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Posts Tagged → ASCO

New Developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 1

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

The cancer research conference season kicked off in earnest in 2013 with the American Society of Clinical Oncology (ASCO)’s Gastrointestinal Symposium, held in San Francisco in late January. Some of the most anticipated data to be presented at ASCO GI was for drugs that treat pancreatic cancer, with three drugs—Celgene’s Abraxane, AB Science’s masitinib, and Sanofi’s S1, generating the most interest.

With this post, we’ll take a closer look at the most advanced of the three agents, Abraxane, which generated encouraging results in a Phase III study. Later this week, we’ll tackle masitinib and S1.

Abraxane is a nanoparticle albumin-bound form of the breast cancer drug paclitaxel, and is designed to improve the activity of the active ingredient. Abraxane is already approved in the US for advanced breast and lung cancers, and recently showed signs of activity in metastatic melanoma.

At ASCO GI, Daniel Von Hoff, director of the Translational Genomics Research Institute, presented data from a randomized phase III study called MPACT that compared the effects of Lilly’s Gemzar, the current standard of care, to a once weekly combination of Gemzar and Abraxane in patients with metastatic adenocarcinoma of the pancreas. With 861 patients, this was a large global study that sought to determine whether the combination would outdo the regulatory standard of care.

A note on the trial design: Although this study uses Gemzar as the standard of care, in practice, many leading oncologists prescribe FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) for advanced pancreatic patients. But because FOLFIRINOX is generic, and is not formally approved by FDA for advanced pancreatic cancer, Phase III studies tend to match new drug candidates up against Gemzar.

As Hedy Kindler, director of gastrointestinal oncology at the University of Chicago, explained, FOLFIRINOX is widely used because the regimen has “the higher response rate, and that has the longer median survival.”

However, FOLFIRINOX also has unpleasant side effects, and in private practice settings, oncologists prefer to use less toxic combinations based on Gemzar—namely, Gemzar alone, GemOx (with oxaliplatin), or GemErlotinib (with Tarceva, an EGFR TKI). To provide context, FOLFIRINOX typically has an improved survival of approximately 11 months, while gemcitabine or gemcitabine plus erlotinib elicit a 6-7 month improvement in median overall survival (MOS).  Erlotinib added 12 days of extra survival over gemcitabine alone, but unfortunately we have no way of selecting those advanced pancreatic patients most likely to respond to EGFR therapy.

Celgene is exploring the combination of Abraxane and Gemzar based on preclinical work that suggests Abraxane can knock out the protective stroma surrounding the tumor, thereby providing better penetration of the tumor.  The phase II data led to a promising 12.2 months improvement in median overall survival.

In general, results from randomized phase III trials tends to be lower than that reported in the smaller studies. This is exactly what happened in the MPACT trial, with the Abraxane combination showing a MOS of 8.7 months versus 6.7 months for Gemzar alone, a highly statistical significant finding (P<0.000015). The hazard ratio (HR) was 0.72, suggesting that the combination gave a 28% reduction in the risk of death versus gemcitabine.

Kindler is eager to use and learn more about the combination and notes that it will be another option for oncologists rather than a new standard of care.

This is encouraging data and met the primary endpoint. Celgene is expected to file for approval for Abraxane in advanced pancreatic adenocarcinoma in the second half of the year. Data on a previously identified biomarker (SPARC expression) was not yet available and is expected to be presented at the annual ASCO meeting in June.  The audience at the GI meeting were clearly expecting survival to be higher in those patients with high SPARC expression, but we will see what happens.

Advanced pancreatic cancer is a particularly devastating disease – the incidence and prevalence are approximately equal, with patients typically having a year of life left.  The symptoms are vague and insidious plus there are no useful screening approaches approved for earlier detection, so the emergence of potential biomarkers for selecting patients most likely to respond to Abraxane or Tarceva in combination with gemcitabine would be a most welcome advance, especially given the toxicities associated with FOLFIRINOX.

 

 

#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation.

However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months.

At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them?

An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research–this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic.

One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone.

Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent. Continue reading →

#ASCO12 Data Digest: Combating Resistance in Lung Cancer

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

The American Society of Clinical Oncology (ASCO) meeting, held in Chicago earlier this month, brought some fascinating presentations on progress in two very tough to treat cancer types, lung cancer and advanced melanoma. This week, we’ll take a look at some of the data that emerged out of ASCO on small molecules that could overcome the limitations of existing therapies.

