Tuesday, October 27, 2015

After Yondelis, which drugs may get OK'ed next?

By Suzie Siegel

Many of us have waited years for the FDA to approve trabectedin (Yondelis) for soft-tissue sarcoma.

Dr. Gina D'Amato
“I was ready to march on Washington if it didn't get approved!” Dr. Gina D’Amato said Friday, after the FDA approved trabectedin for patients with liposarcoma and leiomyosarcoma who have already tried an anthracycline, such as doxorubicin, but have an inoperable tumor or one that has spread. Dr. D’Amato, a board member of the Sarcoma Alliance, treats patients at Georgia Cancer Specialists in Atlanta.

For metastatic leiomyosarcoma, Atara Weinstein had three surgeries and more than 35 rounds of chemotherapy with six different drugs before starting a clinical trial for trabectedin in February.

“I have been fortunate that with Yondelis I've had some stability these past few months. And it will be easier, all round, to get the drug without the hassles and red tape of a clinical trial protocol,” she said. “Spiritually, getting this approved is a big affirmation to never give up hope.

“Until a cure is discovered, chemo can be a good way to stay ahead of the rampage, and even though side effects are definitely a consideration, they can absolutely be managed for quality of life.”

Because sarcomas are rare, they get less money for research, companies have less interest in investing in them, and enrolling enough patients in clinical trials is difficult.

The FDA has approved only six other chemotherapy drugs for soft-tissue sarcoma: Dactinomycin in 1964 for rhabdomyosarcoma, doxorubicin (Adriamycin) in 1973, imatinib (Gleevec) for gastrointestinal stromal tumor (GIST) in 2001, sunitinib (Sutent) for GIST in 2006, pazopanib (Votrient) in 2012 and regorafenib (Stivarga) for GIST in 2013. Doxorubicin and pazopanib are the only ones commonly used in different types of sarcoma.

Some drugs approved for other cancers also help sarcoma patients. Because the FDA hasn’t approved them for sarcoma, however, doctors give them “off-label.” Examples are ifosfamide (Ifex), dacarbazine (DTIC), gemcitabine (Gemzar) and docetaxel (Taxotere).

Dr. Breelyn Wilky
Some doctors may try trabectedin off-label for sarcoma subtypes other than the two for which it got approval. One problem with this practice is that a person’s insurance may not pay for an off-label drug, noted Dr. Breelyn Wilky, assistant professor in the sarcoma program at the Sylvester Comprehensive Cancer Center in Miami.

Scientists and physicians have been working on trabectedin for more than 15 years, back when it was called ET-743. It was approved in Europe in 2007 and is widely used there. U.S. sarcoma doctors have grumbled over the length of time it has taken for FDA approval. This year, a phase III trial confirmed that the drug can keep leiomyosarcoma and liposarcoma from growing and spreading longer than can dacarbazine. The trial couldn’t prove patients live longer on trabectedin, perhaps because of the trial design.

Clinical trials are broken into three phases. The latest trabectedin trial may have succeeded because it focused on the two types of sarcoma that have gotten the most benefit. In the past, the FDA has hesitated to approve drugs that couldn’t be proven to significantly extend patients’ lives. In 2012, however, it didn’t require that proof for pazopanib. It approved the drug for keeping patients stable longer – just like trabectedin.

Dr. Jonathan Trent, co-director of the Musculoskeletal Center at the Sylvester cancer center, said he wants to stress how effective trabectedin is. “We have had metastatic patients in regression for more than two years.”

Trabectedin was synthesized from a sea squirt. The next sarcoma drug that may win approval also comes from the ocean. Eribulin (Halaven) was derived from sea sponges. This month, the FDA gave it Priority Review status, which means the FDA is expected to make a decision within six months. In a phase III clinical trial, eribulin helped patients with liposarcoma and leiomyosarcoma live longer, compared with dacarbazine. The FDA has already approved eribulin for breast cancer.

The FDA has granted Fast Track status to evofosfamide, formerly called TH-302. This designation speeds up the review process, but not as quickly as Priority Review does. Results from phase III studies are expected this year.

There is hope evofosfamide will be safer than its older cousin, ifosfamide. Dr. Trent said ifosfamide can be more dangerous than some drugs because patients have to be monitored more closely, and some oncologists weren’t trained in sarcoma centers that used it regularly. He said he uses higher doses of ifosfamide than some other doctors because he knows how to monitor it.

