Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘MEK inhibitors’

This week in our colorectal cancer mini-series we have covered the validation of Immunoscore as a tool for determining which patients have high T cells in their tuours and are therefore candidates for single agent immunotherapy (Link), as well as microsatellite instability (MSI) and mismatch-repair deficient tumours and how they can respond immunotherapy (Link).

What happens in the majority (95%) of patients, the microsatellite stable (MSS) disease who are mismatch-repair proficient though?  They don’t respond well to checkpoint blockade so how can we help them?

Dr Johanna Bendell ASCO 2016In Chicago, BSB interviewed Dr Johanna Bendell from the Sarah Cannon Research Institute in Nashville, Tennessee to find out more about what she and her colleagues have been doing and where they plan to go next.

You can learn about her perspectives from ASCO by logging in or if you’re new then you can sign up for a BSB subscription…

A diagnosis of stage IV pancreatic cancer is pretty much a death sentence.

People are often diagnosed in the advanced stage of the disease – 49.5% are diagnosed in stage IV – and the prognosis is generally not good.  Sadly most don’t live long, even with the latest treatments.

According to the National Cancer Institute (NCI) SEER survival monograph, the relative survival rates are extremely poor. Across all types of pancreatic cancer, only 5% of people live for 5 years, and only 23% survive 1 year.  Three to five months is the median survival time for those with untreated metastatic pancreatic cancer.

In the United States, there were 33,730 new cases of pancreatic cancer in 2006 and 32,300 deaths!  There is, therefore, an unmet need for effective new pancreatic cancer treatments.

Lake Tahoe Pancreatic Cancer ConferencePreclinical data presented by Nicole Teichmann and colleagues at the recent American Association for Cancer Research (AACR) special conference on Pancreatic Cancer in Lake Tahoe, NV suggests that BAY 86-9766 may be an interesting compound to watch as it moves forward in clinical development.

“We showed in our endogenous mouse model that our novel chemotherapeutic agent leads to dramatic tumor shrinkage after only one week of treatment,” said Nicole Teichmann, Ph.D., of the Klinikum rechts der Isar at the Technische Universität München in Munich, Germany in an AACR press release.

Although impressive tumor shrinkage was seen in the preclinical trial of BAY 86-9766, a novel MEK1/2 inhibitor, “in most animals the tumors relapsed typically after 3 weeks of treatment,” according to Teichmann’s abstract.  This suggests that there is an escape pathway that may also need to be targeted for the drug to be more effective.

One of the signaling pathways involved in pancreatic cancer is the Raf-MEK-ERK pathway (75-90% of pancreatic cancers have a K-ras mutation), which is why a MEK inhibitor such as BAY 86-9766 that targets this pathway may be effective.

However, pancreatic cancer represents a challenge for drug development and many drugs have failed in clinical development.

Sorafenib despite being an inhibitor of Raf-1 kinase and EGFR2, failed to show any effect in pancreatic cancer.  Adding sorafenib to gemcitabine did not improve survival significantly.

Recently, Infinity Pharmaceuticals terminated a pancreatic cancer phase 2 trial with their Hedgehog inhibitor, saridegib (IPI-926).

Despite scientific evidence suggesting that hedgehog signaling plays an important role in pancreatic cancer, patients receiving saridegib with gemcitabine did worse (i.e. lived for a shorter period) than they would if they had just received gemcitabine alone.

The Infinity news release noted that “the median survival for patients receiving saridegib plus gemcitabine was less than the historical median survival for single-agent gemcitabine of approximately six months.” Not surprisingly, the trial was terminated.

Other Hedgehog compounds being evaluated in pancreatic cancer include Roche’s vismodegib (Erivedge), which was initially approved in advanced, refractory basal cell carcinoma last year.  The drug is also being tested in trials for pancreatic cancer, including one with gemcitabine and another with gemcitabine plus nab-paclitaxel (Abraxane).

Interestingly, Celgene are waiting for the final data to mature on their phase III trial in pancreatic cancer with nab-paclitaxel and gemcitabine.  The interim results were encouraging, but it is too early to tell if the outcomes will be significantly improved by the combination. You can read more about the scientific rationale for nab-paclitaxel in pancreatic cancer on Pharma Strategy Blog.

The efficacy and safety of BAY 86-977 in combination with gemcitabine is currently being evaluated in a phase 2 trial of patients with non-resectable, locally advanced or metastatic pancreatic cancer.

Caution must, therefore, be expressed as to whether BAY 86-9766 will be effective given that so many promising pancreatic cancer drugs have failed in drug development.

It remains to be seen whether BAY 86-9766 will live up to the promise of the preclinical data presented at the AACR pancreatic meeting in Lake Tahoe.

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