In Early Trial, Targeted Therapy Fights Advanced Melanoma

By probing deeper into the biological mechanisms that go awry in melanoma, scientists have come up with an experimental drug that has had an effect in a surprising number of patients with advanced melanoma.

The drug, PLX4032, just completed a phase 1 clinical trial in which 81 percent of participants with a particular gene mutation had a partial response, meaning at least some shrinkage of the tumor.

The current standard treatments for metastatic melanoma -- chemotherapy and interleukin-2 (IL2) -- only have response rates in about 15 percent of these patients, said Dr. Paul Chapman, senior author of a study in which the findings are described.

The average survival time for someone diagnosed with melanoma is nine to 11 months, added Chapman, who is an attending physician in the Melanoma Sarcoma Service at Memorial Sloan-Kettering Cancer Center in New York City.

One expert cautioned that it's too early to say whether the drug will actually prolong patient's lives, or if it might be helpful to patients in earlier stages of the disease.

"I don't want to say this is going to change survival rates but they're working with the most ill people, so you can't really generalize [to other patient populations]," said Dr. Alice Pentland, chair of dermatology at the University of Rochester Medical Center. "I think the most important part of this breakthrough is the bigger percentage of people who responded."

The study, which is published in the Aug. 26 issue of the New England Journal of Medicine, was funded by drug makers Plexxikon and Roche Pharmaceuticals.

About nine years ago, scientists discovered that the tumors of about half of patients with melanoma have a mutation in a gene called BRAF.

The gene appears to help drive the runaway cell division that is a hallmark of cancer. "It's always on. It's always signaling to the nucleus [of the tumor cells] that it's time to divide," Chapman explained.

That finding opened the door to potential targeted, molecular therapies for melanoma, which has been sorely lacking in effective treatments.

PLX4032 is the first potent inhibitor of BRAF that has made it to the clinical trial stage, Chapman said.

In the trial, 55 patients received escalating doses of the drug. Ten of 16 patients who had the BRAF gene mutation had a partial response to the drug, meaning the tumor shrank by at least 30 percent, while one had a complete response, with the tumor disappearing altogether.

Among 32 patients with BRAF-mutated melanoma in the second phase of the study, 24 had a partial response and two had a complete response.

"It worked: 81 percent had a partial response -- which has never been seen. I don't know of any solid tumors that have a response rate that high," said Chapman. "What's different here is that we've discovered a molecule that is responsible for driving the melanoma cell. It turns out that the melanoma really cares if we block the gene BRAF. It matters. It's addicted to this pathway."

There are some important caveats, however. It's not known at this time if the drug can improve overall survival, and a sizable proportion of participants developed resistance to the drug, the researchers say.

The findings join other recent reports of potential treatments for melanoma in what appears to be an exciting time for the field. Progress in this field has essentially been stalled for decades, experts say.

Recently, scientists reported that another experimental drug, ipilimumab, prolonged median survival in patients with metastatic melanoma from 6.4 months to 10 months.

"[Existing therapy] is not good for melanoma, so this is really a new opportunity that I think may have some importance to people," Pentland said.

However, she stressed that the best defense against melanoma is to get your skin examined regularly by a professional who knows what to look for.

"Our most successful treatment is to get [the lesion] early, get it before it's thick, get it before it spreads," she said.

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Tumors Deficient In A Specific Enzyme Are Sensitive To A New Drug 'Adi-Peg 20'

Polaris Group scientists and university collaborators reported at the American Association for Cancer Research (AACR), that a number of different cancers have a deficiency in a specific enzyme, argininosuccinate synthetase (ASS), which allows pegylated arginine deiminase (ADI-PEG 20) to inhibit cancer cell growth.

"Polaris has been testing this drug in melanoma patients and patients with hepatocellular carcinoma (HCC), two tumors that are ASS deficient, and we are preparing to initiate a global phase 3 clinical trial in HCC to seek regulatory approval for marketing ADI-PEG 20," said Dr. Bor-Wen Wu, CEO of Polaris. "In addition, these new results show that ADI-PEG 20 may be beneficial in a number of other tumors."

ASS is required for the production of arginine, an amino acid needed for growth and replication of cells. Normal tissue cells have normal levels of ASS and can produce sufficient arginine for their own growth and survival in the presence of ADI-PEG 20. However, growth and replication of ASS-deficient tumor cells is inhibited by ADI-PEG 20 because arginine in these cells is degraded and depleted. The studies presented at AACR have shown that various other tumors also have a deficiency in ASS. He et al, Polaris Group, reported that 30-60% of human breast, lung and gastric cancers were deficient in ASS. Treatment of these and other tumor types in cell culture, including sarcoma, leukemia and plasmacytoma, showed significant inhibition of cell growth by ADI-PEG 20. He et al also established primary renal cell carcinoma cultures from fresh human tumor biopsies which were ASS-deficient. ADI-PEG 20 inhibited growth of these cells. These findings suggest that ASS deficiency may serve as a biomarker for selecting tumors for targeted therapy with ADI-PEG 20.

