Picture Credit: @gene_antibody
For much of the last two years, one of the hottest topics around has been T cell manipulation, which can happen in many different forms.
This is just one area that we have covered extensively in the immuno-oncology space from Chimeric Antigen Receptor (CAR) T cell therapies to checkpoint inhibitors, as well as various antibodies, including the first bispecific T-cell engager (BiTE) to CD19 that recently approved by the FDA called blinatumomab (Blincyto) from Amgen.
Not all cancer patients respond to all these approaches though.
Why is that and what approaches or novel targets can we explore next to address this vexing issue?
At the SITC and SABCS meetings, I saw some really interesting and unusual presentations, together with some recent publications on topic, that really piqued my interest in this challenge. They are early signs of the new directions some of the research in this field could go. Overcoming resistance and understanding different aspects of immune escape will likely be very instructive in developing the next generation of combination studies that could make a positive impact on patients.
Today’s post touches on some of these exciting developments and includes an in-depth interview with Dr Ira Mellman, the scientist behind Genentech’s immunology research program at gRED.
Interested readers can log-in to read more about the exciting new developments that are happening with different types of antibodies in the immuno-oncology space.
One of the most interesting sessions I attended at this year’s American Society of Clinical Oncology (ASCO) annual meeting in Chicago was the Clinical Science Symposium (CSS) on the next generation of EGFR inhibitors.
We’ve previously written on the blog about the data for AZD9291 and CO-1686 presented at ASCO, but the CSS also featured an informative discussion by Larry Schwartz, MD, Professor of Radiology at Columbia University Medical Center which raised questions about how we should evaluate new lung cancer drugs.
In a presentation entitled, “Getting the Right Drug to the Right Patient Faster,” Schwartz who is a diagnostic radiologist, discussed and critiqued abstract 8012 by Dr Gideon Michael Blumenthal and colleagues at the U.S. Food and Drug Administration (FDA).
A meta-analysis of fifteen trials involving 12,534 patients (median N = 698) from nine experimental agents (tyrosine kinase inhibitor = 5, chemotherapy = 2, monoclonal antibody = 2) submitted to the FDA for treatment of metastatic non-small cell lung cancer (NSCLC) cancer in initial or supplemental New Drug or Biologics License Applications since 2003 was performed by Blumenthal and colleagues.
Their analysis showed a strong correlation (R² of 0.89) between overall response rate (ORR) and progression-free-survival (PFS) but only a weak or no correlation between ORR and overall survival (OS) (R² of 0.07) or between PFS and OS (R² of 0.09).
Dr Blumenthal noted in his conclusion that further work is ongoing to corroborate these findings given the lack of correlation between OS and ORR could have been due to high cross-over, under-power and long post-progression survival.
He went on to note that what the findings do show is that “a drug with a large effect on ORR is likely to have a large effect on PFS, conversely a drug with a small ORR may have a small effect on PFS.”
The debate around objective response and outcomes is a very interesting one, as is the drive to find better biomarkers of response to improve chances of clinical trial success.
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Chicago – At the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Charles L Sawyers, MD, President of the American Association for Cancer Research (AACR) and one of the United States leading cancer researchers, told the 30,000 meeting attendees in the plenary session that we need to get to combination therapy faster in order to overcome cancer drug resistance.
Charles L. Sawyers, MD gives 2013 Science of Oncology Award Lecture at ASCO annual meeting
In his Science of Oncology Award lecture entitled “Overcoming Resistance to Cancer Drug Therapy,” he told the audience that drug resistance is universal. It represents one of the key challenges in cancer treatment. A patient may obtain a dramatic response on a new treatment, but as the cancer finds escape routes among the network of cellular signaling pathways, resistance to the drug is acquired and the cancer reappears.
You can read a previous interview with Dr Sawyers on Pharma Strategy Blog.
Daniel O’Day, COO of Roche Pharmaceuticals, referred to Dr Sawyers’ ASCO lecture at a corporate event in Chicago. He told analysts that a key future strategy for Roche will be improving cancer treatment with combinations. The ability to bring effective combinations to market faster will favor large companies such as Roche who have a robust pipeline of cancer drugs in development. You can see Genentech’s perspective on this via a well thought out post from their VP of Clinical Development, Chris Bowden.
The other advantage of a broad robust pipeline for large Pharma is the ability to leverage this strategically and globally as the reimbursement landscape changes. In the HER2 arena, for example, Roche could hold the price of Perjeta while offering discounts to Herceptin, thereby offering a lower price for the combination that might be attractive to purchasers. In Europe, this kind of creative bargaining is becoming more common in the approval process as Health Authorities seek to reduce costs and find more affordable options before giving approval for new drugs in their market.
Dr Sawyers talk was one of the highlights of ASCO 2013 for me. I captured the essence of his presentation from the many tweets that took place as it was presented. Here’s a link to the Storify.
One of the themes of this blog is innovation in biopharmaceutical new product development. Innovation can take many forms ranging from nanotechnology based drug delivery to a novel scientific mechanism of action. The March 17, 2011 edition of Nature, highlights how innovative preclinical animal models are having an impact on drug development.
In their article on translational medicine, “Cancer lessons from mice to humans”, David Tuveson and Douglas Hanahan, describe how preclinical mouse models helped predict the recent phase III clinical trial results for sunitinib and everolimus in pancreatic neuorendocrine tumor (PNET).
The data was a major breakthrough for this disease. As Sally Church noted on Pharma Strategy Blog, sunitinib doubled the progression free survival (PFS) time and improved OS.
Tuveson and Hanahan in Nature note that “a vast number of potential anticancer drugs are currently in the pipelines of biopharmaceutical companies.” The challenge is not one of a shortage of candidates nor of potential targets, but in deciding which have most promise and where to spend valuable clinical development resources.
The authors conclude that there’s now optimism that genetically engineered mouse models may be able to mimic the progression of human cancer at the cellular and tissue levels. The mouse model of PNET (RIP-Tag2) successfully predicted that sunitinib and everolimus would be effective in treating humans.
Of course, not all human cancers can be modeled and adaptive resistance can subsequently occur in clinical trials, suggesting that preclinical models do have their limitations.
I hope we will see further innovation in mouse models of human cancer as translational medicine develops.
Tuveson, D., & Hanahan, D. (2011). Translational medicine: Cancer lessons from mice to humans Nature, 471 (7338), 316-317 DOI: 10.1038/471316a