The addition of the beleaguered drug olaratumab to doxorubicin did not prolong overall survival (OS) in patients with advanced soft tissue sarcomas (STS) compared with doxorubicin alone, the randomized phase III ANNOUNCE trial has shown.
Olaratumab is a fully humanized monoclonal antibody of IgG class 1 that selectively binds to platelet-derived growth factor receptor (PDGFR)-α.
These results were disappointing as an earlier phase II study showed that the addition of olaratumab to doxorubicin followed by olaratumab monotherapy in advanced STS patients improved median OS by 11.8 months compared with single-agent doxorubicin, especially among patients with leiomyosarcoma (LMS) where median OS was 15.1 months longer for the combination arm than the doxorubicin alone arm.
“This trial shows the importance of confirmatory phase III trials to validate results from smaller trials…[as] findings did not confirm the overall survival benefit observed in the phase 2 trial,” William Tap, MD, Memorial Sloan Kettering Cancer Center in New York and multi-center colleagues observed in JAMA.
“Although this study did not show any benefit from the addition of olaratumab to doxorubicin…[it] confirmed the incremental increase in survival for patients with STS treated with doxorubicin-based therapy,” investigators added.
Commenting on the findings, Christina Roland, MD, The University of Texas MD Anderson Cancer Center in Houston and Sandra Wong, MD, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, pointed out that survival rates among patients with STS are poor and have remained unchanged in the last 40 years.
“There is [therefore] a significant unmet need for improved systemic therapies in the treatment of patients with STS,” as they pointed out.
Roland and Wong also pointed out that between 1992 and 2017, 93 cancer drugs were granted “accelerated approval” by the FDA in order to allow investigational drugs to reach the market more quickly.
These drugs were approved based on results from early studies that used surrogate end points, not overall survival data which reduces the quality of evidence needed for FDA approval.
“As demonstrated by the report by Tap and colleagues, there are risks of accelerated approval,” the editorialists observed.
One of these risks is that granting patients earlier access to drugs might mean that patients will be treated with drugs that are less effective than initially thought, such as olaratumab.
“For the 2 years that olaratumab was on the market, thousands of patients received an ineffective therapy that amounted to an estimated $562 million in worldwide sales,” Roland and Wong noted.
“The financial resources, lost to the health care system, may have been better spent in other ways,” they suggested.
Olaratumab was withdrawn from the market in April 2019 following review of early data, Roland and Wong noted.
The ANNOUNCE trial involved a total of 509 adults with advanced STS recruited from 110 sites in 25 countries.
Eligible patients were not allowed to have received prior anthracycline therapy and they had to have a cardiac ejection fraction of 50% or greater.
“Treatment consisted of 21-day cycles of olaratumab or placebo (days 1 and 8) in combination with doxorubicin 75 mg/m2 (day 1) for up to 8 cycles,” the authors explained.
This was followed by either olaratumab or placebo monotherapy.
In cycle 1, the dose of olaratumab was 20 mg/kg which was reduced to 15 mg/kg in subsequent cycles.
The primary end point was OS in all randomized patients as well as in the subset of patients with LMS.
At a median follow-up of 31 months, the median OS in the total STS cohort was 20.4 months for the combination arm compared with 19.7 months for the doxorubicin monotherapy arm for a Hazard Ratio (HR) of 1.05 (95% CI, 0.84-1.30), Tap and colleagues reported.
“Similarly, no survival benefit in the doxorubicin + olaratumab group was observed in the LMS population, with a median overall survival of 21.6 months versus 21.9 months for the doxorubicin + olaratumab…and doxorubicin + placebo…groups,” the authors added, at a HR of 0.95 (95% CI, 0.69-1.31).
Median PFS in the total STS population was 5.4 months in the combination arm versus 6.8 months in the single-agent arm while in the LMS population, median PFS was 4.3 and 6.9 months in the combination arm versus the single-agent arm, respectively.
Objective response rates (ORR) in both the total STS population and the LMS population were low in both arms:
- ORR: Total STS: doxorubicin + olaratumab: 14%.
- ORR: Total STS: doxorubicin + placebo: 18.3%.
- ORR: LMS patients: doxorubicin + olaratumab: 13.4%.
- ORR: LMS patients: doxorubicin + placebo: 22.6%.
Disease control rates (DCR) were comparable in both patient groups as well:
- DCR: Total STS: doxorubicin + olaratumab: 67.4%.
- DCR: Total STS: doxorubicin + placebo: 75.7%.
- DCR: LMS patients: doxorubicin + olaratumab: 63%.
- DCR: LMS patients; doxorubicin + placebo: 82.6%.
Grade 3 or higher adverse events (AEs) seen in both treatment arms included neutropenia at 46.3% versus 49%; leukopenia at 23.3% versus 23.7%, and febrile neutropenia at 17.5% versus 16.5% in the doxorubicin plus olaratumab and doxorubicin alone arm, respectively.
Rates of infusion-related reactions as well as cardiac dysfunction grade 3 or higher were similar in both groups and very low.
The authors speculated that the disparate results between the phase II study and their phase III trial might be explained by the fact that the phase II study was open label in design versus their blinded, placebo-controlled phase III study.
The phase II study also had PFS as its primary end point versus OS for the phase III study.
And enrollment in the phase II was limited to patients from the United States versus global enrollment for the phase III study.
“Additionally, all patients in the phase 2 study had metastatic disease at enrollment, whereas 17.1% of patients in this trial had locally advanced, nonmetastatic disease,” investigators added.
Nevertheless, the authors also pointed out that patients in the ANNOUNCE trial had the longest median OS of any recent, first-line randomized phase III STS trial.
The current improvement in median OS in advanced STS is possibly due to improvements in multidisciplinary and supportive care along with the availability of additional lines of effective systemic therapies for at least some sarcoma subtypes, as they suggested.
Limitations of the study included the fact that higher doses of olaratumab were not tested prior to this study and the dosing regimen used in ANNOUNCE may not have been maximized.