and 40 with bone sarcoma (osteosarcoma, Ewing’s sarcoma, chondrosarcoma).
Response was limited to a few subtypes, most notably undifferentiated pleomorphic sarcoma. For these patients, the 12-week progression-free survival rate was 70%, and overall survival was 90%, in contrast to outcomes in the whole soft-tissue sarcoma population, where median progression-free survival was 18 weeks, the 12-week progression-free survival rate was 55%, and median overall survival was 49 weeks. For the bone subtypes, median progression-free survival was 8 weeks, and median overall survival was 52 weeks.
“There seems to be some signal for pembrolizumab in pleomorphic undifferentiated sarcoma and perhaps liposarcoma,” she said, but cautioned there were only 10 patients per group. “Leiomyosarcoma patients don’t seem to benefit, and there’s also not much signal in the bone subtypes.”
Neoadjuvant and Adjuvant Therapies
“WE KNOW THAT PATIENTS with soft-tissue sarcoma have a very high risk of recurrent disease, and once they develop metastases, the effectiveness of systemic therapy is limited. If patients are at such high risk, shouldn’t we just be treating them all with adjuvant therapy?” Dr. Yushak asked.
More than 20 trials addressing this question have produced mixed results. With early studies of doxorubicin and surgery, vs surgery alone, survival was better with chemotherapy in two studies, better with observation in three studies, and comparable in nine studies.
But in a meta-analysis evaluating 1,568 patients who mostly received single-agent doxorubicin, significant improvements with chemotherapy were shown for multiple endpoints, including recurrence-free interval (HR = 0.73), distant recurrence–free interval (HR = 0.70), and overall recurrence–free survival (HR = 0.75). A trend toward better overall survival was also observed (HR = 0.89).
But studies that have evaluated the newer option of anthracycline plus ifosfamide have had mixed results. Although some benefit was observed in the time to distant metastasis, long-term overall survival was generally no different, she noted.
“For all the positive trials, there are also negative trials, and this has been frustrating to us, with regard to what we should do for adjuvant therapy,” Dr. Yushak commented. “Maybe instead of giving all our patients the same drugs, we should tailor treatment, since we know that subtypes are biologically different.”
Histology-Driven Treatment No Better
THE PHASE III ISG-STS-0110 TRIAL of histology-tailored treatment was designed to answer this question in a variety of subtypes of high-grade, deeply located tumors ≥ 5 cm.5 Patients were randomized to three cycles of epirubicin and ifosfamide or histology-driven treatment as follows: trabectedin (Yondelis) for high-grade myxoid liposarcoma, gemcitabine plus dacarbazine for leiomyosarcoma, ifosfamide for synovial sarcoma, etoposide plus ifosfamide for malignant peripheral nerve sheath tumor, and gemcitabine plus docetaxel for undifferentiated pleomorphic sarcoma.
Disease-free survival at 46 months was significantly better with standard chemotherapy (62%) than with histology-driven therapy (38%; HR = 2.00; P = .006). “While this showed that standard treatment is better,” she said, “this trial still does not answer the question of which patients benefit from adjuvant therapy, vs neoadjuvant therapy, vs observation. That’s a question that has to be individualized.” ■
DISCLOSURE: Dr. Yushak reported no conflicts of interest.
REFERENCES
2. Tap WD, Papi Z, Van Tine BA, et al: Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): An international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol 18:1089-1103, 2017.
5. Gronchi A, Ferrari S, Quagliuolo V, et al: Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): An international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol 18:812-822, 2017.
