Biotech Strategy Blog

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

Posts tagged ‘Cancer Drug Resistance’

A predictive biomarker for prostate cancer drug resistance may lead to new drug development opportunities.

At ASCO 2014, one of the prostate cancer highlights was the oral presentation by Emmanuel Antonarakis MB BCh, Assistant Professor of Oncology at Johns Hopkins.

He presented elegant research, albeit in a small group of patients, about how constitutively active splice variants (AR-V’s) may represent one potential mechanism of resistance to androgen receptor (AR) signalling inhibitors such as enzalutamide (Astellas/Medivation) and androgen synthesis inhibitors such as abiraterone (JNJ).

I spoke to Dr Charles Ryan, Professor of Medicine and Urology at the University of California San Francisco (UCSF) about the significance of the data to clinical practice, and the new drug development opportunities that may follow-on from it.

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The 2013 Molecular Targets and Cancer Therapeutics Conference (twitter #targets13) takes place in Boston from October 19-23 at the Hynes Convention Center. It’s a “must attend” meeting for anyone with an interest in cancer drug development and I’m really looking forward it. Boston is an exciting place for cancer research!

Molecular Targets Meeting AppJointly organized by the American Association for Cancer Research (AACR), European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute (NCI), it alternates each year between Europe the United States.

The molecular targets meeting program and abstracts are now available online. There’s also a meeting App that’s well worth downloading if you plan to be there.

As for what’s interesting at the meeting – the three media briefings give a flavor of what to expect:

Sunday, Oct. 20, 10 a.m. “Emerging Therapeutics,” including research on investigational drugs AZD9291 and PF-06463922, which have the potential to overcome drug resistance in some lung cancers.

Monday, Oct. 21, 9 a.m. “Overcoming Resistance and Hard-to-Treat Cancers,” including research on a new antibody-drug conjugate MLN0264 for pancreatic cancer and a new nanopharmaceutical CRLX101 for cancers resistant to antiangiogenic drugs.

Tuesday, October 22, 9 a.m. “Guiding Treatment for BRAF- and BRCA-related Cancers,” including updated data on the clinical benefit of the PARP inhibitor BMN 673 and a new diagnostic platform to rapidly identify BRAF mutations.

The AACR press team led by Jeremy Moore have done a good job of identifying some of the exciting new drugs in development.

Readers of blog premium content have already read about the potential of AZD9291 in T790M resistant lung cancer from ECCO 2013 in Amsterdam.  While it looks like the ECCO late-breaker did steal some of the thunder from the molecular targets meeting, there’s going to be more granularity on the compound at AACR, and hopefully some updated clinical data.

There are three AZD9291 posters at the meeting, and I’ll be covering all of these while in Boston:

Sunday, Oct 20, 2013, 12:30 PM – 3:00 PM  A109: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma.

Monday, Oct 21, 2013, 12:30 PM – 3:00 PM  B212: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.

Monday, Oct 21, 2013, 12:30 PM – 3:00 PM B94 Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor.

Another compound that I have been following with data at Molecular Targets is ABT-199/GDC-199.

You’ll find me in the poster halls every afternoon, so if you are going to be in Boston for Molecular Targets, I look forward to seeing you there!

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.


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A standing room only audience at the recent annual meeting of the American Association for Cancer Research (AACR) heard from several distinguished speakers on what the future of cancer drug therapy is likely to look like: combinations of novel cancer agents.

This AACR session was one of the highlights of the meeting and would have merited from being part of the plenary program.

Jeffrey Engelman from MGH persuasively presented on why we need combination therapies to overcome resistance. He noted that:

  • Most cancers are not sensitive to currently available single-agent therapies
  • Even when sensitive to single-agent therapies, cancers develop resistance, often necessitating combinations

One of the challenges of this approach will be “identifying effective combinations,” he said.

Roy Herbst from Yale, presented on some of the practical challenges involved with the early phase testing of two drugs, and challenged the audience with a critical question:

“Do we possess the necessary translational tools that will help us identify the right drug combinations, ratios and schedules with the right patient?”

Stuart Lutzker from Genentech described their experiences of clinical trials with rational drug combination of trastuzumab and pertuzumab for HER2+ breast cancer.  He concluded that:

“Rational drug combinations have begun to yield exciting Phase III results and should be preferred over empiric drug combinations.”

The Pharma Strategy Blog video interview with Gordon Mills from ECCO/ESMO 2011 in Stockholm offers some interesting insights into how MD Anderson are helping to facilitate academia-industry combination trials with novel compounds from different companies in order to achieve more rational drug design and improve outcomes for people with cancer.

If two or more novel cancer drugs are required to interrupt key pathways or to avoid adaptive resistance, what does this mean for the regulatory strategy?

Janet Woodcock addressed some of these challenges in her AACR presentation, and discussed how the:

“FDA would not want to approve a combination regimen with two new agents unless each contributed to the effect.”

Draft guidance on “Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination” was published by the Agency in December 2010. Click here for a PDF copy.

The document gives examples of a number of different phase II trial designs that can be used to demonstrate the contribution each drug makes to the combination, and the additive effect seen.

As an example, if each drug in a combination has activity and can be administered individually then the guidance document suggests a multi-arm phase II trial may be needed that compares the impact of either drug alone versus the combination and standard of care.  An adaptive trial may also be used if appropriate.

Dr Woodcock noted that future cancer drug development is likely to include increasing use of combinations, adaptive trials to evaluate various drug and diagnostic combinations and increasing attention to the use of novel biomarkers.

The message I took home from the AACR annual meeting is that the future of cancer therapy is in combinations, and we can expect more clinical trials with two unapproved agents (novel-novel combinations) in the future.

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