Τρίτη, 6 Ιουνίου 2017

ASCO 2017-FINDING THE RIGHT TARGETED THERAPY

CHICAGO — Targeted therapies are helping to transform cancer care, and findings from a new large study show that molecular profiling can be performed in routine practice to find the cancer patients who could benefit from these therapies.
In the ProfiLER study, which included patients who had at least one "actionable" alteration and who received recommended targeted therapy, 53.7% were alive after 3 years, as compared to 46.1% of patients who did not.
The 5-year survival rate was also higher for patients who were treated with a targeted agent (34.8% vs 28.1%).
"This study confirms that comprehensive genomic profiling can be performed in routine practice to select patients for targeted cancer therapies," said lead study author Olivier Tredan, MD, PhD, chair of the Department of Medical Oncology at the Centre Léon Bérard in Lyon, France. "The technology is widely available and requires only a small amount of DNA.
"Theoretically, we could do this testing for every patient in France," he added.
However, patients can face challenges in obtaining treatment with molecularly tailored therapies, because the agents may not be accessible, Dr Tredan noted.

Treatment Tailored to Profile

The ProfiLER is an ongoing molecular profiling clinical trial that is investigating the use of cancer cell genomic alterations to guide therapy in patients with a variety of advanced solid tumors. To date, 2676 patients have been enrolled in the study. The patients had with colorectal, gynecologic, breast, brain, and head and neck malignancies, as well as sarcoma.
Within this cohort, DNA was extracted from either archival or fresh collected tumor samples and was then analyzed by targeted exon sequencing of 60 cancer-related genes and whole-genome array comparative genomic hybridization, Dr Tredan explained.
When actionable alterations were detected, molecular targeted therapy was then recommended by a multidisciplinary molecular board.
Actionable mutations were found in a total of 1004 (52%) tumor samples. Within this group, 609 patients had only one actionable mutation, and 394 patients had two or more.
The most common actionable mutations were on KRAS (n = 156; 8.5%), PIK3CA (n = 150; 8.2%), CDKN2A HD (n = 174; 9.5%), PTEN HD (n = 49, 2.7%), CCND1 (n = 97; 5.3%), FGFR1 (n = 56; 3.1%), MDM2 (n = 53; 2.9%), HER2 (n = 42; 2.3%), and HER1 (n = 41; 2.2%).
Molecularly targeted therapies were recommended by the board for 676 patients, and of this group, 143 received treatment. The majority received the drug via enrollment in a clinical trial.
The remaining 533 patients were not able to receive the recommended therapy for several reasons, explained Dr Tredan. These included poor health, rapid progression of the disease, early death, not meeting eligibility criteria for a clinical trial, or difficulty obtaining medications on the market for off-label use.
The overall survival rates for the 143 patients who had been treated with the targeted therapies were compared with those for 502 patients who had not. Outcomes were superior at both the 3- and 5-year marks, as reported above.
Response among the patients who received the targeted therapies included complete responses (2.3% of patients), partial responses (15.1%), stable disease (33.7%), and progressive disease (48.8%).
The median progression-free survival was 2.8 months, and 24% of patients remained progression free at 6 months.
Dr Tredan noted that the next step is ProfiLER 02, a new randomized clinical trial that will compare the 70-gene test used in the current study to a commercial, 315-gene test.

Experts Weigh In

Several experts weighed in on the ProfiLER trial.
Steven Lipkin, MD, PhD, medical geneticist at Weill Cornell Medicine and New York–Presbyterian Hospital in New York City, pointed out that a number of studies similar to this one have been conducted, but this one had the largest number of patients.
Patients who received targeted therapy had longer survival, so that's the most important point. Dr Steven Lipkin
"It wasn't a randomized trial, but what it basically shows is that patients who received targeted therapy had longer survival, so that's the most important point," he told Medscape Medical News.
"While it's true that only a subset of patients benefited in this study, I think the same can be said for most things in medicine," he said.
He also pointed out that the response rates were much higher than have been seen in other studies, "but this is a fast-evolving field with new drugs that continue to come on the market as well as new actionable targets."
Overall, Dr Lipkin noted, "This is an exciting, positive study that shows a higher rate of patients benefiting than has been seen in previous smaller studies, and the next step is to move to large randomized trials."
ASCO Expert Sumanta Pal, MD, from the City of Hope in Duarte, California, emphasized the need for better access to drugs as well as early molecular testing. "In those cases where treatment could not be defined by the study algorithm, it's important to point out that the dominant cause was lack of availability of a molecular targeted agent, and another large proportion of patients died before treatment could be implemented," he said.
"These elements point to two needs — number one, to expand our repertoire of available targeted therapies. Second, to consider implementing molecular testing sooner in trials such as this one to afford patients an opportunity to participate," explained Dr Pal.
"In the 143 patients who ultimately received a molecular targeted agent, there did seem to be a numerical benefit in 3- and 5-year survival, which provides a hint that this approach of treating tumors based on molecular profiling and independent of the site of origin may ultimately be a viable one," he added.
However, Richard Schilsky, MD, chief medical officer at ASCO, found the study to be somewhat "disappointing."
This study is similar to what many other studies are showing ― the researchers found an actionable mutation in about 50% of patients, which is similar to what other groups have reported in the same ballpark, and then targeted therapy available for about 35% of them."
This translated to only about 100 patients who were able to receive the targeted therapy, with a median progression-free survival of 2.8 months, he pointed out. "So your view of these results depends on whether you are a glass-half-full or a glass-half-empty person – 5% to 10% of patients who get the drug respond, but these responses are relatively short-lived," he said.
Dr Schilsky pointed to similar results from the MOSCATO trial that were publishedthis year in Cancer Discovery. In that trial, researchers performed DNA sequencing on 843 patients. An actionable target was identified in 411 patients, and ultimately 199 received a targeted therapy.
Following targeted therapy, there was an overall response rate of 11%, with two patients achieving a complete response and 20 patients showing a partial response. In addition, 100 had stable disease, and 33 had progressive disease. The median overall survival was 11.9 months.
This is an important reality check. Dr Richard Schilsky
This is an important reality check, because so much of this molecular profiling is going on with the expectation that it will reveal alterations that, when treated, are going to result in dramatic benefits for patients," Dr Schilsky told Medscape Medical News. There is anecdotal evidence of this happening, he commented, but this study shows that this is not always the case.

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