Biotech Strategy Blog

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

Posts tagged ‘PI3K Beta Sparing Inhibitor’

Following on from yesterday’s post on the potential for small basket trials in ER+ breast cancer with the ESR1 mutation, I wanted to highlight another area where these type of highly focused and rational studies appear to be not only useful but also potentially produce stunning responses.

Some of you will recall the fascinating and widely told story of a single bladder cancer patient at Memorial Sloan Kettering who was resistant to multiple lines of therapies. The team sequenced the genome and found a rare TSC1 mutation. Importantly, this is known from pediatric astrocytoma studies, to be sensitive to an mTOR inhibitor, everolimus (Afinitor). The refractory patient was given the drug and responded well. The rest is history, as they say.

Can we learn more from these type of appraches, i.e. genomic sequencing of patients who have relapsed after initial therapy?

Can we also learn more from the few exceptional responders in clinical trials – what was unique about their response that elicited such a stunning effect?

The short answer is a resounding yes.

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Genentech’s next generation PI3-kinase inhibitor, GDC-0032, was the topic of two presentations yesterday at the 2013 annual meeting of the American Association for Cancer Research (AACR) taking place in Washington D.C.

Genentech have put substantial resources into developing new agents that target different elements of the PI3K pathway.  These include: GDC-0941, GDC-0980, GDC-0084, GDC-0349, GDC-0068.  At this year’s AACR, data on their latest compound, GDC-0032, was presented. This agent is a selective inhibitor of PI3K alpha, delta and gamma but spares inhibition of the PI3K-beta isoform.

In the New Drugs on the Horizon session, Alan Olivero from Genentech gave a fascinating talk (if you are a medicinal chemist) on how the chemical structure of GDC-0032 was rationally developed. He described how a slight change in structure can lead to a very different selectivity profile.

One way in which GDC-0032 is novel, is that it spares the beta-isoform of PI3K, which Genentech hypothesize may reduce some of the undesired side effects such as effects on metabolism, previously seen with pan PI3K inhibitors such as GDC-0941.

Olivero noted that GDC-0032 has greater maximal efficacy and more potency than GDC-0941 in PI3K alpha mutant xenograft tumors as compared to wild-type ones.

The results of a first-in-human phase 1a dose escalation study for GDC-0032 were presented at AACR 2013 in yesterday’s Clinical Trial Symposium (Abstract LB-64).

Dejan Juric MD (Massachusetts General Hospital) presented promising early clinical data for GDC-0032 in PI3KCA mutant cancers, especially breast cancer.

The results showed that in PI3KCA mutant breast cancer there were 4 cPR (RECIST -30 to -70%) and 2 SD out of 6 patients, all of whom had measurable disease with pre-treatment.  

One confirmed partial response in PI3KCA mutant breast cancer took place after 11 lines of prior therapy in a 74 year old woman with HER2- breast cancer, who subsequently became triple negative.  Another patient with a confirmed partial response had HER2+ ER+ metastatic breast cancer.

While this early data is promising, further clinical trials are needed to validate it.  Dr Juric concluded his presentation by noting that,

“GDC-0032 is being further explored as a single-agent in solid tumors and in combination with endocrine therapies in breast cancer including letrozole and fulvestrant.”

If you are interested in GDC-0032, then other presentations at AACR this week to watch out for are:

Abstract 2382 (Tuesday Apr 9, 8-12 am Poster Section 2, Board 2) Development of predictive biomarker gene expression signatures that associates with drug sensitivity and kinase activation in breast cancer.

Abstract 4470 (Tuesday Apr 9, 1-5 pm Poster Section 41, Board 28) Mechanisms of acquired resistance to the PI3K inhibitors in colorectal cancer cell lines.

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