Novel Drug 'Remarkable' in Tenosynovial Giant Cell Tumor

Zosia Chustecka

July 30, 2015

An investigational drug, PLX3397 (Plexxikon, Daiichi Sankyo), has shown prolonged tumor regression in patients with tenosynovial giant cell tumor (TGCT), a rare disorder of the joints that leaves patients disabled and in pain. It is usually treated with surgery, but new results from a phase 1 trial show that some patients have a remarkable improvement on the drug and may be able to avoid morbid surgery, including joint replacement.

The findings, from a phase 1 trial in 23 patients, were published in the July 30 issue of the New England Journal of Medicine.

A phase 3 study has already begun.

"TGCT can be a very difficult disease to manage, with treatment options largely limited to surgery to remove as much of the tumor as possible. Despite the best surgical intervention, recurrence of diffuse TGCT is high and the disease may advance to the point where surgery is no longer an option," said lead author William Tap, MD, chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center in New York City.

The new drug was investigated because it targets colony-stimulating factor-1 receptor (CSF-1R), which is a primary growth driver of abnormal cells in the synovium that causes TGCT.

"These preliminary results demonstrate that by targeting CSF-1R, PLX3397 may inhibit tumor growth in some patients with TGCT, potentially offering those patients an alternative nonsurgical treatment option," Dr Tap said.

Patients Are Disabled and in Pain

"Unlike most of the other disease I treat, this is not a malignancy per se, in that patients' lives are not being imminently threatened," Dr Tap commented in an interview. "But it can have a big effect on quality of life and on the trajectory of someone's life," he said, where the disease leaves them disabled, unable to work, and on narcotics for the pain.

TGCT is a rare disorder, with an estimated annual incidence of 11 cases per million, and diagnosed commonly in adults between 20 and 50 years old. The tumors grow in joints, but can also spread to tendon sheaths and damage muscle and bone. The usual treatment is surgery, and this can be extensive, involving joint replacement and sometimes even amputation.

TCGT patients are often treated within the orthopedic community, and they undergo multiple surgeries, Dr Tap explained, and only when the disease is very advanced do they tend to be sent over to medical oncologists and specialists centers. The surgeons get very frustrated with this disease, because it can be exceeding diffuse, affecting both anterior and posterior portions of the joint, and even after surgery, there is a 40% to 60% risk of recurrence in the same location, Dr Tap said.

As specific and potent drugs become available, management of this disease may change, he speculated. In the phase 1 trial of PLX3397, "we saw patients who were very symptomatic often show a remarkable improvement in symptoms very rapidly," Dr Tap said, adding that in some patients, "these tumors seem to melt away." But there are still many questions, he added: How long does the drug need to be taken for, can it lead to a cure of the disease, could drug therapy replace surgery, or would it be used as an adjunct to surgery? The current trials are being conducted in patients with advanced disease, who are facing morbid surgeries, but there may be a place for these drugs much earlier in the course of the disease. "We need to figure all this out," Dr Tap said.

Door Opened to Drug Applications

Dr Tap told Medscape Medical News that the seminal discovery that opened the door for drug application in this rare disorder was understanding that overexpression of CSF is a driver of the disease. The factor is overexpressed and released by the neoplastic cells, which interestingly make up only a minor part of the tumor, he noted. The released CSF then recruits osteoclast, giant cells, and macrophages into the joint, resulting in damage.

The discovery that CSF was involved in this disorder was made in the mid-2000s, and at the time the only drugs available that could be used to block it were imatinib (Gleevec, Novartis) and related agents, Dr Tap said. The first report of benefit came in a 2008 case report that detailed a complete response to imatinib (Ann Oncol. 2008;19:821-822). Other centers then tried the drug, and in 2011, a retrospective review of 29 cases showed benefit from imatinib, suggested a response rate of around 19%, and also reported that many patients showed prolonged stable disease (Cancer. 2012;118:1649-1655). More recently, there has also been a report of benefit with the similar agent, nilotinib (Tasigna, Novartis). "That was really proof of principle that these drug can work," Dr Tap commented.