Treatment for lung cancer and melanoma has commonalities. Small molecule kinase inhibitors targeting a particular aberration driving the tumor have been approved for both types of cancer. But in each case, tumors eventually develop resistance to those kinase inhibitors, usually after about 6 to 9 months of treatment. Researchers are now trying to pinpoint the mechanism that tumor cells use to overcome the activity of kinase inhibitors, and then design new compounds or combinations of drugs that can improve patient outcomes.

Today we’ll focus on advances in non-small cell lung cancer (NSCLC). ASCO brought data from several new agents—most notably, Boehringer Ingelheim’s afatinib, AstraZeneca’s selumetinib, and Novartis’ LDK378—as well as new combinations of existing drugs.

First, some background on the current treatment paradigm in NSCLC: To date, scientists have identified several key protein receptors—EGFR, KRAS, and ALK—as drivers of the disease. Patients with a mutation in EGFR can take Genentech’s Tarceva (erlotinib) or AstraZeneca’s Iressa (gefitinib), but only after undergoing four cycles of chemotherapy. Although Tarceva was approved based on its ability to shrink tumors, it only prolongs survival in NSCLC patients by one month (12 months Tarceva vs. 11 months for placebo). Meanwhile, people who have the anaplastic lymphoma kinase (ALK-ELM4) translocation, can receive Pfizer’s Xalkori (crizotinib), which was approved in the U.S. in 2011.

Unfortunately, people with the KRAS mutation, which is considered mutually exclusive with EGFR, do not benefit from either additional chemotherapy or EGFR inhibitors. New therapies are desperately needed, since prognosis tends to be rather poor.

At ASCO this year, clinicians reported new data that answered some key questions about how best to treat people with these particular mutations: Continue reading →

Pfizer Goes The Kinase Route In Lung Cancer

The American Society of Clinical Oncology (ASCO) meeting in Chicago has been dominating pharma news for the past few days. And while much of the cancer-drug-related news coming out of the meeting is about biologics, the small molecule crizotinib is in the spotlight, too. Crizotinib is an experimental drug that Pfizer is developing for the treatment of lung cancer in a very specific set of patients.

Much of the crizotinib coverage focuses on its targeting of anaplastic lymphoma kinase. While many “targeted” drugs have reached the market in recent years, very few types of cancer are driven by a single genetic mutation, so the drugs’ effect has therefore been limited. One of the rare exceptions is Novartis’ drug Gleevec, which targets a protein kinase called BCR-ABL. Gleevec has been called a miracle drug for its ability to halt a rare type of leukemia; some scientists now think crizotinib could be another of those rare exceptions. Robert Langreth at Forbes quotes Mark Kris, a scientist at Memorial Sloan-Kettering Cancer Center, who likens crizotinib to Gleevec.

While it’s too early to compare an experimental therapy like crizotinib to Gleevec, a successful marketed drug that has had a major impact on cancer research, at a molecular level, Kris is right, since both drugs do go after kinases.

Crizotinib is designed to work on the ~3-5% of lung cancer patients with an alteration in the ALK gene- that’s roughly 10,000 people in the USA, according to the Wall Street Journal. WSJ has articles on crizotinib here and here.

Now, when I see the word kinase, the first place I hunt for information are the archives of KinasePro. That didn’t disappoint- and revealed some more details of the drug’s story.

According to a discussion on KinasePro, the patent literature reveals that the series of compounds that included the future crizotinib was discovered by scientists at Sugen, a company which Pfizer acquired. We alluded to the fact that Pfizer inherited many such molecules in our coverage of drugs targeting Met, a tyrosine-kinase receptor implicated in many cancers. As the WSJ noted, crizotinib’s activity against Met, which was the reason Pfizer acquired it in the first place, has so far turned out to be less important than its effects on ALK. It’s worth noting that Gleevec targets other kinases as well- it’s not perfectly selective for BCR-ABL.

Is there a lesson for cancer research in here? Is high selectivity for one molecular target necessarily a good thing in drug development?

Bonus: If you want to get a real feel for the ‘needle in the haystack’ exercise that pharma is, try downloading the 2004 patent that KinasePro cites as the earliest mention of the series. It’s 300 pages long and packed with compounds, most of which will never get anywhere near a person, let alone a pharmacy shelf.

Structure credit:Biochemistry