New Epigenetic Combo Shows Some Dramatic Responses in NSCLC

Zosia Chustecka

November 10, 2011

November 10, 2011 — An indirect attack, using epigenetic therapy, on gene aberrations that occur in cancer has shown success for the first time in solid tumors, and produced "some dramatic responses" in patients with advanced nonsmall-cell lung cancer (NSCLC).

The results from a trial of 46 NSCLC patients, published online November 9 in Cancer Discovery, were hailed by clinicians and scientists as "ground-breakthrough" during a media briefing hosted by the American Association for Cancer Research. Although they are impressive, the results need to be confirmed in larger studies, they all emphasized.

Epigenetic therapy, which disrupts proteins and modifications that determine whether a gene is turned on or off, is a new approach to the treatment of cancer. It is markedly different from targeted agents that home in on specific genetic mutations and from conventional chemotherapy. This trial used a combination of low-dose azacitidine and entinostat; the low doses were critical for the epigenetic mode of action, the researchers explain.

Azacitidine (Vidaza, Celgene) is approved for use in myelodysplastic syndrome, where it has been shown to improve survival; entinostat (under development by Syndax) is not yet being marketed.

The patients taking part in this study had advanced disease and had already tried a median of 3 therapies, so they had few therapeutic options remaining, said principal investigator Charles Rudin, MD, PhD, professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland. This was an open trial; all patients received azacitidine 9 days a month and entinostat 2 days a month.

"We saw rapid responses and some dramatic improvements," he said. Median overall survival was 6.4 months; typical survival in such patients is around 4 months. In a subgroup of 38 patients who underwent at least 1 full cycle of therapy, median overall survival was 8.6 months. There were also some very dramatic improvements in this subgroup, Dr. Rubin noted, and 2 patients are still alive 4 years after starting this trial.

One patient had a complete response that lasted 14 months, and another had a partial response that lasted 8 months. In 10 patients, disease stabilized for at least 12 weeks, but in one patient it stabilized for 18 months and in another it stabilized for 14 months, and both had prolonged symptomatic improvement.

This 2-drug combination showed very little toxicity, and patients reported a good quality of life, Dr. Rubin noted. One of the patients who had a dramatic response participated in the media briefing, and said that, compared with the adverse effects he experienced during chemotherapy, this combination was "a piece of cake." The most common adverse events were anemia, injection-site reactions, fatigue, nausea, vomiting, constipation, and anorexia.

There is evidence that epigenetic therapy caused changes that made the tumor cells more vulnerable to subsequent chemotherapy, Dr. Rubin added. After the study finished, 19 patients went on to subsequent systemic therapy, and 4 who received chemotherapy (21%) had major objective responses, he noted.

"This opens the door for a low-toxicity therapy that could be used alone or with subsequent chemotherapy," Dr. Rubin concluded.

Impressive Results

"This is a groundbreaking study," declared Jeffrey Engelman, MD, PhD, director of thoracic oncology at Massachusetts General Hospital in Boston. He was not involved in the study, and was invited to the briefing to comment on the results. "This study shows that modifying epigenetics can get real responses in lung cancer. This is difficult, so we take special note of any drugs that do so."

"There are still a lot of questions here. Most important is: Who are the patients that show the dramatic responses?" he said. It would be interesting to try this combination in earlier stage disease, he said.

The results reported in these advanced NSCLC patients are "very impressive," Dr. Engelman said, and are "on par" with what has been reported with targeted drugs in patients selected for genetic mutations, such as crizotinib and the EGFR inhibitors.

This is a markedly different approach to therapy, he emphasized. Instead of targeting genetic aberrations, this therapy is altering the cancer in a fundamental way, changing the expression of genes.

Some of the points raised by Dr. Engelman are already being addressed by the researchers. A trial in early resectable lung cancer is already underway, with the combination being given as adjuvant therapy after surgery, to see if it can improve the recurrence rate (typically a third of patients return with metastatic disease), noted study author Malcolm Brock, MD, associated professor of surgery and oncology at Johns Hopkins.

There is also a clue to which patients respond to the approach. Patients with the longer survival times, including the 2 with dramatic responses, showed signs of gene methylation reversal in at least 2 of 4 key genes. "The silencing status of these 4 genes may represent a 'biomarker' of benefit from the combination in NSCLC," Dr. Rudin explained.

This is just the tip of the iceberg.

"This is just the tip of the iceberg," said Manuel Esteller, MD, PhD, director of the cancer epigenetics and biology program at Bellvitge Biomedical Research Institute, in Barcelona, Spain. This is the first time success has been reported for epigenetic therapy in solid tumors, and it opens the door for further exploration of a new therapeutic approach that has very little toxicity, he told journalists. This study shows that drugs altering the packaging of genes can have as much value as classic drugs, he added.

The epigenetic combination of azacitidine and entinostat was shown to be as effective as the targeted drug erlotinib (Tarceva) in patients with refractory metastatic NSCLC, he notes in a commentary accompanying the study, which was cowritten by Manuel Rodriguez-Paredes from the University of Barcelona.

"It is important to highlight that NSCLC accounts for approximately 80% of lung cancer cases, and that this disease continues to be the main cancer-related cause of death worldwide," they add.

Dr. Rudin and Dr. Brock report acting as consultants to Syntex, the manufacturer of entinostat. Dr. Engelman, Dr. Esteller, and Dr. Rodriguez-Paredes have disclosed no relevant financial relationships.

Cancer Discov. Published online November 9, 2011. Abstract, Commentary

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