The next step was development of drugs with greater selectivity and potency, and one of these is PLX3397, an oral drug specifically targets CSF-1R. The results from the phase 1 trial now reported suggest that it has an overall response rate of 52%, so it appears to be more potent than imatinib in patients with TGCT, Dr Tap commented.

There is another highly specific and potent drug under development — Roche antibody emactuzumab (RG7155) — an antibody to CSF-1R, administered by infusion, for which phase 1 study results have just been reported (Lancet Oncol. 2015;16:949-956).

Approached for comment, Jean-Yves Blay, MD, from the Department of Medicine, Centre Léon Bérard, Lyon, France, who was involved in the trial with emactuzumab, and also was the first to report benefit in these patients with imatinib, indicated that these are very interesting times in TGCT. He is now involved in the phase 3 trial with PLX3397, and said that how these drugs compare with one another in terms of potency and benefit will "be clearer after the forthcoming trials."

Details From the PLX3397 Study

In the NEJM paper, Dr Tap and colleagues report safety findings from a phase 1 dose-escalation study conducted in 41 patients, which led to the dose of 1000 mg per day being chosen.

This dose was then used in a phase 1 extension cohort conducted in an additional 23 patients, who remained on treatment until disease progression or drug intolerance. Most of these patients had disease in their knee: one had metastatic disease, 18 had undergone previous surgery, and four had received prior treatment with imatinib or nilotinib.

The most common adverse events reported by patients on PLX3397 included fatigue, change in hair color, nausea, dysgeusia (abnormal taste), and periorbital edema, but adverse events rarely led to discontinuation of treatment, the researchers note.

Efficacy was assessed by MRI at baseline and every 2 months, utilizing both RECIST 1.1 criteria and tumor volume score (TVS), a novel scoring method developed specifically for TGCT by the study authors.

The MRI RECIST 1.1 results showed a partial response in 12 of the 23 patients and stable disease in seven patients, giving an overall response rate of 52% and a disease control rate of 83%. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months, the authors report.

TVS analysis was available for 14 patients who had a baseline and at least one postbaseline MRI. (The other patients had MRI of inadequate quality, or had already had a joint replacement which didn't allow the TVS to be measured, Dr Tap explained.) By MRI TVS response assessment, 11 of 14 patients achieved a partial response (79%) and an additional three patients had stable disease, providing a disease control rate of 100%. As with the RECIST assessment, patients generally experienced a large decrease in tumor burden by TVS within the first 4 months that persisted over time. Mean TVS reduction was 61%, the authors report.

Dr Tap said that the development of the novel TVS (which was spearheaded by musculoskeletal radiologist Charles Peterfy) allows for more accurate measurement of benefit than the conventional method. The new scoring system will now be validated in the phase 3 trial, he added.

The phase 3 trial, known as ENLIVEN (NCT02371369), is currently enrolling patients with symptomatic TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity, the manufacturer noted. It aims to enroll 126 patients in Australia, Canada, the European Union, and the United States.

One focus in the phase 3 trial will be to measure the effect that the drug has on quality of life, and to this end, detailed patient questionnaires have been designed. There are already anecdotal data to show a large benefit; one patient in the phase 1 trial that was highlighted in the NEJM supplementary material was able to return to work, Dr Tap commented, but "'we now need to quantify this benefit."

PLX3397 has been granted Orphan Drug Designation in the United States and in the European Union for the treatment of TGCT.

The drug is also being investigated in the treatment of glioblastoma, melanoma, and breast cancer, as well as in combination with the anti-PD-1 therapy pembrolizumab (Keytruda, Merck & Co.) for advanced melanoma and other multiple solid tumors.

The studies were funded by Plexxikon.

N Eng J Med. 2015;373:428-437. Abstract


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