With some chemos, more is better, he said. For example, the higher the dose of doxorubicin and ifosfamide, the higher the percentage of patients who benefit.

Results of a phase IIb study of aldoxorubicin were published last month, saying it kept sarcoma stable longer than its cousin, doxorubicin. Because of the danger of damaging the heart, patients are limited on how much doxorubicin they can receive. So far, patients have been getting much more aldoxorubicin without hurting their hearts. A phase III clinical trial is underway.

Dr. Daniel Rushing
In the past, a common chemo combination was dacarbazine, doxorubicin and ifosfamide. Use of dacarbazine peaked in 1993, said Dr. Daniel Rushing, professor of clinical medicine at Indiana University in Indianapolis. It fell out of favor because of nausea and vomiting, he said, but it has made a comeback in recent years as new drugs have better controlled the side effects.

Regorafenib is in a phase II clinical trial for liposarcoma and bone sarcomas. But Dr. Trent said it’s unclear whether it will be approved – the FDA has issued a black-box warning for its potential to damage the liver.

A phase II study of masitinib found it superior to sunitinib for GIST. “I think masitinib could be the next super-Gleevec,” Dr. Wilky said. Another phase II study is looking at the addition of MORAb-004 to gemcitabine + docetaxel.

A phase Ib/II trial this year found olaratumab helped sarcoma patients (a third had leiomyosarcoma) live longer when the drug was added to doxorubicin, as opposed to doxorubicin only. The FDA gave it Breakthrough Therapy Designation.

In phase Ib/II trials, TRC105 + pazopanib got complete remission for two patients with angiosarcoma.

Dr. Jonathan Trent
It’s too early to tell whether AG-120, in a phase I clinical trial for chondrosarcoma, will prove effective, Dr. Trent said. But he describes a patient whose cancer was growing before the trial and now has been stable for nine months. “Is that success? I think so.”

The FDA has approved pembrolizumab (Keytruda) and nivolumab (Opdivo) for other cancers, and they are now in phase II trials for sarcoma. A clinical trial of avelumab may open in 2017. These drugs are anti-PD1 antibodies, a form of immunotherapy. Immunotherapy drugs help the body recognize and attack cancer cells. Immunotherapy has gotten great acclaim.

“Research is exploding,” Dr. Wilky said, adding that alveolar soft-part, synovial and clear cell sarcomas may respond well. In general, however, she sees sarcoma doctors becoming less enthusiastic.

“One issue is that the sarcoma may be growing quickly while the immunotherapy takes longer to work. Another issue is getting the drug into tumors that no longer have a big blood supply. Side effects also can be very dangerous.

“Single-agent anti-PD1 is not going to be enough to cure people.” Immunotherapy will probably need to be combined with other drugs, Dr. Wilky said. Next year, she hopes to open a trial with pembrolizumab + axitinib, which is similar to pazopanib.

PD1 is a checkpoint that keeps the immune system from eating cancers. Ipilimumab (Yervoy) targets another checkpoint, CTLA-4, while palbociclib (Ibrance) inhibits CDK4 and CDK6. The FDA has approved both for other cancers. A phase II trial of palbociclib in liposarcoma had promising results, Dr. Wilky said. She also is interested in the phase I/II clinical trial for ipilimumab + nivolumab.

She recalls how clinical trials were once the last resort for patients. That’s no longer the case, she said, because doctors can better predict which patients will benefit from an experimental drug. “You should consider going on a clinical trial early in your treatment.”

I got a chance to talk to Drs. Wilky and Trent at a patient education conference last month at the Sylvester cancer center, co-sponsored by the Sarcoma Foundation of America. Dr. Trent said it was the first conference for sarcoma patients in South Florida.

For more information, check out Dr. Wilky’s blog post on clinical trials: http://breelynwilkymd.com/2015/10/17/clinical-trials-what-you-should-know-to-make-an-informed-choice-about-your-therapy/ The Sarcoma Alliance has a page on clinical trials: http://sarcomaalliance.org/what-you-need-to-know/clinical-trials/ The Sarcoma Alliance for Research through Collaboration lists its trials: http://sarctrials.org/sarc-clinical-trials And the Sarcoma Foundation of America can help you find a trial: http://www.curesarcoma.org/patient-resources/sarcoma-clinical-trials/

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