Wednesday, January 30, 2019

The failure of olaratumab

By Suzie Siegel

Sarcoma specialists and patients are struggling to make sense of the failure of olaratumab (Lartruvo) in a phase 3 clinical trial.

Dr. Breelyn Wilky
“Like all sarcoma trials, there are very likely patients who individually had benefit with olaratumab, that we can't account for or identify in a large trial where everyone is averaged together,” said Dr. Breelyn Wilky of the University of Colorado in Aurora. “The problem is that we don't understand enough about olaratumab, how it works, or what the targets are, to try to pick out those patients.

“What we learned is that at least for now, the collective benefit across all sarcoma patients is not enough to recommend … adding it to doxorubicin. If a patient is currently on olaratumab with or without another drug and is having benefit, at least the early statements from Lilly are that they will continue to allow that patient to continue with olaratumab. But new patients will not and should not be started on olaratumab.”

Doxorubicin, an old drug also known as adriamycin, is often the first chemotherapy offered to patients whose sarcomas have spread. It’s considered a “first-line” or "frontline" drug. A phase 2 trial compared doxorubicin by itself to dox combined with olaratumab. It found the combination helped sarcoma patients live longer.

The FDA gave “accelerated approval” to olaratumab, allowing it to be prescribed even to patients who were not enrolled in the phase 3 clinical trial. This was the first time in decades that the FDA had approved a new first-line drug for a wide range of sarcoma subtypes.

I think most sarcoma doctors expected the phase 3 clinical trial to confirm the results of the phase 2 trial. But Lilly, the maker of the drug, announced Jan. 18 that the phase 3 trial could not confirm that olaratumab helped patients live longer. Sarcoma specialists on Twitter expressed shock and dismay.

“Sarcoma docs all depressed today,” tweeted Dr. Melissa Burgess of the University of Pittsburgh.

Dr. Brian Van Tine
“I am a sarcoma doctor,” tweeted Dr. Brian Van Tine of Washington University in St. Louis. “I was one yesterday and will be one tomorrow. I will not let the setbacks of today prevent me from trying to change the outcomes for my patients. Clinical trials are the only way things will ever change.”

Dr. Seth Pollack of the University of Washington in Seattle asked: “Do you think this could scare off companies thinking of developing their drugs [in] sarcoma?”

Dr. Sam Blackman, a pediatric oncologist involved in drug development, replied: “Not any company I work for.”

Critics said the FDA shouldn’t have given accelerated approval to olaratumab. But Dr. George Demetri of Dana-Farber Cancer Institute in Boston praised the FDA for taking a gamble on a drug that seemed to have so much promise.

“In brief, the classic adage ‘hindsight is 20/20’ applies, and we are all sad for the patients and families who depend on us all to make things better,” he tweeted.

Dr. Winette van der Graaf
This isn’t the first sarcoma drug to fail in a phase 3 trial after looking good in an earlier one, noted Dr. Winette van der Graaf of the Royal Marsden Hospital in London and the Netherlands Cancer Institute in Amsterdam. This also happened to palifosfamide and evofosfamide.

“The biology behind the benefit of [olaratumab] in the randomised phase 2 [trial] was difficult to understand and we had already concerns,” she tweeted. The FDA can approve drugs that work even if no one knows exactly why. An example is trabectedin (Yondelis).

Discussing olaratumab, Dr. Demetri tweeted: “There was always a red flag about the phase 2 data. Why no big PFS benefit with putative huge OS benefit?”

Progression-free survival (PFS) refers to how long patients can live without their cancer growing. Overall survival (OS) is how long they live, whether or not they’re still dealing with disease.

The FDA has approved drugs, such as trabectedin, on the basis of PFS. The goal (“endpoint”) of the olaratumab trial was OS. Overall survival sounds like the best goal — we all want cancer drugs that will help us live longer! But the problem of using that as the goal in clinical trials is that there may be other reasons someone lived longer than another person. Some of the most obvious reasons include being insured and in good health otherwise.

Dr. Cesar Serrano Garcia
“OS is a challenging endpoint,” tweeted Dr. Cesar Serrano Garcia of Vall d’Hebron Barcelona Hospital. The impact of the micro-environment of the soft-tissue sarcoma and immunology “are not yet completely understood and might be fooled by the intrinsic complexity of STS and its management.”

Dr. Patrick Schoffski of University Hospitals Leuven in Belgium noted that overall survival for people treated with doxorubicin continues to climb as patients get better care from multidisciplinary sarcoma doctors. This makes it harder for new drugs to compete against it.

The olaratumab trial had two “arms”: Patients in one arm got doxorubicin + olaratumab. Patients in the other arm got doxorubicin by itself. Doctors didn’t decide which patients got which. Patients were assigned randomly. This randomization is supposed to make both arms equal, instead of one arm full of people who have a better chance of survival. But sarcoma clinical trials can’t enroll as many patients as the more common cancers, and thus, we have fewer unique individuals to randomize.

Because sarcoma is rare, clinical trials often lump together people with different subtypes, instead of splitting them up into separate trials.

“We need more splitting rather than lumping in clinical trials. [It’s] too difficult to predict and statistically account for behavior of 50+ sarcoma subtypes,” said Dr. Victor Villalobos of the University of Colorado Cancer Center.

Dr. Anthony Conley of MD Anderson Cancer Center in Houston tweeted: “A review of all prior frontline trials in metastatic soft tissue sarcoma should occur to determine causes of these problems. I agree that splitting, rather than lumping, may be necessary moving forward and we should critically appraise endpoints and response tools.”

Dr. Tom Wei-Wu Chen
The olaratumab trial did this, but it also kept track of data on leiomyosarcoma, which was expected to respond better than other subtypes. But Dr. Tom Wei-Wu Chen of the National Taiwan University Hospital and Cancer Center noted that even leiomyosarcoma can be broken into subtypes.

Dr. Demetri suggested we just need better drugs. “After all, olaratumab did not fail simply because of sarcoma disease heterogeneity — it failed even in the single subtype of leiomyosarcoma. Complete fail.”

A challenge will be asking drug companies and the National Cancer Institute to fund clinical trials with smaller subsets of sarcoma patients, Dr. Wilky tweeted. She said we need more biomarkers and more evidence of how a drug works before a clinical trial begins.

Dr. Bill Tap of Memorial Sloan-Kettering in New York was the principal investigator of the olaratumab trial. He and Lilly representatives are expected to discuss the data at the annual meeting of the American Society of Clinical Oncology in June.

Ironically, this will probably be the most important sarcoma data presented at the meeting, Dr. Wilky tweeted.

“Do you think it will amount to a ‘shoulder shrug’ or will we … really learn something that moves the field forward, maybe even helps future studies?” asked Dr. Pollack.

“I hope [there] was enough data captured during the course of this trial for a proper ‘post-mortem’,” tweeted Dr. Herbert Loong of the Chinese University in Hong Kong. “We owe this to all [patients] who have been on trial and countless more who are on it commercially. It's important to establish whether or not it's a failure in trial design vs. drug itself.”

Despite this setback, a number of experimental drugs remain in the pipeline. Doctors are also using drugs developed for other cancers to target sarcomas with similar gene mutations and fusions.