Cediranib for alveolar soft part sarcoma: a randomised study in relation to clinical practice

In The Lancet Oncology, Ian Judson and colleagues, investigators of the Cediranib for Alveolar Soft Part Sarcoma (CASPS) trial, report on a randomised, placebo-controlled, phase 2 trial testing the tyrosine-kinase inhibitor cediranib in metastatic alveolar soft part sarcoma (ASPS).1Judson I Morden JP Kilburn L et al.Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial.Lancet Oncol. 2019; (published online May 31.)http://dx.doi.org/10.1016/S1470-2045(19)30215-3Scopus (51) Google Scholar The study was formally positive, although the clinical benefit of cediranib was small. ASPS is a rare subtype of sarcoma that mostly affects young adults, with a high frequency of distant metastasis leading to poor long-term survival despite a typically indolent disease course. Activity of cediranib in metastatic ASPS has previously been shown in a phase 2 study in gastrointestinal stromal tumours and sarcomas, including six patients with ASPS, four of whom had a durable partial response and one had prolonged stable disease.2Judson I Scurr M Gardner K et al.Phase II study of cediranib in patients with advanced gastrointestinal stromal tumors or soft-tissue sarcoma.Clin Cancer Res. 2014; 20: 3603-3612Crossref PubMed Scopus (57) Google Scholar Additionally, in a National Cancer Institute study3Kummar S Allen D Monks A et al.Cediranib for metastatic alveolar soft part sarcoma.J Clin Oncol. 2013; 31: 2296-2302Crossref PubMed Scopus (165) Google Scholar of 46 patients (43 evaluable) with ASPS, 15 (35%) achieved a Response Evaluation Criteria in Solid Tumour (RECIST)-defined overall response, 26 (60%) stable disease, and 36 (84%) controlled disease (ie, stable disease and partial responses) at 24 weeks. In the CASPS trial, 32 patients with ASPS were treated with cediranib and 16 were given placebo, and after 24 weeks (or sooner if disease progression occurred) all patients on placebo were crossed over to cediranib. With a median follow-up of 34·3 months (IQR 23·7–55·6) at the time of data cutoff for these analyses (April 11, 2018), this study met its primary endpoint, which was based on tumour response, defined as percentage change in the median sum of the longest diameters of target marker lesions at 24 weeks. Judson and colleagues aimed to detect a 20% difference in favour of cediranib, and found a significant difference in the median sum of the diameters of target marker lesions of 22% at 24 weeks (−8·3% [IQR −26·5 to 5·9] in the cediranib group vs 13·4% [1·1 to 21·3] in the placebo group; one-sided p=0·0010), even though the number of patients enrolled was relatively low (overall n=48, evaluable population n=44). Unexpectedly, of the evaluable participants at week 24 (n=28), 11% (n=3) achieved a RECIST defined partial response and 50% (n=14) had stable disease, results that are inferior to previous phase 2 studies of cediranib.2Judson I Scurr M Gardner K et al.Phase II study of cediranib in patients with advanced gastrointestinal stromal tumors or soft-tissue sarcoma.Clin Cancer Res. 2014; 20: 3603-3612Crossref PubMed Scopus (57) Google Scholar, 3Kummar S Allen D Monks A et al.Cediranib for metastatic alveolar soft part sarcoma.J Clin Oncol. 2013; 31: 2296-2302Crossref PubMed Scopus (165) Google Scholar This randomised study treated fewer patients with ASPS with cediranib than the NCI phase 2 study.3Kummar S Allen D Monks A et al.Cediranib for metastatic alveolar soft part sarcoma.J Clin Oncol. 2013; 31: 2296-2302Crossref PubMed Scopus (165) Google Scholar Our question is to what extent the randomised study design, which selected response as the primary endpoint in this specific population and tested this class of drugs, increased the reliability of the CASPS trial results compared with other uncontrolled, phase 2 studies. Concerns about spontaneous disease stabilisation and slow progression of metastatic ASPS were the basis for conceiving the placebo-controlled design and for requiring evidence of progression in the previous 6 months among the entry criteria. This design required a longer study duration than other uncontrolled, phase 2 studies and made cediranib available to fewer patients, although admittedly after 24 weeks the patients in the placebo group were switched to cediranib. However, 44% (n=7) of patients in the placebo group had stable disease at 24 weeks, suggesting that the requirement of disease progression in the previous 6 months did not add substantially to the study design. Patients in the placebo group did not show spontaneous regression, by contrast with the placebo group in a randomised trial4Gounder MM Mahoney MR Van Tine BA et al.Sorafenib for advanced and refractory desmoid tumors.N Engl J Med. 2018; 379: 2417-2428Crossref PubMed Scopus (196) Google Scholar testing sorafenib in treatment-refractory and advanced desmoid tumours, a mesenchymal neoplasm notable for its different natural history. Although, in our opinion, progression-free survival would have been a more appropriate primary endpoint than response for this study, more patients would have been needed to detect a longer progression-free survival in the cediranib group, challenging the completion of the trial in such a rare disease. In this study, cediranib did not significantly improve progression-free survival compared with placebo, but the study was not powered to test this difference and therefore cannot conclude on this endpoint. However, RECIST responders had a valuable median duration of response of 16·0 months (IQR 15·7–26·0). In other words, from the clinical point of view, few patients had relatively long-lasting responses. The CASPS trial provides evidence that antiangiogenics are active in ASPS, although they might not have been created equally, and cross-resistance between them might be restricted. So far, the only antiangiogenic approved in sarcomas is pazopanib,5Stacchiotti S Mir O Le Cesne A et al.Activity of pazopanib and trabectedin in advanced alveolar soft part sarcoma.Oncologist. 2018; 23: 62-70Crossref PubMed Scopus (41) Google Scholar, 6van der Graaf WT Blay JY Chawla SP et al.Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.Lancet. 2012; 379: 1879-1886Summary Full Text Full Text PDF PubMed Scopus (1452) Google Scholar as second-line therapy, leaving doxorubicin as the standard first-line therapy, although ASPS is refractory to anthracyclines. Ongoing studies are testing new antiangiogenics (eg, anlotinib [NCT03016819])7Chi Y Fang Z Hong X et al.Safety and efficacy of anlotinib, a multikinase angiogenesis inhibitor, in patients with refractory metastatic soft-tissue sarcoma.Clin Cancer Res. 2018; 24: 5233-5238Crossref PubMed Scopus (157) Google Scholar and immunotherapy8D'Angelo SP Mahoney MR Van Tine BA et al.Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials.Lancet Oncol. 2018; 19: 416-426Summary Full Text Full Text PDF PubMed Scopus (342) Google Scholar, 9Conley AP Trinh VA Zobniw CM et al.Positive tumor response to combined checkpoint inhibitors in a patient with refractory alveolar soft part sarcoma: a case report.J Glob Oncol. 2018; 4: 1-6PubMed Google Scholar alone or in combination for metastatic ASPS, fostering new hopes in this patient population. We do not believe that future trials in such a rare tumour would need a placebo-controlled group like in the CASPS trial, for all the limitations mentioned here, and because antitumor activity can be studied in uncontrolled, phase 2 trials. Although the development of innovative response criteria is a good idea in theory, response duration and progression-free survival are the most clinically meaningful endpoints to assess the effect of new therapies. SS declares grants from Novartis, Bayer, Pfizer, and Advechen, and personal fees from Bayer outside of the submitted work. SP declares no competing interests. Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trialGiven the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. Full-Text PDF Open Access