The following article features coverage from the American Society of Clinical Oncology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Despite the existence of 50 to 80 different subtypes of sarcoma, there is only one drug that has been recognized as the gold standard: doxorubicin. Doxorubicin alone or in combination has been the go-to treatment for all sarcoma types since the mid-1970s.

For patients with sarcoma who have metastatic disease, median survival is approximately 14 to 19 months, and 2-year survival rates are 20% to 30%. These dismal statistics shed light on the intense interest in bringing a new and efficacious treatment solution to the market — and they also help, in part, to explain why there was great anticipation surrounding the launch of olaratumab.

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Olaratumab was granted accelerated approval in 2016 by the US Food and Drug Administration following the release of results from a phase 1b/2 study in advanced or metastatic soft tissue sarcoma that found strong antitumor activity in patients.

Then, during 2017 to 2018, the drug was awarded additional accelerated, conditional, and full approvals in more than 40 countries worldwide.

The accelerated approval status was somewhat of a shaky win, however — olaratumab was allowed on this high-speed regulatory journey only if the manufacturer could authorize the drug’s benefits in confirmatory trials.

ANNOUNCE (ClinicalTrials.gov Identifier: NCT02451943), a randomized, double-blind, placebo-controlled phase 3 study, represented the researchers’ efforts to validate their study conduct and to check the integrity of the data they collected from earlier trials. The primary objective of the study was to show an improvement in overall survival by intention to treat (ITT) in the leiomyosarcoma population, in the liposarcoma patients, or in both cohorts. Key secondary end points of the study were PFS, overall response rate, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity.

William D. Tap, chief, sarcoma medical oncology service, Memorial Sloan Kettering Cancer Center in New York, New York, and the investigator who led the ANNOUNCE trial said that the survival results that were seen in that phase 1b/2 trial “were highly scrutinized,” — and while it was good news that the drug was responsible for a significant improvement in overall survival, critics questioned why it did not also improve PFS measures to a higher degree. Dr Tap noted that the confounders from the trial were (and still are) being rigorously debated among experts.

During a plenary presentation at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr Tap reported that in the intention to treat (ITT) populations, “ANNOUNCE showed no differences between overall survival in the total soft tissue sarcoma population or in the Leio subpopulation.”

Researchers are still trying to make sense of ANNOUNCE’s outcomes and the differences seen between the 2 studies. Dr Tap noted that the phase 1b/2 and phase 3 trials had notable study design differences, and also admitted that “it is possible that olaratumab has no activity in soft tissue sarcomas” and that the results seen in phase 1b/2 could be due to a variety of factors, such as the study’s small, open-label design, the fact that numerous histologies were present, the fact that it was a United States-centric study, because it did not include a placebo, and, perhaps, just “by chance.”

“Olaratumab gained wide usage and acceptance, but not unconditionally” Dr Tap said. This suggests that the effect of its approval — and its subsequent withdrawal from the market — could have a lingering effect, even though the drug alone did not cause direct harm to patients.

These effects have already been extremely costly. In a discussion after Dr Tap’s talk, Jaap Verweij, MD, PhD, Erasmus University Medical Center in The Netherlands, reported that sales of the drug in the third quarter of 2018 were in the hundreds of millions; Dr Verweij estimated olaratumab’s total financial burden to society was $1 billion dollars — all “for a drug without evidence of efficacy.”

Lilly recently provided feedback on this plenary presentation and discussion. “In relation to the sales numbers given by Dr Verweij, I would like to provide clarity: the total Lartruvo worldwide sales through the first quarter of 2019 were $562M,” Anne White, president of Lilly Oncology, wrote to Cancer Therapy Advisor. “Lilly believes that the accelerated approval process is an important program that allows patients earlier access to potentially life-saving medicines when there is a serious need. Advanced soft tissue sarcoma is a rare and difficult-to-treat cancer. We pursued bringing Lartruvo to market knowing that the sarcoma community hadn’t seen progress in more than 40 years. While only a portion of indications under the FDA’s Accelerated Approval program fail to verify clinical benefit, it shows that the checks and balances of the clinical trial process works.”

Despite the disappointment following the announcement that olaratumab had no clinical benefit in soft tissue sarcoma, that it would no longer be prescribed to new patients, and that the withdrawal of olaratumab was in progress, there may be a silver lining: the docetaxel alone arm used as a control in ANNOUNCE “had the highest OS for dox in any randomized soft tissue sarcoma trial,” according to Dr Tap.

Dr Verweij concluded that the best approach to developing new therapies for sarcoma, then, may include the avoidance of grouping together divergent histologies in sarcoma clinical trials, developing a biomarker-driven approach to treatment, and/or tweaking the current model of accelerated approval.

Update: This article was updated to include comments from Lilly.

Read more of Cancer Therapy Advisor‘s coverage of ASCO’s annual meeting by visiting the conference page.

Reference

  1. Tap WD, Wagner AJ, Papai Z, et al. ANNOUNCE: A randomized, placebo (PBO)-controlled, double blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS). Presented at: 2019 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4; Chicago, IL. Abstract LBA3.