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Royal Marsden Hospital and Institute of Cancer Research
London, United Kingdom
Robin L. Jones, BSc, MBBS, MRCP, MD(Res), has disclosed that he has received consulting fees from Adaptimmune, Astex, Athenex, Bayer, BI, Blueprint, Clinigen, Daichii Sankyo, Deciphera, Eisai, Epizyme, Immunedesign, Immunicum, Karma Oncology, Lilly, Merck, Mundipharma, PharmaMar, Spring Works, SynOx, and Tracon.
The treatment of advanced osteosarcoma and nonadipocytic soft tissue sarcomas (STS) remains difficult, but exciting data have recently emerged with tyrosine kinase inhibitors (TKIs). Below, I will discuss these data, as well as ongoing trials evaluating TKIs.
Regorafenib in Advanced Osteosarcoma
Treatment of recurrent osteosarcoma has been challenging, but several interesting trials have reported on the activity of TKIs, in particular those blocking VEGFR2 and other kinases, which show that these agents are active in relapsed osteosarcoma. It is important to note that these reported trials are randomized, which—given the rarity of the disease—is very good news and an important advance for sarcomas.
In the randomized, double-blind phase II SARC024 trial, patients with previously treated, metastatic osteosarcoma were randomized to receive regorafenib or placebo (N = 42). The primary endpoint of median progression-free survival (PFS) was met, with a median PFS of 3.6 months with regorafenib vs 1.7 months with placebo—a significant difference. There was no significant difference in overall survival (OS), which is likely due to the crossover design of the trial.
REGOBONE was another randomized, double-blind phase II trial of regorafenib in multiple sarcoma types, including osteosarcoma (N = 43). In the osteosarcoma cohort, the trial met its primary endpoint of nonprogression at 8 weeks of follow-up, with 65% of patients receiving regorafenib without progression vs 0% of patients receiving placebo. Median PFS was 16.4 weeks vs 4.1 weeks for regorafenib and placebo, respectively.
In both trials, the adverse event (AE) profile was comparable to previous reports for regorafenib in sarcomas, with hypertension, hand–foot skin reaction, fatigue, and gastrointestinal toxicities among the most common AEs. All AEs were generally manageable with dose interruptions and reductions, coupled with supportive care.
In view of the activity of TKIs in relapsed/refractory osteosarcoma, regorafenib is now being evaluated in the maintenance setting in ongoing placebo-controlled trials. The randomized phase II REGOSTA trial is currently recruiting patients aged 16 years or older with primary osteosarcoma who have previously received treatment for localized or metastatic disease and achieved complete remission (or have no evidence of disease if metastatic). The primary endpoint is relapse-free survival, and secondary endpoints will evaluate time to treatment failure, OS, quality of life, and safety. REGOMAIN is a randomized phase II trial enrolling patients with osteosarcoma aged 16 years or older with measurable residual disease not amenable to resection at diagnosis or first relapse. The primary endpoint is PFS, and secondary endpoints include overall response rate, OS, quality of life, and safety. Both trials are comparing maintenance regorafenib with placebo.
Regorafenib, Pazopanib, and Anlotinib in Nonadipocytic STS
Nonadipocytic STS encompasses a wide variety of subtypes, and TKIs have demonstrated efficacy in some subtypes. The phase II REGOSARC trial enrolled patients with liposarcomas, leiomyosarcomas, synovial sarcomas, and other sarcomas who had received prior doxorubicin or another anthracycline and ≤3 cycles of prior systemic treatment. Patients were randomized to receive regorafenib or placebo, and the primary endpoint was PFS. In patients with nonadipocytic sarcomas, the primary endpoint of PFS was met (HR: 0.50), but there was no benefit for patients with liposarcomas. In addition to demonstrating clinical benefit for TKIs, these results highlight the need for a better understanding of the biology of the various types of sarcomas to elucidate why some therapies may be better for certain subtypes.
EREMISS is an ongoing randomized phase II trial of regorafenib as maintenance therapy in patients with metastatic or locally advanced STS with progressive or stable disease after first-line chemotherapy. The primary endpoint is PFS, and secondary endpoints include OS, overall response rate, and safety.
Pazopanib is another TKI with a different target profile from regorafenib. The phase III PALETTE trial showed significant improvement in PFS with pazopanib vs placebo in patients with metastatic leiomyosarcoma, synovial sarcoma, and other sarcomas (4.6 vs 1.6 months, respectively). Pazopanib is now approved by the FDA for patients with advanced STS who have received prior chemotherapy.
Another novel TKI, anlotinib, has demonstrated clinical benefit in STS. In the randomized phase II/III ALTER0203 trial, anlotinib significantly improved median PFS to 6.70 months vs 1.60 months with placebo (HR: 0.34; P <.0001), meeting the primary endpoint of PFS. The most pronounced PFS benefit was observed in patients with alveolar soft-part sarcoma at 18.23 months. The APROMISS trial compared anlotinib with dacarbazine in patients with synovial sarcoma and met its primary endpoint with a median PFS of 2.89 months with anlotinib vs 1.64 months with dacarbazine (HR: 0.45; 95% CI: 0.270-0.744; P = .0015). Of note, several patients derived durable benefit from anlotinib.
Together, these trials indicate that TKIs have potential in nonadipocytic STS but highlight the need for additional studies to better understand which TKIs will offer the best benefit in a specific subtype of sarcoma.
Future Directions in Sarcomas
What does the future hold for TKI therapy in sarcomas? As mentioned above, several ongoing trials are evaluating the safety and efficacy of TKIs in the maintenance setting. Should these studies report positive outcomes, I think they have the potential to be practice changing. Our patients need more and better alternatives to improve disease-free survival and, we hope, OS. When thinking of the maintenance setting, it is important to realize that some patients are ready to stop therapy after the initial chemotherapy, whereas others are interested in continuing therapy with a goal of preventing or delaying recurrent disease. So, it is quite important to discuss treatment options and goals of therapy with patients and incorporate their preferences into treatment decisions.
Other studies are evaluating TKIs in combination with immunotherapy, particularly in alveolar soft-part sarcoma. Based on early studies in alveolar soft-part sarcoma, combination therapy seems tolerable and synergistic, so it will be interesting to see more data on efficacy. Such combination therapies may be better suited for younger patients who are better able to tolerate the additional AEs from combination approaches. This is a fruitful avenue for further exploration.
TKIs clearly have activity in osteosarcoma and STS, but not all patients receive a benefit from therapy. Thus, one of the key issues is finding and validating predictive biomarkers that will enable healthcare professionals to optimize treatment choices and improve patient outcomes. This is still a very challenging area.
Finally, all these data highlight the importance of offering patients with sarcoma the opportunity to participate in clinical trials, because that is how we will make improvements in care and further elucidate some of the underlying biology of this complex group of diseases. It is wonderful to observe that we can do these trials in a randomized fashion—even in this rare disease—and that it is feasible to have studies with selected histologic or molecular subtypes of sarcoma. In a very rare disease, even a negative trial can provide a benchmark that can move the field forward.
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