Rubin et al, Cleveland Clinic, showed that 88% of 45 different human sarcomas were ASS-deficient. Treatment of two sarcomas, gastrointestinal stromal tumor (GIST) and malignant peripheral nerve sheath tumor (MPNST) with ADI-PEG 20 resulted in inhibition of proliferation.

Based on analysis by Jungbluth and collaborators, Ludwig Institute for Cancer Research New York Branch at Memorial Sloan-Kettering Cancer Center, demonstrating that ~50% of human small cell lung cancer (SCLC) tumor specimens were ASS-deficient, Kelly et al, showed that growth of ASS negative cell lines was inhibited by ADI-PEG 20 in cell culture. They further showed that ADI-PEG 20 treatment of mice bearing ASS-deficient SCLC xenograft tumors caused significant and dose dependent inhibition of tumor growth in the animals.

It has been well established that treatment of human cancer with two or more drug combinations can be much more effective than the individual drugs administered alone. Two reports provided evidence that ADI-PEG 20 plus cisplatin treatment in cell cultures of ASS-deficient malignant pleural mesothelioma (Szlosarek et al, Barts Cancer Research UK Centre) and melanoma (Feun et al, University of Miami) resulted in synergistic cytotoxic effects on the cancer cells compared to either agent alone. Additional evidence of inhibition of pancreatic xenograft tumors was presented by Bold et al, University of California at Davis. Mice bearing ASS-deficient human pancreatic tumors were treated with ADI-PEG 20 plus gemcitabine and showed that the two drugs in combination inhibited tumor growth much more effectively that either drug alone.

Based on these and other findings, ADI-PEG 20 clinical trials are planned to begin in the near future for treatment of patients with malignant mesothelioma, SCLC, sarcoma, leukemia or pancreatic cancer.

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New Drug in Phase 1 Trial Shows Objective Responses in Metastatic Melanoma Patients

A new drug which targets a genetic mutation found in 50 percent to 60 percent of melanoma cases, 10 percent to 15 percent of colorectal tumors and 8 percent of other solid tumors, caused tumor shrinkage and extended progression-free survival among patients during a Phase 1 clinical trial. Igor Puzanov, M.D., assistant professor of Medicine, and Jeffrey A. Sosman, M.D., professor of Medicine and Ingram Professor of Cancer Research, led Vanderbilt-Ingram Cancer Center’s participation in the multi-center study. Puzanov delivered the initial findings from the study during a poster session May 31 at the American Society of Clinical Oncology conference in Orlando, Fla.

PLX4032 is a novel, oral and highly selective drug that targets the BRAFV600E cancer-causing genetic mutation which occurs in more than one-half of melanomas and subgroups of other solid tumors, including colorectal, thyroid and other cancers. In addition to tumor shrinkage and delay in tumor progression, some patients reported clinical improvement in symptoms.

PLX4032 is being developed by Plexxikon, Berkeley, Calif., and Roche, headquartered in Basel, Switzerland.

“The BRAFV600E mutation activates the MAP kinase signaling pathway, causing cells to proliferate. One of the hallmarks of cancer is this uncontrolled, unregulated cell proliferation,” said Puzanov. “The new drug is a very selective inhibitor which appears to target only this mutation, and it blocks the unregulated cell growth and causes cell death. We saw tumor responses and symptom improvement in less than a week in some cases.”

In the dose escalation phase of the study, 55 cancer patients were treated, including 24 mutation-positive melanoma patients and three mutation-positive thyroid cancer patients. An additional 28 melanoma, rectal and ovarian cancer patients, who did not have the mutation or whose mutation status was unknown, also have been treated.

In 16 BRAF mutation-positive melanoma patients treated with PLX4032 at doses of 240 mg or above twice daily (BID).
• PLX4032 was well tolerated at very high doses, with 960 mg (BID) under evaluation as the maximum tolerated dose
• Objective partial responses in nine patients by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with seven confirmed on repeat scans
• Regression of metastatic lesions in every site in which melanoma commonly spreads, including liver, lung and bone
• Minor responses in four patients showing tumor regression less than that required to meet RECIST criteria for an objective response
• Disease control lasting up to 14 months with continuous therapy, with many patients still receiving treatment
• Interim median progression-free survival of at least six months, with many responding patients still receiving treatment

In patients without the mutation, no clinical response to treatment was observed and progression-free survival was less than two months, consistent with historical data. Side effects included rash, photosensitivity, fatigue and joint pain and were more evident at higher doses. In addition, some patients developed squamous cell skin cancers, easily removed by their dermatologist.

