Novartis punts a late-stage PI3K drug...

LoriCA

Interesting read for anyone following the research of PI3K inhibitors, notes several that have been dumped or received black box warnings due to fatal toxicities.

Novartis punts a late-stage PI3K drug with a worrying safety profile to one of China's upstart biotechs

https://endpts.com/novartis-punts-a-late-stage-pi3k-drug-with-a-worrying-safety-profile-to-one-of-chinas-upstart-biotechs/

ShetlandPony

Thanks, Lori. The drug Novartis punted appears to be buparlisib (BKM120), a pan-class 1 inhibitor (PIK3 alpha, beta, gamma).

"Grade 3/4 adverse events were reported in close to two out of three patients in the drug arm, compared to 34% in the control group. Serious adverse events, though, were reported in 22% of the drug arm, compared to 16% in the control group, with one treatment-related death to report in each arm. There were also three suicide attempts in the buparlisib group, raising concerns about suicidal ideation among patients exposed to the drug."

Yikes.

I considered that drug in the past. I am interested in PIK3 drugs because my Foundation One report showed a mutation in PIK3C2B. About 1 1/2 years ago I was therefore looking for a trial with a drug that targeted more than just PIK3A, which is more commonly seen in breast cancer. An interesting note from my onc was that the broader the target of these drugs, the worse the side effects. Buparlisib was one such broader-target drug. I looked at trials with buparlisib (targeting PIK3 alpha, beta, and gamma) and sapanisertib (TORC 1/2 inhibitor), and decided against them. Instead I tried Afinitor (mTOR inhibitor) + Faslodex for four months (did not work), then switched to gemcitabine (Xeloda) which has worked extremely well for over a year now. Interestingly, the GeneCards info on PIK3C2B says "increased viability with tamoxifen" and "decreased viability with gemcitabine". This is only based on a laboratory cell studies and not people, but I'm just sayin'. Tamoxifen was an epic fail for me and gemcitabine has me at NEAD. So it looks like my decision was a good one.

The article also mentions that taselisib, a selective inhibitor of PIK3CA, was dumped by Roche "a few weeks ago at the end of a disappointing Phase III." This is the drug in the SANDPIPER trial, combined with fulvestrant (Faslodex). This trial required a PIK3CA mutation in the tumor.

https://endpts.com/novartis-punts-a-late-stage-pi3...

biotechs/

The other PIK3 inhibitors I have seen when looking at trials that include breast cancer are:

alpelisib (BYL719) which is for PIK3A ( i.e. alpha; minimal effect on beta)

fimepinostat (CUDC-907) which is for PIK3A

And then there are other drugs which I understand address pathways that are somehow related to PIK3 (This is where I get in too far over my head):

sapanisertib (MLN0128), a TORC 1/2 inhibitor I have seen in a trial

everolimus (Afinitor), an mTOR inhibitor which is a standard mbc treatment combined with Aromasin and more recently other anti-estrogens including Faslodex

Any other cancer nerds out there (Zarovka's term) have comments to add?

Cure-ious

Well, I wish Z herself would chime in (Hello Z, we need you!!) but anyway, we really need a good PI3K inhibitor because it hits one of the most common mutations to pop up once cells become resistant to estrogen inhibitors.

One recent study showed the existing (Affinitor) and newer PI3K/mTOR inhibitors all work much better if combined with an Aurora A kinase inhibitor- of which only one (Alisertib) has been tested clinical trials, and apparently the manufacturer (Takeda Pharm) announced recently they were dumping the drug because it hasn't helped much when tested on its own or in different combos in trials for various cancers, so hopefully somebody will pick it back up and do an mTOR/Affinitor-Faslodex-Alisertib triple-combo clinical trial for MBC.

LoriCA

Thanks for adding more detailed info ShetlandPony. Since I'm HER2+ I haven't been following PI3K inhibitors too closely and don't know much about them, just knew that I'd seen a lot of discussion about them here, especially in the Liver Mets forum, and hoped that someone would find this article interesting. Those results certainly scared me! Curious that instead of shelving it completely, they passed it on to a Chinese company for further research.

ShetlandPony

I agree, Cure-ious. My sense is that the current thinking (for example, from an expert forum I watched) seems to be that with targeted therapy for ER+, Her 2 negative mbc, the most effective therapy is probably combined therapy, in order to close off alternative pathway(s). Triplet therapy ought to be better than double therapy, but then we also layer side effects. Ugh. The aforementioned article on PI3K drugs says that "noted cancer researcher Siddhartha Mukherjee is beginning a human study to determine if a ketogenic diet can close a feedback loop that defeats these drugs' ability to fight cancer."

Yeah, Lori. I wonder what the Chinese company will do with it.

LoriCA

I read that the study on a ketogenic diet is because the PI3K inhibitors increase insulin production to a very high level, so there's some thinking that possibly that is what's interfering with the the drugs' effectiveness.