This article is more than 5 years old. Information may no longer be current.
Olaratumab improves OS, PFS in patients with advanced, metastatic soft tissue sarcoma
The addition of olaratumab to doxorubicin significantly prolonged OS in patients with advanced soft tissue sarcoma, according to phase 2 study results.
The study also met its predefined primary endpoint for PFS, results showed.
William D. Tap
These outcomes suggest a potential paradigm shift for the treatment of soft tissue sarcomas, according to William D. Tap, MD, chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center.
“A lot of times, we conduct phase 2 studies just to get a signal on the drug’s activity, or to see if a drug has activity,” Tap told HemOnc Today. “To see such a dramatic improvement in OS is really amazing, and it is really allowing us to delve back into the science, and to learn why we saw such dramatic responses.”
Doxorubicin serves as the current standard of care for patients with metastatic soft tissue sarcoma, for whom median OS ranges between 12 months and 16 months. Few novel treatments have been able to improve outcomes.
Tap and colleagues sought to evaluate the safety and efficacy of olaratumab (LY3012207, Eli Lilly) — a recombinant human immunoglobulin G subclass 1 monoclonal antibody that binds to platelet-derived growth factor receptor alpha (PDGFR alpha) — in combination with doxorubicin in this patient population.
The researchers enrolled 15 patients in an open-label phase 1b trial to assess the safety of olaratumab. They then conducted a randomized phase 2 study in 129 patients (median age, 58.5 years; range, 22-86) with histologically confirmed locally advanced or metastatic soft tissue sarcoma.
The researchers randomly assigned patients in the phase 2 study to 15 mg/kg IV olaratumab and 75 mg/m2 doxorubicin on days 1 and 8 of a 21-day cycle (n = 64), or to doxorubicin alone on day 1 of each cycle (n = 65). Treatment continued for up to eight cycles.
PFS served as the primary endpoint. Key secondary endpoints included OS, objective response rate, safety and pharmacokinetics.
Patients assigned the combination achieved a median PFS of 6.6 months (95% CI, 4.1-8.3), compared with 4.1 months (95% CI, 2.8-5.4) among patients assigned doxorubicin alone (HR = 0.67; 95% CI, 0.44-1.02). These data met the study’s protocol-defined level of significance for final PFS (two-side adjusted alpha level of 0.1999).
An independent data review recorded a median PFS of 8.2 months for olaratumab and 4.4 months for doxorubicin alone (HR = 0.67; 95% CI, 0.04-1.12).
Combined olaratumab and doxorubicin conferred an 11.8-month improvement in OS compared with doxorubicin alone (26.5 months vs. 14.7 months; stratified HR = 0.46; 95% CI, 0.3-0.71).
ORR was 18.2% (95% CI, 9.8-29.6) with the combination vs. 11.9% (95% CI, 5.3-22.2) for doxorubicin alone.
A pharmacokinetics analysis showed that steady state olaratumab serum concentrations were reached during the third treatment cycle. Mean maximum concentrations ranged from 419 g/mL (geometric coefficient of variation in percentage [CV%], 26.2) to 487 g/mL (CV%, 33). Mean trough concentrations ranged from 123 g/mL (CV%, 31.2) to 156 g/mL (CV%, 38).
Thirty-one patients in the combination arm and 17 patients in the doxorubicin arm completed all eight cycles. Progressive disease served as the most common reason for treatment discontinuation in the combination (n = 8) and doxorubicin (n = 12) arms.
Common any-grade adverse events in the combination and doxorubicin-alone arms included nausea (73% vs. 52%), fatigue (69% vs. 69%), neutropenia (58% vs. 35%), mucositis (53% vs. 35%), vomiting (45% vs. 18%) and diarrhea (34% vs. 23%). Both groups had similar rates of any-grade (13% vs. 14%) and grade 3 (11% vs. 14%) febrile neutropenia.
Thirty-nine deaths occurred in the combination group and 51 deaths occurred in the doxorubicin group. Disease progression served as the most common cause of death in both groups (olaratumab, n = 38; doxorubicin, n = 44).
One patient in each group died of an unknown cause. Six patients in the doxorubicin group died of adverse events, including aspirational pneumonia, respiratory failure, sepsis, septic shock and small bowel obstruction.
Olaratumab has been granted priority review, breakthrough therapy and orphan drug designation by the FDA. ANNOUNCE, a double blind, placebo-controlled phase 3 study, is underway at Memorial Sloan Kettering.
“The phase 3 investigation needs to validate these results,” Tap said. “We have also powered the next phase of the study to look at specific subtypes, particularly leiomyosarcoma, and to allow for clinical and laboratory research programs to observe what PDGFR alpha does in sarcoma and the tumor microenvironment. In rare diseases, we really need to be able to get that snippet of information that allows us to delve deeper into the biology, and I hope that this study represents that.”
Questions regarding time to progression continue to persist despite survival gains, Winette T.A. van der Graaf, MD, PhD, professor of personalized oncology and team leader in clinical and translational sarcoma research, wrote in an accompanying editorial.
“The difference in OS of almost a year, which is far beyond the gain in PFS of 2.5 months, is as much promising as puzzling,” van der Graaf wrote. “Histologies seem to be reasonably balanced between the groups, with leiomyosarcomas as the largest group. The exact effect of various post-study treatments, including local treatments, is not easy to interpret. Differences in pace of progression before start of treatment might have affected the results because no specific time period in which progression should have occurred before patients entered the study was defined and only the group with shorter history of disease showed a significant increase in OS.
“In view of the desperate need of patients with soft tissue sarcomas for new active drugs, the findings of Tap and colleagues are promising but need confirmation in a larger study,” van der Graaf continued. “The results of ANNOUNCE are eagerly awaited, alongside a better understanding of the mode of action of olaratumab and a biomarker related to PDGFR alpha for optimum patient selection.” – by Cameron Kelsall
For more information:
William D. Tap, MD, can be reached at tapw@mskcc.org.
Disclosure: Eli Lilly provided funding for this study. Tap reports personal fees from Advaxis, Ariad, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, EMD Serono, Morphotek and Plexxikon. Please see the full study for a list of all other researchers’ relevant financial disclosures. Van der Graaf reports personal fees from Eli Lilly and research grants from GlaxoSmithKline and Novartis.