“This is personalized medicine at its best,” said Jeffrey Sosman. “If continued trials confirm the agent works only in patients with this mutation, we can target those patients for this drug and spare other patients from undergoing a treatment that won’t work. It is very exciting to have a drug that may be effective for metastatic melanoma because these patients have few treatment options, with a median survival of less than a year.”

The research group was led by Keith T. Flaherty, principal investigator, assistant professor of Medicine, University of Pennsylvania, Philadelphia, and Paul B. Chapman, Memorial Sloan-Kettering Cancer Center, New York City. Other investigators included Antoni Ribas, University of California, Los Angeles, Kevin B. Kim, M.D. Anderson Cancer Center, Houston, Grant A. McArthur, Peter MacCallum Cancer Centre, Melbourne, Australia, Kate L. Nathanson and George Xu, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Joe F. Grippo and Richard Lee, Hoffmann-La Roche, Nutley, N.J., Keith Nollop, Gideon Bollag and Peter Hirth, Plexxikon, Berkeley, Calif.

“We know this drug causes tumor shrinkage in patients with melanomas harboring the target mutation, we know it works quickly, and we know it helps patients who are terribly symptomatic,” said Puzanov. “We do not know enough about its duration of effect on tumors and whether it can improve overall survival. We hope to try to improve its effects by combining it with other drugs, including other targeted agents. We will be working with the drug developers as well as our partner investigators to answer those questions.”

Two extension studies with the drug are being conducted in mutation-positive melanoma and colorectal cancer patients and plans are in place to start Phase II and Phase III clinical trials.

The Vanderbilt-Ingram Cancer Center is a National Cancer Institute Comprehensive Cancer Center, one of two centers in Tennessee and 40 in the country to earn this highest distinction. Its nearly 300 faculty members generate more than $140 million in annual federal research funding, ranking it among the top 10 centers in the country in competitive grant support, and its clinical program sees approximately 4,000 new cancer patients each year. Vanderbilt-Ingram, based in Nashville, Tenn., recently joined with 21 of the world’s leading centers in the National Comprehensive Cancer Network, a non-profit alliance dedicated to improving cancer care for patients everywhere.

Source : www.mc.vanderbilt.edu

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Help For Deadly Melanoma?

A small clinical trial of an experimental drug has even battle-hardened melanoma experts excited.

Almost nothing works against melanoma once it spreads beyond the skin. Chemotherapy and other treatments only shrink tumors in 10 to 15 percent of cases.

Numerous experimental drugs have bombed in trials, including drugs from Synta Pharmaceuticals and Pfizer .

That is why melanoma doctors at a meeting of the American Society of Clinical Oncology in Orlando, Fla., are buzzing about a preliminary trial of a new drug from Roche and privately-held Plexxikon that targets a crucial gene mutation found in about half of melanomas.

In the trial, which included 55 patients, tumors dramatically shrank in 9 of 16 very advanced patients with the gene mutation who got high doses--a better response rate than doctors have remembered seeing in a trial for advanced melanoma. Patients in the trial so far lived about six months without their tumors progressing, versus two months typically seen for such patients.

"It is what we have been waiting for to see in melanoma for years," says University of California, Los Angeles, melanoma expert Antoni Ribas, who is involved in the trial. He calls the response rates "unprecedented." University of Pennsylvania melanoma expert Keith Flaherty, who led the trial, said the high rate of responses is somewhat reminiscent of the first trials of Gleevec, Novartis' breakthrough leukemia drug. "The excitement level is very high," he says. One melanoma patient who had tumors clogging her lungs was able to go off oxygen within weeks of starting on the drug.

Only far larger trials will reveal whether the drug actually helps patients live longer. Melanoma is a far more aggressive disease than leukemia, and some of the patients have already relapsed after just a few months. Still, doctors are hopeful that the drug may help a larger percentage of patients live with their disease for longer than is possible today. Advanced melanoma grows like wildfire and typically kills patients within a year.

The drug is an early example of a wave of super-targeted cancer drugs winding their way through early human trials. The new drugs target very specific subsets of patients with the disease and will come with gene tests to pluck out which patients are likely to respond.

Source : www.forbes.com

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